PI: Ambroggio, Lilliam Title: Metabolomics Evaluation of the Etiology of Pneumonia

Received: 07/08/2016 FOA: PA16-190 Council: 01/2017

Competition ID: FORMS-D FOA Title: MENTORED RESEARCH SCIENTIST DEVELOPMENT AWARD 

(PARENT K01)

1 K01 AI125413-01A1 Dual: Accession Number: 3955629

IPF: 615001 Organization: CINCINNATI CHILDRENS HOSP MED CTR

Former Number: Department: Pediatrics

IRG/SRG: MID-B AIDS: N Expedited: N

Subtotal Direct Costs 

(excludes consortium F&A) 

Year 1:

Year 2:

Year 3:

Year 4:

Year 5:

Animals: N 

Humans: Y 

Clinical Trial: N

Current HS Code: 30 

HESC: N

New Investigator: N

Early Stage Investigator: N

Senior/Key Personnel: Organization: Role Category:

Lilliam Ambroggio Cincinnati Childrens Hospital Medical 

Center

PD/PI 

Samir Shah Cincinnati Children's Hospital Medical 

Center

Other Professional-Mentor

Maurizio Macaluso Cincinnati Children's Hospital Medical 

Center

Other Professional-Co-Mentor

Richard Ruddy Cincinnati Children's Hospital Medical 

Center

Other Professional-Co-Mentor

Kathleen Stringer University of Michigan Other Professional-Co-Mentor

Heidi Sucharew Cincinnati Children's Hospital Medical 

Center

Other Professional-Co-Mentor

Lindsey Romick-Rosendale Cincinnati Children's Hospital Medical 

Center

Other (Specify)-Collaborator

Assem Ziady Cincinnati Children's Hospital Medical 

Center

Other (Specify)-Collaborator

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OMB Number: 4040-0001

Expiration Date: 06/30/2016

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

APPLICATION FOR FEDERAL ASSISTANCE

SF 424 (R&R)

3. DATE RECEIVED BY STATE State Application Identifier

1. TYPE OF SUBMISSION* 4.a. Federal Identifier

❍ Pre-application ❍ Application ● Changed/Corrected

Application

b. Agency Routing Number

2. DATE SUBMITTED Application Identifier

FP00011450

c. Previous Grants.gov Tracking Number

GRANT12210373

5. APPLICANT INFORMATION Organizational DUNS*: 071284913

Legal Name*: Cincinnati Childrens Hospital Medical Center

Department:

Division: Hospital Medicine

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

ZIP / Postal Code*:

Person to be contacted on matters involving this application

Prefix: First Name*: Kathy Middle Name: Last Name*: Goodin Suffix: 

Position/Title: DIRECTOR-SPO

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

ZIP / Postal Code*:

Phone Number*: Fax Number: Email: 

6. EMPLOYER IDENTIFICATION NUMBER (EIN) or (TIN)* -

7. TYPE OF APPLICANT* M: Nonprofit with 501C3 IRS Status (Other than Institution of Higher

Education)

Other (Specify):

Small Business Organization Type ❍ Women Owned ❍ Socially and Economically Disadvantaged

8. TYPE OF APPLICATION* If Revision, mark appropriate box(es).

❍ New ● Resubmission ❍ A. Increase Award ❍ B. Decrease Award ❍ C. Increase Duration

❍ Renewal ❍ Continuation ❍ Revision ❍ D. Decrease Duration ❍ E. Other (specify) :

Is this application being submitted to other agencies?* ❍Yes ●No What other Agencies?

9. NAME OF FEDERAL AGENCY*

National Institutes of Health

10. CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER

TITLE:

11. DESCRIPTIVE TITLE OF APPLICANT'S PROJECT*

Metabolomics Evaluation of the Etiology of Pneumonia

12. PROPOSED PROJECT

Start Date* Ending Date*

04/01/2017 03/31/2022

13. CONGRESSIONAL DISTRICTS OF APPLICANT

OH-001
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

SF 424 (R&R) APPLICATION FOR FEDERAL ASSISTANCE Page 2

14. PROJECT DIRECTOR/PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Prefix: First Name*: Lilliam Middle Name: Last Name*: Ambroggio Suffix: 

Position/Title: ASSISTANT PROFESSOR

Organization Name*: Cincinnati Childrens Hospital Medical Center

Department: Pediatrics

Division: Hospital Medicine

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

ZIP / Postal Code*:

Phone Number*: Fax Number: Email*: 

15. ESTIMATED PROJECT FUNDING

a. Total Federal Funds Requested* $

b. Total Non-Federal Funds* $0.00

c. Total Federal & Non-Federal Funds* $

d. Estimated Program Income* $0.00

16. IS APPLICATION SUBJECT TO REVIEW BY STATE

EXECUTIVE ORDER 12372 PROCESS?*

a. YES ❍ THIS PREAPPLICATION/APPLICATION WAS MADE

AVAILABLE TO THE STATE EXECUTIVE ORDER 12372

PROCESS FOR REVIEW ON:

DATE:

b. NO ● PROGRAM IS NOT COVERED BY E.O. 12372; OR

❍ PROGRAM HAS NOT BEEN SELECTED BY STATE FOR

REVIEW

17. By signing this application, I certify (1) to the statements contained in the list of certifications* and (2) that the statements herein

are true, complete and accurate to the best of my knowledge. I also provide the required assurances * and agree to comply with

any resulting terms if I accept an award. I am aware that any false, fictitious, or fraudulent statements or claims may subject me to

criminal, civil, or administrative penalties. (U.S. Code, Title 18, Section 1001)

● I agree*

* The list of certifications and assurances, or an Internet site where you may obtain this list, is contained in the announcement or agency specific instructions.

18. SFLLL or OTHER EXPLANATORY DOCUMENTATION File Name: 

19. AUTHORIZED REPRESENTATIVE

Prefix: First Name*: Kathy Middle Name: Last Name*: Goodin Suffix: 

Position/Title*: DIRECTOR-SPO

Organization Name*: Cincinnati Childrens Hospital Medical Center

Department:

Division: Sponsored Programs

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

ZIP / Postal Code*:

Phone Number*: Fax Number: Email*: 

Signature of Authorized Representative*

Kathy.Goodin

Date Signed*

07/08/2016

20. PRE-APPLICATION File Name: Mime Type:

21. COVER LETTER ATTACHMENT File Name:Cover_Letter_Ambroggio_July_2016.pdf Mime Type: application/pdf
424 R&R and PHS-398 Specific

Table Of Contents Page Numbers

SF 424 R&R Cover Page----------------------------------------------------------------------------------------- 1

 Table of Contents------------------------------------------------------------------------- 3

Performance Sites--------------------------------------------------------------------------------------------- 4

Research & Related Other Project Information------------------------------------------------------------------ 5

 Project Summary/Abstract(Description)----------------------------------------------------- 6

 Project Narrative------------------------------------------------------------------------- 7

 Bibliography & References Cited----------------------------------------------------------- 8

 Facilities & Other Resources-------------------------------------------------------------- 12

Research & Related Senior/Key Person-------------------------------------------------------------------------- 20

Research & Related Budget Year - 1---------------------------------------------------------------------------- 73

Research & Related Budget Year - 2---------------------------------------------------------------------------- 76

Research & Related Budget Year - 3---------------------------------------------------------------------------- 79

Research & Related Budget Year - 4---------------------------------------------------------------------------- 82

Research & Related Budget Year - 5---------------------------------------------------------------------------- 85

Budget Justification------------------------------------------------------------------------------------------ 88

Research & Related Cumulative Budget-------------------------------------------------------------------------- 91

PHS398 Cover Page Supplement---------------------------------------------------------------------------------- 92

PHS 398 Career Development Award------------------------------------------------------------------------------ 94

 Introduction to Application--------------------------------------------------------------- 96

 Candidate Information and Goals for Career Development------------------------------------ 97

 Specific Aims----------------------------------------------------------------------------- 101

 Research Strategy------------------------------------------------------------------------- 102

 Training in the Responsible Conduct of Research------------------------------------------- 109

 Plans and Statements of Mentor and Co-Mentor(s)------------------------------------------- 110

 Letters of Support from Collaborators,Contributors, and Consultants----------------------- 116

 Description of Institutional Environment-------------------------------------------------- 120

 Institutional Commitment to Candidate's Research Career Development----------------------- 121

 Protection of Human Subjects-------------------------------------------------------------- 122

 Inclusion of Women and Minorities--------------------------------------------------------- 125

 PHS Inclusion Enrollment Report----------------------------------------------------------- 126

 Inclusion of Children--------------------------------------------------------------------- 127

 Vertebrate Animals------------------------------------------------------------------------ 128

 Select Agent Research--------------------------------------------------------------------- 129

Appendix

Number of Attachments in Appendix: 2

Contact PD/PI: Ambroggio, Lilliam

Table of Contents Page 3
Contact PD/PI: Ambroggio, Lilliam

OMB Number: 4040-0010

Expiration Date: 06/30/2016

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190. Received Date:

2016-07-08T13:23:03.000-04:00

Project/Performance Site Location(s)

Project/Performance Site Primary Location ❍ I am submitting an application as an individual, and not on behalf of

a company, state, local or tribal government, academia, or other type of

organization.

Organization Name: Cincinnati Childrens Hospital Medical Center

Duns Number:

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Project/Performance Site Congressional District*: OH-001

File Name Mime Type

Additional Location(s)

 Page 4
Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190. Received Date:

2016-07-08T13:23:03.000-04:00

OMB Number: 4040-0001

Expiration Date: 06/30/2016

RESEARCH & RELATED Other Project Information

1. Are Human Subjects Involved?* ● Yes ❍ No

1.a. If YES to Human Subjects

 Is the Project Exempt from Federal regulations? ❍ Yes ● No

If YES, check appropriate exemption number: 1 2 3 4 5 6

If NO, is the IRB review Pending? ❍ Yes ● No

IRB Approval Date: 04-15-2016

Human Subject Assurance Number 00002988

2. Are Vertebrate Animals Used?* ❍ Yes ● No

2.a. If YES to Vertebrate Animals

Is the IACUC review Pending? ❍ Yes ❍ No

IACUC Approval Date:

Animal Welfare Assurance Number

3. Is proprietary/privileged information included in the application?* ❍ Yes ● No

4.a. Does this project have an actual or potential impact - positive or negative - on the environment?* ❍ Yes ● No

4.b. If yes, please explain:

4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an

environmental assessment (EA) or environmental impact statement (EIS) been performed?

❍ Yes ❍ No

4.d. If yes, please explain:

5. Is the research performance site designated, or eligible to be designated, as a historic place?* ❍ Yes ● No

5.a. If yes, please explain:

6. Does this project involve activities outside the United States or partnership with international

collaborators?*

❍ Yes ● No

6.a. If yes, identify countries:

6.b. Optional Explanation:

Filename

7. Project Summary/Abstract* Project_Summary_Ambroggio_K01.pdf Mime Type: application/pdf

8. Project Narrative* Project_Narrative_Ambroggio_July_2016.pdf Mime Type: application/pdf

9. Bibliography & References Cited References.pdf Mime Type: application/pdf

10.Facilities & Other Resources FACILITIES_AND_OTHER_RESOURCES_Ambroggio_K01_2.pdf Mime Type: application/pdf

11.Equipment

Contact PD/PI: Ambroggio, Lilliam

 Page 5
Project Summary 

Lilliam Ambroggio, PhD, MPH is an infectious diseases epidemiologist whose overarching career goal is to 

improve outcomes for children with common, serious infections by developing methods to improve diagnostic 

accuracy and implementing these methods into clinical practice. The research she proposes entitled 

Metabolomic Evaluation in the Etiology of Pneumonia (MEEP) combines advanced statistical techniques with 

1

H-Nuclear Magnetic Resonance (NMR) metabolomics methodology to identify metabolites, which will facilitate 

etiologic diagnosis of community-acquired pneumonia (CAP) in children. Such pathogen identification will result 

in timely and accurate diagnosis that will permit targeted and effective management of this disease. 

Candidate: Dr. Ambroggio is an Assistant Professor of Pediatrics with a joint appointment in the Divisions of 

Hospital Medicine and Biostatistics and Epidemiology at Cincinnati Children’s Hospital Medical Center 

(CCHMC). She completed a Master’s in Public Health and a Ph.D. in Epidemiology at Drexel University prior to 

beginning a post-doctoral fellowship at CCHMC. Her previous work in the clinical management of CAP focusing 

on antibiotic prescribing and diagnostic tools to detect pneumonia in combination with her previous training in

molecular and cellular biology have prepared her to conduct the proposed research. The proposed career 

development plan will build upon her previous training with four training goals to enhance her trajectory toward 

becoming an independent investigator: 1) Experiential and didactic learning in study design and execution of 

quantitative 1

H-NMR metabolomics; 2) Acquire and apply advanced statistical analyses; 3) Interpret 

metabolomics data and its biological context and 4) Develop leadership and professional skills to execute 

multicenter studies. Dr. Ambroggio proposes training activities that include didactic and experiential learning to 

enable her to gain the necessary skills for metabolomic research. 

Mentors/Environment: Dr. Ambroggio and her primary mentor, Samir S. Shah, MD, MSCE, have assembled a 

strong team of co-mentors and advisors to guide Dr. Ambroggio through the proposed training and research 

activities. The proposed career development plan utilizes the intellectual and metabolomics resources available 

through the University of Cincinnati and CCHMC, as well as resources available at the University of Michigan 

through Dr. Ambroggio’s external mentor, Kathleen Stringer, PharmD. In addition Dr. Ambroggio will attend 

national seminars and workshops when optimal training is not available locally. As an institution CCHMC is 

committed to supporting junior faculty members through internal grants, administrative support and structured 

opportunities for faculty networking and education. Dr. Ambroggio will be obtaining biological specimens for this 

proposal from a fully operational, externally-funded prospective cohort study, CARPE DIEM. Both the ED and 

inpatient services at CCHMC provide an established research infrastructure and a large ambulatory and 

hospitalized patient population to conduct the proposed research. In addition all mentors have agreed to 

participate on Dr. Ambroggio’s scholarly oversight committee which has been meeting quarterly since 2013. 

Research: There is currently no accurate method to identify the etiology of CAP in children. This results in 

overtreatment with antibiotics or delays in appropriate treatment in children who are at risk for CAP-related 

morbidity. This proposal is the first step in developing a specific, fast and noninvasive approach for pathogen 

identification in children diagnosed with CAP. Aim 1 characterizes the sources (e.g. age and sex) of variation 

that exist in a healthy child's metabolome over three points. Aim 2 compares metabolite profiles from children 

who had a positive PCR test from either the nasopharynx or the blood for a virus, bacterial infection such as 

Mycoplasma pneumoniae, or Streptococcus pneumoniae with children who have no known infections. The 

purpose of this aim is to identify unique metabolite profiles using quantitative 1

H-NMR for each pathogen 

identified. Aim 3 will use urine samples from patients with CAP and compare them with samples from healthy 

contorls over three time points to determine the impact of antibiotic treatment on metabolite profiles. The 

completion of these aims will generate a metabolite profile database of common pathogens associated with 

childhood CAP and drive a systems biology approach to CAP diagnosis and treatment. 

Summary: The innovation of the proposed research is the integration of robust clinical phenotype data from an 

ambulatory population with quantitative NMR metabolomics using novel statistical methods to address the 

clinically challenging problem of pediatric CAP diagnostics. The strong collaborations between the Divisions of 

Hospital Medicine, Biostatistics and Epidemiology, and Emergency Medicine at CCHMC and with the 

metabolomics core at the University of Michigan ensure the success of the proposed research. This award will 

provide Dr. Ambroggio with the training and research needed to be successful in a future, multi-center study to 

validate the metabolite profiles of pathogens causing CAP in children. Furthermore, this career development 

award will facilitate Dr. Ambroggio’s development into a nationally-recognized independent investigator and 

leader conducting research that improves diagnostic tools for children with infectious diseases, specifically 

CAP.

Contact PD/PI: Ambroggio, Lilliam

Project Summary/Abstract Page 6
Project Narrative 

Community-acquired pneumonia (CAP) causes substantial morbidity in children. It is the fifth most common 

cause of pediatric hospitalization and, cumulatively, the most costly among infants and children. Currently 

there is no single test available that can distinguish between the >10 pathogens that cause CAP. The objective 

of this prospective cohort study is to determine distinct metabolite profile for major classes of pathogens that 

cause CAP in children (e.g. virus, typical and atypical bacteria). Urine and blood samples will be collected from 

children diagnosed with CAP in the Emergency Department or who are hospitalized at Cincinnati Children’s 

Hospital Medical Center. Urine from children whose PCR tests are positive for a virus, typical bacteria or 

atypical bacteria will be sex and aged-matched to control samples. All urine samples will then be evaluated 

using quantitative 1

H-nuclear magnetic resonance. Advanced statistical methods will be applied to the 

identified metabolite dataset to determine unique metabolite profiles. These profiles will be used as the 

foundation for future studies in the diagnostic capabilities of 1

H-NMR for pathogen identification in children 

diagnosed with CAP. In addition, the concepts learned through this grant, as well as the career development 

pursued by the investigator, will be readily applicable to diagnostic testing for multiple infectious diseases. 

Contact PD/PI: Ambroggio, Lilliam

Project Narrative Page 7
Contact PD/PI: Ambroggio, Lilliam

Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

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Gambia, West Africa: findings from a pilot study. PLoS One 2010;5.

59. Galetto‐Lacour A, Alcoba G, Posfay‐Barbe KM, et al. Elevated inflammatory markers combined with positive

pneumococcal urinary antigen are a good predictor of pneumococcal community‐acquired pneumonia in children.

Pediatr Infect Dis J 2013;32:1175‐9.

60. Song JY, Eun BW, Nahm MH. Diagnosis of Pneumococcal Pneumonia: Current Pitfalls and the Way Forward.

Infect Chemother 2013;45:351‐66.

61. Carvalho Mda G, Tondella ML, McCaustland K, et al. Evaluation and improvement of real‐time PCR assays

targeting lytA, ply, and psaA genes for detection of pneumococcal DNA. J Clin Microbiol 2007;45:2460‐6.

62. Butler JC, Bosshardt SC, Phelan M, et al. Classical and latent class analysis evaluation of sputum polymerase

chain reaction and urine antigen testing for diagnosis of pneumococcal pneumonia in adults. J Infect Dis 2003;187:1416‐

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63. Michelow IC, Lozano J, Olsen K, et al. Diagnosis of Streptococcus pneumoniae lower respiratory infection in

hospitalized children by culture, polymerase chain reaction, serological testing, and urinary antigen detection. Clin Infect

Dis 2002;34:E1‐11.

64. Stralin K, Tornqvist E, Kaltoft MS, Olcen P, Holmberg H. Etiologic diagnosis of adult bacterial pneumonia by

culture and PCR applied to respiratory tract samples. J Clin Microbiol 2006;44:643‐5.

65. Abdeldaim G, Herrmann B, Molling P, et al. Usefulness of real‐time PCR for lytA, ply, and Spn9802 on plasma

samples for the diagnosis of pneumococcal pneumonia. Clin Microbiol Infect 2010;16:1135‐41.

66. Azzari C, Cortimiglia M, Moriondo M, et al. Pneumococcal DNA is not detectable in the blood of healthy carrier

children by real‐time PCR targeting the lytA gene. Journal of medical microbiology 2011;60:710‐4.

67. Harris KA, Hartley JC. Development of broad‐range 16S rDNA PCR for use in the routine diagnostic clinical

microbiology service. Journal of medical microbiology 2003;52:685‐91.

68. Harris KA, Turner P, Green EA, Hartley JC. Duplex real‐time PCR assay for detection of Streptococcus

pneumoniae in clinical samples and determination of penicillin susceptibility. J Clin Microbiol 2008;46:2751‐8.

69. Gollomp K, Rankin SC, White C, et al. Broad‐range bacterial polymerase chain reaction in the microbiologic

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Testing. Journal of the Royal Statistical Society Series B (Methodological) 1994;57:289‐300.

72. Bouatra S, Aziat F, Mandal R, et al. The human urine metabolome. PLoS One 2013;8:e73076.

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73. Jokinen J, Scott JA. Estimating the proportion of pneumonia attributable to pneumococcus in Kenyan adults:

latent class analysis. Epidemiology 2010;21:719‐25.

74. Florin TA, Ambroggio L. Biomarkers for community‐acquired pneumonia in the emergency department. Current

infectious disease reports 2014;16:451.

75. Swann JR, Tuohy KM, Lindfors P, et al. Variation in antibiotic‐induced microbial recolonization impacts on the

host metabolic phenotypes of rats. J Proteome Res 2011;10:3590‐603.

Contact PD/PI: Ambroggio, Lilliam

References Cited Page 11
1

FACILITIES AND OTHER RESOURCES

The research infrastructure at Cincinnati Children’s Hospital Medical Center (CCHMC) (Section 1) and at the 

University of Michigan (Section 2) including facilities, personnel, faculty, students, and equipment is among the 

best in the nation and provides the ideal environment for carrying out the proposed research. 

Section 1: Cincinnati Children’s Hospital Medical Center

Clinical and Research Resources: Cincinnati Children’s Hospital Medical Center (CCHMC) is a not-for-profit 

hospital and research center pioneering breakthrough treatments, providing outstanding family-centered 

patient care and training healthcare professionals for the future. CCHMC was founded in 1883 and relocated in 

1926 to its present site across the street from the University of Cincinnati College of Medicine (UC). William 

Cooper Procter, a benefactor of the hospital, funded a building devoted to research in children’s diseases that 

opened in 1931, and included a $2.7 million endowment, currently valued at $1.6 billion in 2012. He 

established that income from the endowment would support research and development, a principle that 

continues to form the core philosophical approach to the relationship of the endowment and research today. 

Today, CCHMC is a free-standing children’s hospital with 629 beds and over 30,000 annual admissions that 

houses the Department of Pediatrics for UC. CCHMC is the primary provider of inpatient, subspecialty and 

emergency care in Greater Cincinnati and the surrounding counties serving over 2 million people. CCHMC has 

an extensive clinical and research community and is committed to promoting and expanding pediatric research 

and quality improvement. CCHMC has a long and rich history of research focused on diseases of children and 

young adults. Research breakthroughs have included the Sabin oral polio vaccine, rotavirus vaccine 

(Rotarix®), the first practical heart-lung machine, and the first successful bone marrow transplant for sickle cell 

disease. CCHMC again received Magnet status by the American Nurses Credentialing Center in 2014. In the 

U.S. News and World Report’s 2014-2015 Best Children’s Hospitals Honor Roll, CCHCM was ranked third 

among Departments of Pediatrics. CCHMC ranks second nationally among pediatric medical centers in NIHfunded research ($129 million in overall sponsored program awards in 2013-2014). Furthermore, toward our 

goal of discovery, institutional support for research in fiscal year 2012 totaled $84 million. CCHMC is the 

largest pediatric research institution in the nation, with nearly 1.5 million square feet of research space. 

Cincinnati Children’s Hospital Medical Center Research Foundation (CCRF) is the administrative and 

organizational entity for pediatric research missions. It includes all 41 divisions – six of which are basic 

research divisions – within the Department of Pediatrics. Total CCRF funding has doubled to over $450 million 

since 2003. Research administration and regulatory oversight groups oversee a total research budget of $275 

million. National Institutes of Health funding of $129 million represents the second largest in the US among all 

Children’s Hospitals or Pediatric Departments. Furthermore, the research endowment of ~$2 billion supports 

scientific training, infrastructure, and core services for basic research development and CCHMC. CCRF has 

724 faculty members engaged in basic, clinical and translational research and is one of the largest pediatric 

research institutions in the country. They are committed to promoting the advancement of science and 

medicine as well as career advancement of young investigators while being a leader in improving pediatric 

quality of care and safety. In FY2015, the faculty collectively published more than 2,000 peer reviewed 

manuscripts. CCRF has dedicated research space encompassing almost 1.5 million square feet, making it the 

largest pediatric research institution in the nation. 

The Division of Hospital Medicine, directed by Dr. Ambroggio’s primary mentor, Samir S. Shah, MD, MSCE, 

includes 45 academic faculty members, 7 fellows, and 15 support staff. The division includes 3 clinical 

services: Burnet Campus inpatient units (A6N and A6S, 24 beds each), Liberty Campus inpatient unit (12 

beds), and the Hospital Medicine Surgical Service (A3N, 24 beds), the latter of which partners with the 

CCHMC surgical subspecialists to provide medical co-management for medically-complex patients who require 

surgical procedures. The division cares for more than 25,000 encounters each year; this patient volume 

represents one-fourth of all patients hospitalized at CCHMC. The Division of Hospital Medicine, in which Dr. 

Ambroggio has a primary appointment, cares for the majority of virtually all children hospitalized with 

community-acquired pneumonia. Dr. Ambroggio has access to a Clinical Research Manager, 6 Clinical 

Research Coordinators (CRCs), a Regulatory Coordinator, and a Grants Specialist. The six clinical research 

Contact PD/PI: Ambroggio, Lilliam

Facilities & Other Resources Page 12
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coordinators will aid in sample collection from patients who consented to be included in the project when they 

originally presented in the Emergency Department. In 2015, division members published 122 peer-reviewed 

publications and received ~$1 million in grant support.

CCHMC received accreditation from the Association for the Accreditation of Human Research Protection

Programs (AAHRPP) in 2007. The Office for Research Compliance and Regulatory Affairs (ORCRA) and the

Office of Sponsored Programs offer a number of educational opportunities, including sessions addressing 

informed consent, writing clinical study protocols, grant budgetary management, and IRB issues. Furthermore, 

research in the Division of Hospital Medicine is further supported by having a dedicated institutional review 

board liaison (“research compliance specialist”) who assists with efficiently developing and modifying protocols 

to facilitate research while maintaining strict protection of human subjects.

Computer/AV Equipment: Dr. Ambroggio has an HP desktop and laptop computer that with a secure 

connection to the CCHMC server allows her to transport work easily between CCHMC and University of 

Michigan as needed. The computers are equipped with standard word processing, bibliographic and data 

management software. Additionally, Dr. Ambroggio has the software needed for analysis and presentation of 

quantitative data (i.e. SAS version 9.3.2). Dr. Ambroggio has access to a photocopier, a fax machine, and a 

digital scanner that are available within the suite where her office is located. Dr. Ambroggio has sufficient 

space (50 gigabytes and more available if needed) on the CCHMC server, which is backed up nightly, to store 

all data collected for the grant. As part of Dr. Ambroggio’s joint appointment with the Division of Biostatistics 

and Epidemiology, she will be able to run large datasets that require large amounts of memory by using a 

server based version of SAS stored on a HP ProLiant DL585 G2 system, containing four Opteron 8218 2.6 

GHz dual core processors. The server offers 32 GB of RAM, and each user can initially obtain 500 GB of 

dedicated storage. In addition, there is 400 GB available for SAS temporary files. The operating system is 

SUSE Linux Enterprise Server 10.3 (x86_64). The server has redundant power supplies, is located in a secure 

data center and is backed up daily. 

Office: The Division of Hospital Medicine is housed in a contemporary office space on the 5th and 6th floor of 

the Old Research Building on the CCHMC main campus. This 10,200 square foot office space includes 31 

private offices, 3 conference rooms, 2 huddle offices, and 37 work stations for administrative support and 

research staff. This space also includes a fax machine, copier, and several laser printers, including a highquality color laser printer. Within that space, Dr. Ambroggio has her own office, located directly across the hall 

from the office of her primary mentor, Dr. Samir Shah. Her co-mentor, Dr. Maurizio Macaluso, is located in an 

adjacent building. Her office can be locked and has multiple locking file cabinets, as well as shelving, to store 

both research-related materials and references. Dr. Ambroggio has access to an administrative assistant with 

a desk outside her office, and clinical research coordinators in the same suite. All of Dr. Ambroggio’s local 

mentors and advisors have their individual offices in either the same building as her office or in a building 

nearby.

The Division of Emergency Medicine, directed by Dr. Stephen Porter and until June 2015, Dr. Ambroggio’s 

advisory committee member, Richard Ruddy, MD, is responsible for managing two large emergency 

departments (ED) and four urgent care facilities together with annual visits of over 163,000 pediatric and

adolescent patients with 42 faculty. This research will take place in the primary emergency department 

(Avondale) which is a Level 1 Trauma Center that had over 92,000 visits in 2014. Faculty research aims to 

improve healthcare delivery among the ED population, with research interests including infectious diseases, 

traumatic brain injury/concussion, asthma, resuscitation/airway management, patient-family experience of 

care, simulation, and mental health. Divisional faculty received >$1.67 million in direct annual grant support in 

2014.

The Division has a sophisticated infrastructure of research personnel who assist emergency medicine 

investigators and collaborators with all aspects of their research. The Research Team consists of a Clinical 

Research Manager, a Clinical Research Supervisor, a Financial Analysist and ten Clinical Research 

Coordinators (CRCs), a Regulatory Coordinator, a Quality Assurance Specialist, and a Grants Specialist. The 

Research Manager assists with formulating and maintaining research budgets, initial study design and 

Contact PD/PI: Ambroggio, Lilliam

Facilities & Other Resources Page 13
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determining the feasibility of the study. The Grant Specialist aids with the development of grants as well as 

post-grant management. The Regulatory Coordinator ensures that the study follows all internal IRB 

requirements, federal, state and internal regulations. The CRCs work directly with the investigators to develop 

a manual of operations for each study, enroll patients, and maintain documentation and research forms in 

compliance with Federal HIPAA and human subjects’ regulations. Research enrollment will occur in the 

Emergency Department, which sees >1100 cases of community-acquired pneumonia annually, by the ED 

CRCs, who will then coordinate subsequent sample collection with the CRCs in the Division of Hospital 

Medicine.

The Pediatric Emergency Care Applied Research Network (PECARN) is the first federally funded pediatric 

emergency medicine research network in the United States and consists of 18 pediatric emergency 

departments (www.pecarn.org). PECARN consists of six research nodal centers. Dr. Ruddy, the Emergency 

Medicine Division Director at CCHMC is the nodal principal investigator of the Hospitals of the Midwest 

Emergency Research Node (HOMERUN) of PECARN. PECARN works to conduct high-priority, multiinstitutional research on the prevention and management of acute illnesses and injuries in children and 

adolescents and could also be a home for multi-center pneumonia projects. 

The Division of Biostatistics and Epidemiology (DBE), where Dr. Ambroggio holds a joint faculty 

appointment and is directed by Maurizio Macaluso, DrPH, MD, offers a depth and expertise across a broad 

range of biostatistical and epidemiologic methods. This breadth of expertise allows all faculty and staff within 

the division easy access to peer consultation and technical review. The DBE conducts both independent and 

collaborative research and has a total of 21 primary, 14 jointly-appointed faculty members, 58 professional staff 

members and 5 support staff members. In FY 2016, DBE faculty received $11.69M in grant funding support 

and had a total of 138 peer-reviewed publications. DBE also enjoys strong ties to the University of Cincinnati 

(Department of Mathematics, and Department of Environmental Health, Division of Epidemiology and 

Biostatistics). The Division includes a Data Management Center (DMC) that supported 90 studies in 2015 by 

assisting with grant application and protocol review, budgeting and resourcing for data management, case 

report form design, database development, data entry and documentation, discrepancy management, data 

cleaning and preparation for analysis. Dr. Ambroggio’s data manager, Judd Jacobs, and data programmer, 

Jessi Poteet, are members of the DMC and take primary responsibility for managing the master study 

database used in parent study CARPE DIEM. Mr. Jacobs and Ms. Poteet merge all clinical, specimen and 

laboratory data into one large database for CARPE DIEM, which can then be used for final analysis. The DMC 

also maintains the REDCap database containing all clinical data from CARPE DIEM and performs quality 

checks throughout the study to ensure proper data entry from all systems, including data entered by the clinical 

research coordinators, biomedical informatics, Biomaterial Tracking and Management software, and the clinical 

laboratory. These data checks are extremely important in maintaining the highest quality of data and staying in 

compliance with our regulatory policies.

The CCHMC Division of Biomedical Informatics (BMI) supports researchers with resources such as data 

storage systems, database servers, collaboration tools, and an inventory of research software applications. 

They provide consultations to support these applications and to help determine the best option to meet a 

researcher’s data management and storage needs. BMI extracts and maintains clinical data from our electronic 

medical records into our secure REDCap database as part of the parent study, CARPE DIEM.

Laboratory: The Clinical Laboratory at CCHMC is part of the Division of Pathology and Laboratory Medicine, 

and directed by Paul Steele, MD. This laboratory is the main clinical laboratory for CCHMC and consists of 5 

core clinical laboratories: phlebotomy/processing, chemistry, hematology, coagulation and microbiology. The 

laboratory has extensive experience performing a host of clinical testing for patients at CCHMC, in addition to 

collaborating with researchers. The laboratory is CLIA-certified and College of American Pathologistsaccredited. Standard operating procedures are in place to ensure reliable and reproducible test results. The 

Clinical Laboratories perform conventional biomarker testing for the parent study Catalyzing Ambulatory 

Research in Pneumonia Etiology and Diagnostic Innovations in Emergency Medicine (CARPE DIEM),

including complete blood counts with differential, C-reactive protein and blood cultures.

Contact PD/PI: Ambroggio, Lilliam

Facilities & Other Resources Page 14
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The Laboratory for Specialized Clinical Studies (LSCS), directed by Monica Malone McNeal and housed 

within the CCHMC Division of Infectious Diseases, has a 20-year history of providing support for clinical and 

vaccine trials. The LSCS provides testing capabilities targeted to support clinical research. The laboratory 

specializes in the development and validation of customized assays and includes integration of customized 

statistical software. The laboratory employs experienced staff trained to conduct numerous specialized bioanalytical procedures. The 7000 square foot laboratory is CAP- and CLIA-accredited. All assays are conducted 

following GLP guidelines. Extensive documentation is maintained in compliance with GLP and all testing is fully

auditable. A laboratory quality assurance officer and an independent regulatory affairs department support

laboratory services. Laboratory space and equipment includes two separate tissue culture areas, a walk-in

freezer, a walk-in warm room, extensive ultracold freezer storage, automated liquid nitrogen storage, biosafety

cabinets and incubators, fume hoods, sterilizers, and glassware prep area. A state-of-the-art Rees Centron

system monitors all controlled temperature units 24/7 and alerts personnel in case of equipment or power

failure. The laboratory is approved for Biosafety Level 2 (BL2) containment. Laboratory personal have specific 

training for blood, urine, and nasopharyngeal samples. Access to the laboratory is limited when work is being 

conducted. Laboratory personal have personal protective equipment (PPE) for handling chemicals, human 

samples and Class II pathogens according to the Safety Guidelines in Policy #108 of the CCHMC Environment 

of Care Manual. Technicians must adhere to the practice of Standard Precautions as stated in Infection 

Control and Prevention Program Policy IC-1.2. The LSCS will perform quantitative real-time polymerase chain 

reaction (PCR) that is used to measure the pneumococcal bacterial load, respiratory viral polymerase chain 

reaction (PCR) and M. pneumoniae PCR

The Cincinnati Biobank Core Facility (CBCF) occupies space in the research building dedicated to 

processing and storing samples (e.g., tissues, DNA, serum, plasma). The Biobank is the site of all specimen 

storage for the biorepository developed for CARPE DIEM, and leveraged in this K01 proposal. The Biobank

Facility has 1,000 square feet within its on-site facility at CCHMC, with five workstations and multiple freezer 

units. The Biobank Facility also has an off-site facility located approximately 10 miles away from campus that 

has four workstations and 42 freezer units. The Biobank Facility has ten full-time employees, including a PhDlevel director, three regulatory research assistants, five laboratory research assistants and a database 

manager. An AutoGenFlex STAR automated DNA extraction instrument (DNA from up to 5 mL of whole blood, 

saliva, or tissue), a Promega Maxwell 16 (DNA or RNA from up to 350 ul of whole blood, saliva, or PAXgene 

tubes), a Fluidigm EP1 HX (tests 96 SNPs on 96 samples using microfluidics) and a Trinean DropSense 96 

multichannel spectrophotometer are available. Three -80°C and two -20°C upright freezers, a 4°C refrigerator, 

a custom portable freezer pan (-20°C cold table), a Hereaus Megafuge 16R centrifuge, and desk space with 

networked computer work stations for 5 technicians are available. Additional -80°C freezers, a liquid nitrogen 

freezer, and -20°C freezer are available 2 floors above in the main Department of Pathology space. A 

monitored alarm system and emergency generators are maintained by CCHMC for all freezers. Each freezer 

operates on a unique circuit, and all equipment is included on the facility’s emergency generator system. The 

CBCF uses specimen tracking software, Biomaterial Tracking and Management, to electronically record the 

location and availability of every aliquot of every specimen collected from each patient. Dr. Ambroggio has 

access to this software and is able to easily track the specimens and their individual aliquots collected as part 

of this proposal.

NMR-based Metabolomics Core Facility: The NMR-based Metabolomics Core (NBMC) provides state-ofthe-art technology in a centralized location accessible to research investigators and clinicians, serving CCHMC 

and UC COM communities. The NMR-based Metabolomics Core facilitates broad spectrum and targeted 

metabolomics analysis of polar components, as well as methods for targeted analysis of metabolites, with 

experience in the analysis of cells, organ tissue (e.g. liver, muscle, intestines, tongue, and tumor), biological 

fluids (e.g. urine, serum, plasma, amniotic fluid and saliva), and exhaled breath collected from human subjects 

or animal models. The NBMC Facility measures concentrations of small molecules in biological samples. We 

use Bruker Biospin licensed TopSpin and Amix softwares in conjunction with Chenomx NMR Suite for analysis 

of unbiased metabolomics data. In short, proton (1H) NMR spectra of all study groups are compared and 

analyzed using automated methodologies employing both univariate and multivariate statistical tools such as 

analysis of variance (ANOVA), significant difference spectra (SDS), principal component analysis (PCA) and 

partial least squares (PLS)(1). Processed 1H NMR spectra will be binned to small regions (0.01-0.005ppm) and 

Contact PD/PI: Ambroggio, Lilliam

Facilities & Other Resources Page 15
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analyzed using AMIX (Bruker Biospin, Inc., Billerica, MA), for PCA analysis. The binned data prepared during 

the PCA analysis will also be analyzed using a univariate approach, based on bin-by-bin differences between 

groups of spectra from different sites. In order to identify the NMR peaks that are significantly different between 

the study populations, 1H significant difference spectra (SDS) will be generated using the same peak 

intensities in each bin. To avoid significant false discovery rates, the Student’s t-test between groups was 

subjected to False Discovery Rate (FDR) control at the 0.05 level.

The NBMC facility, located within the Division of Pathology at CCHMC, utilizes a Bruker IVDr 600MHz NMR 

system that is fully-automated, designed specifically for metabolomics based studies of biological fluids, 

housed in the Medical Science Building (MSB) at University of Cincinnati College of Medicine (UC COM). The 

primary spectrometer utilized by the NBMC provides a high field multi-nuclear NMR capability to CCHMC, 

UCCOM and external academic and industry collaborators. The Bruker IVDr, a top-of-the-line spectrometer, is 

capable of running most contemporary homonuclear, heteronuclear one and two-dimensional pulse 

sequences, using pre-designed software, and is equipped with a 96-well SampleJet auto-sampler unit that 

renders the NMR system fully-automated. The Bruker spectrometer is equipped with a 5mm triple resonance 

conventional probe, which allows for routine acquisition of 1D and 2D 1H1H correlations as well as 1D 13C and 

2D 1H13C correlations used to confirm small metabolite identities. If higher field spectra are required, CCHMC 

researchers have access to a state-of-the-art Varian 800MHz NMR instrument also located with the UC COM 

NMR Facility. The usual array of peripheral analytical equipment is available including an electronic balance, 

pH meters, distillation equipment, bench-top centrifuges, rotary evaporators, a dual SpeedVac concentrator 

and lyophilizer system, and a cryogenic homogenizer. Dr. Ambroggio has access and permission from the 

director, Dr. Rosendale-Romick, to use the dedicated space and equipment for her experiments under the 

supervision of the director.

The NBMC operates under Biosafety Level 2 (BL2) regulations and follows all NIH guidelines for ensuring the use of 

proper microbiological practices and laboratory techniques. Laboratory personal have specific training for blood, 

urine, and nasopharyngeal samples. Access to the laboratory is limited when work is being conducted. All residual 

specimen and specimen containers are disposed of in the appropriate biohazard container within the lab. All 

samples are transported to the core lab in biohazard bags to minimize risk of exposure. All samples that are not 

being immediately analyzed are stored in our 80 freezer located inside our locked core lab space. All lab staff are 

outfitted in proper lab attire including lab coats and appropriate personal protective equipment (PPE) at all times.

Ziady LC/MS2 Laboratory: Dr. Ziady’s laboratory occupies approximately 800 sq. ft. with an additional 144 sq. 

ft. room, which houses a Tandem Liquid Chromatography-Mass Spectrometer. The imaging and analysis 

systems are located primarily within the R building, occupying 1,500 square feet (in the same building 

containing the CF research laboratories of Drs. Ziady and also Dr. Ambroggio’s office). Access to the imaging 

suite is controlled by keycard and user login and will be accessible to Dr. Ambroggio during her training period 

in the 4th year of the award. Dr. Ziady’s laboratory operates under Biosafety Level 2 (BL2) regulations and 

follows all NIH guidelines for ensuring the use of proper microbiological practices and laboratory techniques

Animal: n/a

Other:

Center for Clinical and Translational Research (CCTST): Research across UC and the Academic Health 

Center (AHC) is supported by the Center for Clinical and Translational Science and Training (CCTST), funded 

in part by our Institutional Clinical and Translational Science Award (CTSA). Access to the CCTST is available 

to every investigator via Research Central, a physical and virtual portal staffed by research methods experts. 

The CCTST coordinates a wide range of services, including biostatistics, biomedical informatics, data 

management, training grant application assistance, inpatient and outpatient clinical research services for both 

adult and child studies, support for community engagement activities, and regulatory knowledge (the AHC’s 

regulatory and management infrastructure includes 4 Institutional Review Boards, 2 Institutional Animal Care 

and Use Committees, 2 Institutional Biosafety Committees, 2 Radiation Safety Committees, and 2 clinical trials 

offices). The CCTST also coordinates a number of institutional programs, including pilot grant programs, the 

MS in Clinical and Translational Research and Certificate in Clinical and Translational Research training 

Contact PD/PI: Ambroggio, Lilliam

Facilities & Other Resources Page 16
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programs, the KL2 and 2 K12 programs, and novel technologies and affiliated cores. Additional details are 

available at http://cctst.uc.edu. 

Faculty Development: CCHMC has an Office for Faculty Development led by Dr. Jessica Kahn, who also 

serves as the Assistant Chair of Academic Affairs and Faculty Development. This office sponsors numerous 

seminars on topics such as developing effective collaborations, setting career goals, scientific writing, and 

negotiation strategies. All of the Faculty Development seminars are recorded and archived to increase 

accessibility to this important resource. An organized peer group (the “K club”) of CCHMC and UC faculty who 

are applying for or have received NIH career development awards meet twice a month. This group provides 

mentorship, as well as career development and networking opportunities, with the primary goal of ensuring 

successful completion of K awards and transition to R01 funding.

Library resources: The CCHMC Pratt Library is located in a connected building adjacent to Dr. Ambroggio’s

office and is a primary resource for both books and journals, including >350 print journal subscriptions and 

nearly 400 additional journal titles available via electronic access. The library employs three full-time librarians 

to assist with literature searches and locating needed electronic and print media resources. Also, the Health 

Sciences Library of the University of Cincinnati College of Medicine is located across the street from the 

CCHMC main campus and offers online access to more than 4000 journals. Both libraries offer training and 

educational opportunities as well as assistance with literature searches and locating references.

Environment: Contribution to Success: The scientific environments at CCHMC and UC provide an ideal 

setting for Dr. Ambroggio to establish herself as an expert in pediatric infectious diseases and, with the support 

of a career development award, achieve research independence. The resources of CCHMC and the CCTST, 

combined with experienced mentors and a large patient population, ensure the success of the proposed 

research and career development. Specifically, the proposed research and career development plan utilize the 

intellectual resources available through CCHMC, including research support from the CCTST and relevant 

CCHMC offices. Additionally, the Divisions of Hospital Medicine, Biostatistics and Epidemiology and 

Emergency Medicine have an extensive track record of successful collaboration and the large patient 

populations necessary for the successful completion of this proposal. Additionally, as an institution, CCHMC is 

committed to institutional support of early investigators through internal grants, administrative support, and 

structured opportunities for faculty networking and education. 

Section 2: University of Michigan

I have an established collaboration with the state-of-the-art facilities at the University of Michigan, College of 

Pharmacy (CoP) and the Biochemical Nuclear Magnetic Resonance (NMR) core, and as necessary, the 

Michigan Regional Comprehensive Metabolomics Research Core (MRC) to successfully accomplish our 

proposed aims.

Stringer Laboratory: Dr. Kathleen Stringer, external metabolomics mentor on this proposal, has a fully 

equipped laboratory (~500 sq. ft) on the 3rd floor of the College of Pharmacy (CoP) building on the central 

University of Michigan (Ann Arbor) campus. Her lab is fully equipped to process urine samples and conduct 

the proposed metabolomics experiments. In addition, her lab houses lyophilizers and speedvac for 

serum/plasma/blood sample extractions that are necessary for conducting metabolomics assays in these 

biofluids. Her laboratory is also equipped with a fume hood, refrigerators, and -20°C and -80°C freezers. Dr. 

Stringer’s laboratory is approximately 1⁄4 mile from the (MRC)2in Brehm Tower which can be easily reached on 

foot or by utilizing the University of Michigan’s bus system. The Stringer Laboratory provided analysis for the 

samples used for pilot data for this proposal and will do so for the samples generated by this study.

Computers and Software: Dr. Stringer and her laboratory personnel including Dr. Larisa Yeomans and Ms. 

Cora McHugh, have their own personal computers for secure data entry and analysis. All computers are 

internet and email capable and are equipped with the necessary software for word processing, data entry and 

statistical analysis. In addition, a computer in Dr. Stringer’s laboratory is equipped with Chenomx software 

Contact PD/PI: Ambroggio, Lilliam

Facilities & Other Resources Page 17
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(chenomx.com) that will be used to identify and quantify metabolites from the NMR spectra generated under 

the two proposed aims.

Biochemical Nuclear Magnetic Resonance (NMR) Core (CoP): The acquisition of NMR spectra for 

untargeted metabolomics will be conducted in the CoP’s Biochemical NMR core laboratory. The CoP facility 

houses a state-of-the-art Varian 500 NMR spectrometer which has pulsed field gradients, auto tune, auto shim, 

a 3mm ONE probe and a twelve slot sample changer robot. It is a "research grade" instrument capable of 

performing all of the solution NMR techniques commonly reported in the literature. It is computer operated via 

the VNMRJ 3.2 software package. Commonly performed experiments include simple spectra, T1 and T2 

relaxation experiments, solvent suppression, selective decoupling and nOe experiments, as well as one (1D) 

and two-dimensional (2D) COSY, NOESY, HSQC and HMBC. In addition to the needed NMR equipment, the 

core also houses several computers equipped with spectral analysis software including Chenomx NMR suite 

7.6 (chenomx.com). 

Michigan Regional Comprehensive Metabolomics Research Core ((MRC)2), Ann Arbor, MI 

(http://mrc2.umich.edu/): The (MRC)2is a fully integrated program that provides researchers nation-wide with 

the expertise and infrastructure to determine the levels of known and unknown metabolites in cells, tissues and 

biological fluids. In addition, the (MRC)2 provides opportunities for training in the technology of metabolomic 

analysis, statistical analysis and bioinformatic evaluation of metabolite data as well as approaches to 

incorporation of metabolomics into basic, preclinical, translational and clinical research.

The (MRC)2is one of six NIH-funded regional metabolomics facilities (http://www.metabolomicsworkbench.org)

that also supplies expertise and method development for both untargeted and targeted metabolomic analysis. 

The untargeted analysis platform uses high mass resolution and accuracy LC/MS-TOF and GC/MS to assess 

the relative levels of nearly >5000 molecular features (metabolites) which are reproducibly found in plasma, 

other biological fluids, and tissues. Assigning the molecular structural identity of specific features is aided by a 

library of over 1,000 authentic chemical compounds. A network of statisticians (e.g., Dr. George Michailidis) 

and bioinformatics faculty (e.g., Dr. Alla Karnovsky) and staff can help with interpretation of large untargeted 

datasets containing many observations. Directed assays are performed using traditional multiple reaction 

monitoring (MRM) methods, including internal standards, typically resulting in COV values of 15%-20% for 

analytes such as amino acids, acyl-carnitines, glycolytic and TCA cycle intermediates, steroids, and other 

biochemical compound classes as outlined on the website (http://www.med.umich.edu/mmoc/cores/ 

molecular.html). 

For metabolomics assays conducted in (MRC)2, all solvents are similarly purchased in bulk from a single 

manufacturer’s lot in sufficient quantity to complete planned experiments. All samples are bar-coded by the 

(MRC)2laboratory information management system (LIMS) and all chromatographic runs are LIMS-scheduled 

tasks. Raw data files are tracked and processed by their LIMS identifiers and archived to a DVD at regular 

intervals. The (MRC)2 uses the LIMS system which is specifically designed to store the results of the LC/MS 

experiments. It provides a web-based user-friendly interface that provides secure access to the data. (MRC)2

has developed an infrastructure to support data processing and analysis.

The (MRC)2 comprises 2200 ft2 of laboratory space in Brehm Tower and has the full range of expertise to 

successfully complete sample measurements and analyses, currently processing ~800 samples per month. 

The Core is well equipped with standard laboratory equipment and includes the following suite of mass 

spectrometers:

1) Two Agilent 6890 gas chromatograph (GC) equipped with HP5973 mass detector GC/MS system with 

electron impact ionization (EI) and GC/ECNI/MS and positive/negative ion capabilities. The instruments are 

equipped with an autosampler and an on-column injector. The GC/MS systems will be used to measure 

derivatized amino acids, low molecular polar and non-polar metabolites, nucleic acids and lipid metabolites. In 

addition, this versatile instrument is capable of analysis of complex lipoproteins, glycolipids, sphingolipids and 

other small molecule analytes quantitatively.

Contact PD/PI: Ambroggio, Lilliam

Facilities & Other Resources Page 18
8

2) Two Agilent Triple Quadrupole mass spectrometers (6410 and 6490) coupled with Agilent 1290 UHPLC. 

These instruments offer exceptional sensitivity for directed metabolomics in the MRM mode for lipids, amino 

acids and products of intermediary metabolism. They have the ability to perform both ESI and atmospheric 

pressure chemical Ionization (APCI) and can be utilized both for directed and undirected metabolomic analysis.

3) An Agilent LC/MSD Time of flight mass spectrometer. This instrument has high mass accuracy and is ideal 

for directed and undirected metabolomic profiling of small molecules for accurate mass determination. It can 

also be utilized to perform both ESI and APCI.

4) Three Quadrupole TOF instrument (Q-TOF) instruments coupled Agilent Rapid Resolution HPLC or UPLC 

which provide high sensitivity, high mass accuracy, high mass range, and rapid throughput ideal for 

metabolomic profiling. This instrument has high mass accuracy and capability to perform tandem MS analysis 

making it ideal for both directed and undirected metabolomic studies. This can provide extremely valuable 

structural information and may simplify, for example, in determining complex metabolite structures. 

Additionally, these instruments can be utilized for untargeted metabolomics.

5) The Core also has an Agilent 6890 GC and a Jasco HPLC system equipped with variable UV detector, 

fluorescence detector, electrochemical detector and diode array detector. Both instruments have an 

autosampler. These instruments are capable of analyzing a wide variety of small molecules, preparing internal 

standards for GC/MS and LC/MS analysis and purifying the samples prior to injection into the mass 

spectrometer.

Contact PD/PI: Ambroggio, Lilliam

Facilities & Other Resources Page 19
Contact PD/PI: Ambroggio, Lilliam

OMB Number: 4040-0001

Expiration Date: 06/30/2016

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED Senior/Key Person Profile (Expanded)

PROFILE - Project Director/Principal Investigator

Prefix:  First Name*: Lilliam Middle Name  Last Name*: Ambroggio Suffix: 

Position/Title*: ASSISTANT PROFESSOR

Organization Name*: Cincinnati Childrens Hospital Medical Center

Department: Pediatrics

Division: Hospital Medicine

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Phone

Number*: 

Fax Number:  E-Mail*: 

Credential, e.g., agency login: 

Project Role*:  PD/PI Other Project Role Category: 

Degree Type:  MPH, PHD Degree Year:  2008, 2011

File Name Mime Type

Attach Biographical Sketch*: Ambroggio_NIH_Biosketch_2016_06_27.pdf application/pdf

Attach Current & Pending Support:

 Page 20
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

PROFILE - Senior/Key Person

Prefix:  First Name*: Samir Middle Name  Last Name*: Shah Suffix: 

Position/Title*: Professor of Pediatrics

Organization Name*: Cincinnati Children's Hospital Medical Center

Department:

Division:

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Phone

Number*: 

Fax Number:  E-Mail*: 

Credential, e.g., agency login: 

Project Role*:  Other Professional Other Project Role Category: Mentor

Degree Type:  Degree Year: 

File Name Mime Type

Attach Biographical Sketch*: Shah_NIH_Biosketch_6_30_16.pdfapplication/pdf

Attach Current & Pending Support: SamirShah_Other_Support.pdf application/pdf

PROFILE - Senior/Key Person

Prefix:  First Name*: Maurizio Middle Name  Last Name*: Macaluso Suffix: 

Position/Title*: Professor and Director

Organization Name*: Cincinnati Children's Hospital Medical Center

Department:

Division:

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Phone

Number*: 

Fax Number:  E-Mail*: 

Credential, e.g., agency login: 

Project Role*:  Other Professional Other Project Role Category: Co-Mentor

Degree Type:  Degree Year: 

File Name Mime Type

Attach Biographical Sketch*: Macaluso_NIH_Biosketch_5_12_2016.pdf application/pdf

Attach Current & Pending Support: Other_Support_Macaluso_5_26_16.pdf application/pdf

 Page 21
Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

PROFILE - Senior/Key Person

Prefix:  First Name*: Richard Middle Name  Last Name*: Ruddy Suffix: 

Position/Title*: Professor of Pediatrics

Organization Name*: Cincinnati Children's Hospital Medical Center

Department:

Division:

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Phone

Number*: 

Fax Number:  E-Mail*: 

Credential, e.g., agency login: 

Project Role*:  Other Professional Other Project Role Category: Co-Mentor

Degree Type:  Degree Year: 

File Name Mime Type

Attach Biographical Sketch*: Ruddy_NIH_Biosketch_5_28_2016_Reviewed.pdf application/pdf

Attach Current & Pending Support: Ruddy_Other_Support_6_20_2016.pdf application/pdf

PROFILE - Senior/Key Person

Prefix:  First Name*: Kathleen Middle Name  Last Name*: Stringer Suffix: 

Position/Title*: Professor

Organization Name*: University of Michigan

Department:

Division:

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Phone

Number*: 

Fax Number:  E-Mail*: 

Credential, e.g., agency login: 

Project Role*:  Other Professional Other Project Role Category: Co-Mentor

Degree Type:  Degree Year: 

File Name Mime Type

Attach Biographical Sketch*: Stringer_NIH_Biosketch_5_12_2016_Reviewed.pdf application/pdf

Attach Current & Pending Support: Stringer_OtherSupport_Jun2016_FINAL.pdf application/pdf

Contact PD/PI: Ambroggio, Lilliam

 Page 22
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

PROFILE - Senior/Key Person

Prefix:  First Name*: Heidi Middle Name  Last Name*: Sucharew Suffix: 

Position/Title*: Assistant Professor

Organization Name*: Cincinnati Children's Hospital Medical Center

Department:

Division:

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Phone

Number*: 

Fax Number:  E-Mail*: 

Credential, e.g., agency login: 

Project Role*:  Other Professional Other Project Role Category: Co-Mentor

Degree Type:  Degree Year: 

File Name Mime Type

Attach Biographical Sketch*: Sucharew_biosketch_05_23_16_Reviewed.pdf application/pdf

Attach Current & Pending Support: Other_Support_Heidi_6_17_16.pdf application/pdf

PROFILE - Senior/Key Person

Prefix:  First Name*: Lindsey Middle Name  Last Name*: Romick-Rosendale Suffix: 

Position/Title*: Assistant Professor

Organization Name*: Cincinnati Children's Hospital Medical Center

Department:

Division:

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Phone

Number*: 

Fax Number:  E-Mail*: 

Credential, e.g., agency login: 

Project Role*:  Other (Specify) Other Project Role Category: Collaborator

Degree Type:  Degree Year: 

File Name Mime Type

Attach Biographical Sketch*: Romick_Rosendale_NIH_Biosketch_5_12_2016_Revie.pdf application/pdf

Attach Current & Pending Support:

 Page 23
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

PROFILE - Senior/Key Person

Prefix:  First Name*: Assem Middle Name  Last Name*: Ziady Suffix: 

Position/Title*: Associate Professor

Organization Name*: Cincinnati Children's Hospital Medical Center

Department:

Division:

Street1*:

Street2:

City*:

County:

State*:

Province:

Country*:

Zip / Postal Code*:

Phone

Number*: 

Fax Number:  E-Mail*: 

Credential, e.g., agency login: 

Project Role*:  Other (Specify) Other Project Role Category: Collaborator

Degree Type:  Degree Year: 

File Name Mime Type

Attach Biographical Sketch*: Ziady_NIH_biosketch_5_12_2016_Reviewed.pdf application/pdf

Attach Current & Pending Support:

 Page 24
Contact PD/PI: Ambroggio, Lilliam

1

OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) 

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors. 

Follow this format for each person. DO NOT EXCEED FIVE PAGES. 

NAME: Ambroggio, Lilliam 

   eRA COMMONS USER NAME (agency login):

POSITION TITLE: Assistant Professor 

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, 

include postdoctoral training and residency training if applicable.)

INSTITUTION AND LOCATION DEGREE

(if applicable)

Completion Date 

MM/YYYY

FIELD OF STUDY 

University of Washington BS 06/2003 Molecular and Cellular Biology 

Drexel University MPH 06/2008 Epidemiology 

Drexel University PHD 06/2011 Epidemiology 

Cincinnati Children’s Hospital Fellow 08/2011 Post-Doctoral Fellowship in Clinical Research 

A. PERSONAL STATEMENT

My long-term research goal is to improve outcomes for children with common, serious infections by 

developing methods to improve diagnostic accuracy and implementing these methods into clinical practice. 

The objective of the proposed research is to combine advanced statistical and NMR metabolomics 

methodologies to inform pathogen-detection in childhood pneumonia. This research proposes the use of 

novel methods to identify pathogens causing CAP in an ambulatory and inpatient population of children 

with different levels of disease severity. My previous work has focused on antibiotic resistance, empiric 

antibiotic choice, and imaging modality in managing CAP in children. I am uniquely positioned to 

accomplish the aims stated in this proposal as I have a strong foundation in molecular and cellular biology 

and epidemiological methodology and have outlined a strong training plan to gain expertise in NMR 

metabolomics and advanced statistical methodology. In addition, the CARPE DIEM study infrastructure 

including recruitment and sample collection for children with CAP that is being leveraged as part of this 

proposal is fully funded by the Gerber Foundation and the Ohio Governor’s Fund. I am currently a full-time 

Assistant Professor in the Divisions of Hospital Medicine and Biostatistics and Epidemiology. I plan to 

continue to conduct research in infectious diseases in children, focusing on developing and improving 

diagnostic tools for children diagnosed with common infectious diseases, such as pneumonia, globally. A 

K01 award would provide me with the resources to conduct novel research in the area of etiology 

identification for pediatric pneumonia. 

B. Research and/or Professional Experience:

Positions and Employment

2003 - 2006 Research Technician, Division of Clinical Research and Human Biology, Clurman Laboratory, 

Fred Hutchinson Cancer Research Center, Seattle, WA 

2006 - 2007 Practicum, Project Dulce, Esperanza Health Center, Philadelphia, PA 

2007 - 2007 Research Intern, Latino Adolescent Sexual Health Preference Study, Concern for Health 

Options: Information, Care and Education, Philadelphia, PR 

2007 - 2008 Research Intern, Public Health Governance in Ethiopia, International Clinical Epidemiology 

Network Inc., Philadelphia, PA 

2007 - 2011 Teaching Assistant, Department of Epidemiology and Biostatistics, Drexel University, 

Philadelphia, PA 

2011 - 2013 Research Fellow, Division of General & Community Pediatrics Research, Cincinnati Children’s 

Hospital and Medical Center, Cincinnati, OH 

Biosketches Page 25
2

2013 - Assistant Professor, Assistant Professor, Divisions of Hospital Medicine and Biostatistics and 

Epidemiology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati 

College of Medicine , Cincinnati, OH 

 

Honors 

2008 Member, Hygeia Academic Honor Society, School of Public Health, Drexel University 

2008 Excellence in Communication Award, School of Public Health, Drexel University 

2011 Graduate Student Travel Award, College of Graduate Studies, Drexel University 

2012 Infectious Disease Week Conference Trainee Travel Award, Infectious Disease Society of 

America 

2012 Principal Investigator, Early Career Award, Thrasher Research Fund 

2012 Outstanding Promise Doctoral Award in Physical and Life Sciences, Drexel University 

2013 Principal Investigator, Trustee Award, Cincinnati Children’s Hospital Medical Center 

2013 Principal Investigator, Young Investigator Award, Academic Pediatric Association 

2013 #10 on “The Drexel 40 Under 40”, Drexel Magazine, Drexel University 

2014 Academic-Community Research Partnership Award for the project “Reduced Variability in the 

Management of CAP”, Center for Clinical and Translational Science and Training, University of 

Cincinnati 

2014 Award for Excellence in Teamwork in Quality Improvement, Series of projects entitled 

“Improving adherence to evidence-based recommendations for common serious childhood 

infections”, Team Leader on Appropriate Antibiotic Prescribing for Childhood CommunityAcquired Pneumonia, Society of Hospital Medicine 

C. Contributions to Science

1. Pediatric Pneumonia Diagnosis and Management. Healthcare utilization and clinical management 

among children who are hospitalized with common infectious diseases has been shown to vary across 

institutions. The following publications demonstrate clinical outcomes associated with these variations 

and my methodological expertise in conducting healthcare service research including comparative 

effectiveness studies and in using administrative databases such as the "Pediatric Health Information 

System" (PHIS) in studying these questions. In the first study a high-risk subgroup of HSV-infected 

infants, those with cardiac congenital anomalies, warranted additional clinical interventions to improve 

outcomes. We determined the comparative effectiveness of β- lactam monotherapy and β-lactam and 

macrolide combination therapy on clinical outcomes in the treatment of children hospitalized with 

community-acquired pneumonia (CAP). The findings from this study suggested macrolide antibiotics 

do not have a role in the treatment of young children with CAP. In contrast, older children hospitalized 

with CAP may benefit from use of macrolide antibiotics, likely due to the effect of macrolides on 

atypical bacteria such as Mycoplasma pneumoniae. In addition, we wanted to determine the influence 

of hospital-level penicillin non-susceptible Streptococcus pneumoniae patterns on individual-level 

antibiotic prescription. This cross-sectional study used a multi-level analysis combining hospital-level 

microbiologic data obtained by survey with patient-level billing data. Hospitals reporting higher levels of 

penicillin-resistance among pneumococcal bacteria disproportionately prescribed broad-spectrum 

antibiotics. This study lends support to the hypothesis that physician prescribing habits can be 

meaningfully altered by strategies that focus on microbiologic reporting rather than direct physician 

education. 

 Other Experience and Professional Memberships

2006 - 2010 Member, American Public Health Association 

2009 - Member, Society of Epidemiologic Research 

2011 - Member, Academic Pediatric Association 

2011 - Member, Infectious Diseases Society of America 

2012 - Member, American College of Epidemiology 

2013 - Member, European Society of Pediatric Infectious Diseases 

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 26
Contact PD/PI: Ambroggio, Lilliam

3

a. Ambroggio L, Lorch SA, Mohamad Z, Mossey J, Shah SS. Congenital anomalies and resource 

utilization in neonates infected with herpes simplex virus. Sex Transm Dis. 2009 Nov;36(11):680-

5. PubMed PMID: 19617865; PubMed Central PMCID: PMC2783783. 

b. Ambroggio L, Tabb LP, O'Meara T, Sheffler-Collins S, McGowan KL, et al. Influence of antibiotic 

susceptibility patterns on empiric antibiotic prescribing for children hospitalized with communityacquired pneumonia. Pediatr Infect Dis J. 2012 Apr;31(4):331-6. PubMed PMID: 22228236. 

c. Ambroggio L, Taylor JA, Tabb LP, Newschaffer CJ, Evans AA, et al. Comparative effectiveness of 

empiric β-lactam monotherapy and β-lactam-macrolide combination therapy in children hospitalized 

with community-acquired pneumonia. J Pediatr. 2012 Dec;161(6):1097-103. PubMed PMID: 22901738. 

d. Ambroggio L, Test M, Metlay JP, Graff TR, Blosky MA, et al. Adjunct Systemic Corticosteroid Therapy 

in Children with Community-Acquired Pneumonia in the Outpatient Setting. Journal of the Pediatric 

Infectious Diseases Society. 2014 March 27; 4(1):21-27. 

2. Implementation and Standardization of Care for Pediatric Pneumonia. The Institute of Medicine 

reported that it can take almost 14 years to incorporate evidence into practice. Quality improvement 

science has been used to implement processes at a systems level rather than relying on individuals. 

Therefore we used quality improvement methods to implement the PIDS/IDSA childhood pneumonia 

guideline at our institution. We first implemented the antibiotic recommendations, supportive of narrowspectrum antibiotics as first-line therapy, in our emergency department and inpatient service. We 

increased guideline-recommended prescribing from <40% to 100% over a 6 month period. In addition we 

found that there were no negative consequences of increasing narrow spectrum antibiotic prescribing. We 

also performed another QI study to increase the number of blood cultures ordered for children hospitalized 

with pneumonia. Similarly we found no negative consequences related to this increase. 

a. Ambroggio L, Thomson J, Murtagh Kurowski E, Courter J, Statile A, et al. Quality improvement 

methods increase appropriate antibiotic prescribing for childhood pneumonia. Pediatrics. 2013 

May;131(5):e1623-31. PubMed PMID: 23589819; PubMed Central PMCID: PMC3639461. 

b. Thomson J, Ambroggio L, Murtagh Kurowski E, Statile A, Graham C, et al. Hospital outcomes 

associated with guideline-recommended antibiotic therapy for pediatric pneumonia. J Hosp Med. 2015 

Jan;10(1):13-8. PubMed PMID: 25263758; PubMed Central PMCID: PMC4322863. 

c. Murtagh Kurowski E, Shah SS, Thomson J, Statile A, Sheehan B, et al. Improvement Methodology 

Increases Guideline Recommended Blood Cultures in Children With Pneumonia. Pediatrics . 

2015 March 16; 

3. Methodological Content Expertise. The following reviews and commentaries demonstrate 

specific areas of content and methodological interest. 

a. 

b. Ambroggio LV, Shah SS. Administrative data: expanding the infrastructure for pediatric research. J 

Pediatr. 2013 Apr;162(4):681-4. PubMed PMID: 23196133. 

c. Shah SS, Ambroggio L, Florin TA. Invited Editorial: Biomarkers for Predicting Illness Severity in 

Children with Acute Lower Respiratory Tract Infections. Journal of the Pediatric Infectious Diseases 

Society. 2014; 

d. Florin TA, Ambroggio L. Biomarkers for community-acquired pneumonia in the emergency department. 

Curr Infect Dis Rep. 2014 Dec;16(12):451. PubMed PMID: 25348745. 

Complete List of Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/myncbi/1- 

9npwz8rCo5V/bibliograpahy/47384868/public/?sort=date&direction=ascending

D. RESEARCH SUPPORT

Ongoing Research Support 

2016/07/01-2017/06/30 

Biosketches Page 27
Contact PD/PI: Ambroggio, Lilliam

4

Stephen Waggoner (PI) 

Human natural killer cell responses in cytomegalovirus infection and vaccination 

Overall Goal: A vaccine to prevent diseases associated with cytomegalovirus is desperately needed. Protection 

against cytomegalovirus requires virus-specific antibodies and T cells, the stimulation of which we have 

discovered is inhibited by natural killer (NK) cells in mice. These studies will reveal the role of NK cells and guide 

innovative strategies to modulate these cells in prevention of cytomegalovirus infection. 

Role: Statistician 

2016/01/15-2018/12/31 

Academic Research Committee Award, Cincinnati Children’s Hospital Medical Center 

Lilliam Ambroggio (PI) 

Catalyzing Ambulatory Research in Pneumonia Etiology and Diagnostic Innovations in Emergency Medicine 

(CARPE DIEM) Extension 

Overall Goal: The objective of this study is to identify distinct metabolite profiles for the major classes of 

pathogens that cause CAP in children (e.g. virus, typical and atypical bacteria). Urine, blood samples, and 

nasopharyngeal swabs will be collected from children diagnosed with CAP in the Emergency Department or 

who are hospitalized at Cincinnati Children’s Hospital Medical Center. All urine samples will then be evaluated 

using quantitative 1H-nuclear magnetic resonance. Advanced statistical methods such as partial least squaresdiscriminant analysis will be applied to the identified metabolite dataset to determine unique metabolite 

profiles. 

Role: PI 

2015/01/10-2017/09/30 

Governor’s Office, State of Ohio 

Octavio Ramilo (PI) 

Children’s Hospitals Research Initiative in Pneumonia (CHIRP) 

Overall Goal: The objectives of this study are: to improve etiologic diagnosis of pediatric CAP using a 

combination of molecular diagnostic assays and host gene expression profiles (RNA biosignatures) and to 

evaluate the utility of a Molecular Distance to Health genomic score to triage patients based on severity and 

clinical outcomes. 

Role: Site Co-Investigator 

 

2013/08/01-2016/07/30 

Research Initiation Funds, Cincinnati Children’s Hospital Medical Center 

Lilliam Ambroggio (PI) 

Overall Goal: This grant has been used to set up the PI’s research program during her first three years as 

faculty at CCHMC. These funds also support the infrastructure for Catalyzing Ambulatory Research in 

Pneumonia Etiology and Diagnostic Innovations in Emergency Medicine (CARPE DIEM). 

Role: PI

Completed Research Support

2013/07/01-2015/06/30 

Biosketches Page 28
Contact PD/PI: Ambroggio, Lilliam

5

132925, Place Outcomes Research Award 

Shah, Samir (PI) 

Reduced Variability in the Management of CAP 

Role: Co-PI 

2011/09/12-2013/07/01 

NRSA T32HP10027, Ruth L. Kirschestein National Research Service Award 

Copeland, Kristen (PI) 

General and Community Pediatric Research 

The objective of this fellowship is to improve the health of children by developing future independent 

investigators in primary care research. 

Role: Fellow 

Biosketches Page 29
Contact PD/PI: Ambroggio, Lilliam

OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES.

NAME: Shah, Samir S.

eRA COMMONS USER NAME (agency login):

POSITION TITLE: James M. Ewell Professor of Pediatrics

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,

include postdoctoral training and residency training if applicable.)

INSTITUTION AND LOCATION DEGREE

(if

applicable)

Completion Date

MM/YYYY

FIELD OF STUDY

University of Pennsylvania, Philadelphia, PA BA 05/1993 Biology

Yale University School of Medicine, New Haven, CT MD 05/1998 Medicine

University of Pennsylvania School of Medicine,

Philadelphia, PA

MSCE 05/2007 Epidemiology

Children's Hospital of Philadelphia, Philadelphia, PA N/A 06/2001 Pediatrics Internship/Residency

Children's Hospital of Philadelphia, Philadelphia, PA N/A 06/2005 Pediatric Infectious Diseases

Fellowship

Children's Hospital of Philadelphia, Philadelphia, PA N/A 06/2005 Academic General Pediatrics

Fellowship

A. PERSONAL STATEMENT

I have content and methodological expertise in studies examining approaches to improve the diagnosis and

treatment of childhood pneumonia. I am a Pediatric Infectious Diseases and Pediatric Hospital Medicine

physician with formal training in research methodology and extensive experience in patient-oriented clinical

research. I am an expert in childhood pneumonia as recognized by my role as Associate Chair of the National

Childhood Pneumonia Diagnosis and Management Guidelines Committee, jointly sponsored by the Infectious

Diseases Society of America and the Pediatric Infectious Diseases Society. This clinical practice guideline,

recently published with me as co-first author, informs Dr. Ambroggio’s proposed project. There is a pressing

need for the development of accurate diagnostic testing to guide empirical treatment and predict outcomes in

children with community-acquired pneumonia. Dr. Ambroggio’s focus on children with pneumonia aligns with

the intent of the national guideline emphasis on identification of biomarkers relevant to childhood pneumonia. I 

have demonstrated a successful track record of multi-center collaboration and leadership in my role as Vice

Chair of the Pediatric Health Information Systems (PHIS) Research Group, which includes 35 physicians from

18 hospitals. I am also an Executive Council Member of the Pediatric Research in Inpatient Settings Network,

an organization sponsored by leading academic societies with >100 hospital members to create research

infrastructure to facilitate the conduct of multi-center patient-oriented research. The network has received >$18

million in grant support over the past five years. I will aide in Dr. Ambroggio’s collaboration with this network for

subsequent grants.

B. POSITIONS AND HONORS

Positions and Employment

2005 - 2011 Assistant Professor of Pediatrics at the Children's Hospital of Philadelphia, University of

Pennsylvania School of Medicine, Philadelphia, PA

2005 - 2011 Attending Physician in Infectious Diseases and General Pediatrics, The Children's Hospital of

Philadelphia, Philadelphia, PA

2006 - 2011 Senior Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

School of Medicine, Philadelphia, PA

2011 - 2011 Associate Professor of Pediatrics and Epidemiology at the Children's Hospital of Philadelphia,

University of Pennsylvania School of Medicine, Philadelphia, PA

2011 - Attending Physician in Infectious Diseases and Hospital Medicine, Cincinnati Children's

Hospital Medical Center, Cincinnati, OH

2011 - 2012 AssociateBiosketches Professor of Pediatrics at Cincinnati Children's Hospital Page 30 Medical Center, University of
Cincinnati College of Medicine, Cincinnati, OH

2012 - Professor of Pediatrics at Cincinnati Children's Hospital Medical Center, University of

Cincinnati College of Medicine, Cincinnati, OH

2012 - Director, Division of Hospital Medicine, Cincinnati Children's Hospital Medical Center,

Cincinnati, OH

2012 - James M. Ewell Endowed Chair, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Other Experience and Professional Memberships

- Member (elected), American Pediatric Society

2005 - Fellow, American Academy of Pediatrics

2006 - Member, Clinical Affairs Committee, Pediatric Infectious Diseases Society

2007 - Member, Editorial Board, JAMA Pediatrics

2007 - Chair, Pediatric Health Information Systems Research Group

2008 - Infectious Diseases Society of America

• Associate Chair, National Childhood Pneumonia Guidelines Writing Committee

(published in 2011)

• Member, National Bone/Joint Infections Guideline Writing Committee (2014-Present)

2008 - 2012 Editorial Advisory Board, Infection Control and Hospital Epidemiology

2009 - Executive Leadership Council, Pediatric Research in Inpatient Settings Network

• Vice Chair (2015-Present)

2009 - 2010 Assistant Editor, Journal of Hospital Medicine

2011 - Founding Associate Editor, Journal of the Pediatric Infectious Diseases Society

2011 - 2012 Associate Editor, Journal of Hospital Medicine

2012 - Deputy Editor, Journal of Hospital Medicine

2013 American Pediatric Society (elected member)

Honors

C. CONTRIBUTIONS TO SCIENCE (articles selected from >200 peer-reviewed publications)

1. Variation in care contributes to health care delivery inefficiency and increased costs. My work highlighting

care variation has spurred development of national guidelines for the diagnosis and management of

childhood pneumonia, which I co-authored. Additional accomplishments include demonstrating the

association between process measures and clinical outcomes in common respiratory conditions, including

pneumonia and bronchiolitis. 

a. Bradley JS, Byington CL, Shah SS* and Alverson B, Carter ER, Harrison C, Kaplan SL, Mace SE,

McCracken GH Jr., Moore MR, St. Peter SD, Stockwell JA, Swanson JT. The management of

community-acquired pneumonia in infants and children older than 3 months of age: clinical practice

guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.

2007 Faculty Teaching Honor Roll, The Children's Hospital of Philadelphia

2008 Jean A. Cortner Division Teaching Award (Infectious Diseases), The Children's Hospital of

Philadelphia Pediatric Residency Program

2009 Excellence in Research Award, Society of Hospital Medicine

2011 Young Investigator Award, Pediatric Infectious Diseases Society

2013 Division Teaching Award (Hospital Medicine), Cincinnati Children's Hospital Medical Center

Residency Program

2014 Excellence in Teamwork in Quality Improvement Award, Society of Hospital Medicine

2014 Academic-Community Research Partnership Award, Center for Clinical and Translational

Science and Training

2015 Miller-Sarkin Mentoring Award, Academic Pediatric Association

2015 Pediatric Hospital Medicine Award for Research Excellence, jointly awarded by the American

Academy of Pediatrics, the Academic Pediatric Association, and the Society of Hospital

Medicine (inaugural award; awarded for substantial research contributions to improve the care

of hospitalized children)

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 31
Clin Infect Dis 2011 Oct;53(7):e25-e76. PubMed PMID: 21880587 (*denotes that Bradley, Byington,

and Shah are co-listed as first authors)

b. Florin TA, Byczkowski T, Ruddy R, Zorc JJ, Test M, Shah SS. Variation in management of bronchiolitis

persists after the 2006 AAP bronchiolitis guidelines. J Pediatr 2014

c. Florin TA, French B, Zorc JJ, Alpern ER, Shah SS. Variation in emergency department diagnostic

testing and disposition outcomes in children with community-acquired pneumonia. Pediatrics 2013

Aug;132(2):237-244. PubMed PMID: 23878049

d. Morse RB, Hall M, Fieldston ES, McGwire G, Anspacher M, Sills MR, Williams K, Oyemwense N, Mann

KJ, Simon HK, Shah SS. Hospital-level compliance with asthma care quality measures at children's

hospitals and subsequent asthma-related outcomes. JAMA. 2011 Oct 5;306(13):1454-60. PubMed

PMID: 21972307. 

2. Implementing evidence is essential to improving hospital-based care. I have led or been a part of work in

this area, focusing on understanding barriers and challenges to implementing evidence-based guidelines,

specifically around bronchiolitis and pneumonia, identify approaches to overcome such barriers.

a. Neuman MI, Hall M, Hersh AL, Brogan TV, Parikh K, Newland JG, Blaschke AJ, Williams DJ, Grijalva

CG, Tyler A, Shah SS. Influence of hospital guidelines on management of children hospitalized with

pneumonia. Pediatrics. 2012 Nov;130(5):e823-30. PubMed PMID: 23090342. 

b. Mittal V, Hall M, Morse R, Wilson KM, Mussman G, Hain P, Montalbano A, Parikh K, Mahant S, Shah

SS. Impact of institutional bronchiolitis clinical practice guideline implementation on tests and

treatments. J Pediatr 2014 Sep;165(3):570-576. PubMed PMID: 24961787

c. Parikh K, Hall M, Mittal V, Montalbano A, Mussman GM, Morse RB, Hain P, Wilson KM, Shah SS. 

Establishing benchmarks for the hospitalized care of children with asthma, bronchiolitis, and

pneumonia. Pediatrics. 2014 Sep;134(3):555-62. PubMed PMID: 25136044. 

d. Ambroggio LV, Thomson J, Kurowski EM, Courter J, Statile A, Graham C, Sheehan B, Iyer S, Shah

SS, White CM. Quality improvement methods to increase appropriate antibiotic prescribing for

childhood pneumonia. Pediatrics 2013 May;131(5):e1623-e1631. PubMed PMID: 23589819

3. As Vice Chair of the Pediatric Research in Inpatient Settings (PRIS) Network, I have extensive experience

with conducting large multi-center studies that combine data from multiple sources, including the Pediatric

Health Information System. My work has demonstrated that early conversion from intravenous to oral

antibiotic therapy for bone infections is associated with fewer complications and no difference in treatment

failure compared with prolonged intravenous therapy. We also established new data sources for

comparative effectiveness research, including the Society of Thoracic Surgeons-Pediatric Health

Information System joint database and PHIS+, a database that combines administrative data from PHIS

with clinical data from 6 children’s hospitals. 

a. Keren R, Shah SS, Srivastava R, Rangel S, Bendel-Stenzel M, Harik N, Hartley J, Lopez M, Seguias

L, Tieder J, Bryan M, Gong W, Hall M, Localio R, Luan X, deBerardinis R, Parker A. Comparative

effectiveness of intravenous vs oral antibiotics for postdischarge treatment of acute osteomyelitis in

children. JAMA Pediatr. 2015 Feb;169(2):120-8. PubMed PMID: 25506733. 

b. Pasquali SK, Jacobs JP, Shook GJ, O’Brien SM, Hall M, Jacobs ML, Welke KF, Gaynor JW, Peterson

ED, Shah SS, Li JS. Linking clinical registry data with administrative data using indirect identifiers:

implementation and validation in the congenital heart surgery population. Am Heart J 2010

Dec;160(6):1099-1104. PubMed PMID: 21146664; PubMed Central PMCID: PMC3011979. 

c. Gouripeddi R, Warner PB, Mo P, Levin JE, Srivastava R, Shah SS, de Regt D, Kirkendall E, Bickel J, 

Korgenski EK, Precourt M, Stepanek RL, Mitchell JA, Narus SP, Keren R. Federating clinical data from

six pediatric hospitals: process and initial results for microbiology from the PHIS+ consortium. AMIA

Annu Symp Proc 2012 Nov;2012:281-290. PubMed PMID: 23304298; PubMed Central PMCID:

PMC3540481. 

d. Steenhoff AP, Josephs JS, Rutstein RM, Gebo KA, Siberry GK, GaurAH, Warford R, Korthuis PT,

Spector SA, Shah SS. Incidence of and risk factors for community-acquired pneumonia in US HIVinfected children, 2000-2005. AIDS 2011 Mar;25(5):717-720. PubMed PMID: 21252630; PubMed

Central PMCID: PMC3576877. 

4. Much of my work has focused in defining comparative effectiveness of treatments for childhood

pneumonia. This work has demonstrated that narrow-spectrum antibiotic therapy is effective and that

different pleural fluid drainage approaches for pleural empyema result in comparable outcomes. 

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 32
a. Shah SS, Hall M, Newland JG, Brogan TV, Farris RW, Williams DJ, Larsen G, Fine BR, Levin JE,

Wagener JS, Conway PH, Myers AL. Comparative effectiveness of pleural drainage procedures for the

treatment of complicated pneumonia in childhood. J Hosp Med. 2011 May;6(5):256-63. PubMed PMID:

21374798; PubMed Central PMCID: PMC3112472. 

b. Thomson J, Ambroggio L, Murtagh Kurowski E, Statile A, Graham C, Courter JD, Sheehan B, Iyer S, 

White CM, Shah SS. Hospital outcomes associated with guideline-recommended antibiotic therapy for

pediatric pneumonia. J Hosp Med 2015 Jan;10(1):13-18. PubMed PMID: 25263758; PubMed Central

PMCID: PMC4322863.

c. Ambroggio L, Taylor JA, Tabb LP, Newschaffer CJ, Evans AA, Shah SS. Comparative effectiveness of

empiric β-lactam monotherapy and β-lactam-macrolide combination therapy in children hospitalized

with community-acquired pneumonia. J Pediatr. 2012 Dec;161(6):1097-103. PubMed PMID: 22901738. 

d. Queen MA, Myers AL, Hall M, Shah SS, Williams DJ, Auger KA, Jerardi KE, Statile AM, Tieder JS.

Comparative effectiveness of empiric antibiotics for community-acquired pneumonia. Pediatrics. 2014

Jan;133(1):e23-9. PubMed PMID: 24324001. 

D. RESEARCH SUPPORT

Ongoing Research Support

2015/10/01-2017/9/30

Governor’s Office of the State of Ohio

Ramilo, O. (PI)

Children’s Hospitals Research Initiative in Pneumonia (CHIRP)

This project establishes a multicenter network of Ohio children’s hospitals to focus on developing novel

methods to identify etiology and predict illness severity in children with pneumonia. The main areas of focus

include transcriptional profiles, procalcitonin, and metabolomics.

Role: Site PI

2014/04/01-2019/03/31

R01 HL122261, National Heart Lung and Blood Institute

Pasquali, Sara K. (PI) 

Understanding quality and costs in congential heart surgery

This project applies advanced Bayesian methods to empirically combine information across multiple quality

domains to develop a composite quality metric in congenital heart surgery. The metric will be evaluated against

current quality indicators, as well as measures of resource utilization. 

Role: Co-I 

2014/05/01-2017/04/31

IHS-1306-00811, Patient-Centered Outcomes Research Institute

Shah, Samir S. (PI) 

Improving post-discharge outcomes by facilitating family-centered transitions from hospital to home

The goal is to improve the outcomes of inpatient to outpatient transitions for hospitalized children and their

families. The study uses qualitative methods to identify barriers to the transition home, implementation

methods to ensure that a nurse home visit addresses those barriers, and a randomized controlled trial to

determine the efficacy of nurse home visits in improving patient transitions.

Role: PI

2011/10/01-2016/09/30

U19 HS021114, Agency for Healthcare Research and Quality

Lannon, Carole (PI) 

Center for Education on Research and Therapeutics (CERTs) Research Center

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 33
The Centers for Education and Research on Therapeutics (CERTs) program is a national initiative to increase

awareness of the benefits and harms of new, existing, or combined uses of therapeutics (drugs, medical

devices, and biological products) through education and research. 

Role: Co-I 

Recently Completed Research Support 

2013/01/02-2016/01/01

Cycle 2, Patient-Centered Outcomes Research Institute

Keren, Ron (PI) 

Comparative effectiveness of home intravenous vs. oral antibiotic therapy for serious bacterial infections. 

Role: Site PI

2015/03/11-2015/09/12

Hirschfeld, S. (PI)

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Medical Science and Computing Consulting Agreement: Pediatric Terminology Harmonization InitiativePediatric Infectious Diseases

The goal of this contract was to create a rigorously defined group of “controlled” or “harmonized” terminologies

to facilitate communication of research efforts. This particular project focused on ~600 terms used in pediatric

infectious diseases. 

Role: Working Group Co-Lead

2013/07/01-2015/06/30

N/A, Place Outcomes Research Award

Shah, Samir S. (PI) 

Reducing variability in the management of children with community-acquired pneumonia

This multicenter study includes 10 pediatric office practices with a goal of implementing the national childhood

pneumonia guideline outpatient recommendations and measuring the association between adherence and

patient outcomes.

Role: PI

2013/07/01-2015/06/30

N/A, Place Outcomes Research Award

Schaffzin, Joshua K. (PI) 

Surgical site infection prevention continuum development

This study implements pre- and post-operative standardize approaches to pre- and post-operative infection

prevention and systematic information transfer across the continuum of surgical care spanning the pre-, intra-, 

and post-operative periods with a goal of decreasing surgical site infections. 

Role: Co-PI

2010/09/01-2015/01/31

R01 HS019862, Agency for Healthcare Research and Quality

Keren, Ron (PI) 

PHIS+: Augmenting the Pediatric Health Information System with clinical data

This project created an infrastructure for comparative effectiveness research by merging administrative data

from the Pediatric Health Information System with clinical, laboratory, microbiology, and radiology data from 6 

of the largest children's hospitals in the U.S. The database includes information on more 1 million hospitalized

children.

Role: Site PI

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 34
Contact PD/PI: Ambroggio, Lilliam

OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES.

NAME: Maurizio Macaluso

eRA COMMONS USER NAME (credential, e.g., agency login): 

POSITION TITLE: Professor and Director, Division of Biostatics and Epidemiology

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency 

training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION

DEGREE

(if 

applicable)

Completion 

Date

MM/YYYY

FIELD OF STUDY

University of Palermo, Italy M.D. 1979 Medicine and Surgery

University of Palermo, Italy Residency 1982 Hygiene and Preventive 

Medicine

University of Alabama at Birmingham Dr. P.H. 1991 Epidemiology

A. Personal Statement

As the Director of the Division of Biostatistics and Epidemiology of Cincinnati Children Hospital Medical Center 

(CCHMC) and the co-director of the Biostatistics, Epidemiology and Research Design Core of the Center for 

Clinical and Translational Research and Training I have been able to and will continue to contribute 

methodological expertise to Dr. Ambroggio’s training plan and current research proposal. I have over 30 years’ 

worth of content and methodological expertise in biomedical, public health and epidemiological research. My 

work has touched immunology, epidemiologic research methods, and infectious disease epidemiology. I have 

acted as a mentor for basic bench scientists and behavioral and social scientists, including masters’ and 

doctoral-level students, post-doctoral fellows and junior scientists. I have done so in academic institutions, in 

government agencies and in four continents. Dr. Ambroggio’s proposal is well aligned with our Division’s vision 

of “Big Data for Little Children,” bringing high-dimensional data from areas such as –omics research from the 

bench to the bedside to the community, in what is the ideal trajectory of translational science applied to child 

health.

B. Positions and Honors

2011-Present: Professor (tenured), Department of Pediatrics, University of Cincinnati College of Medicine;

 Director, Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical 

 Center, Cincinnati, OH 

2000-2011: Chief, Women’s Health and Fertility Branch, Division of Reproductive Health, National Center 

for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and 

 Prevention, Atlanta, GA (CDC)

2000-2003 Professor (tenured), Department of Epidemiology and International Health, School of Public 

Health, University of Alabama at Birmingham, Birmingham, AL (UAB) (Leave of absence 

3/14/01-3/13/03) 

1994-2000 Associate Professor (tenured), Department of Epidemiology and International Health, School of 

 Public Health, UAB 

1991-1994 Assistant Professor, Department of Epidemiology, School of Public Health, UAB

Secondary Appointments

2012-Present Professor, Department of Environmental Health, University of Cincinnati College of Medicine, 

Cincinnati, OH

2011-Present Director, Biostatistics, Epidemiology and Research Design Core, Center for Clinical and 

Translational Science and Training, University of Cincinnati, Cincinnati, OH

Biosketches Page 35
1998 - 2001 Co-Director, UAB Center for Contraceptive Development and Technology Transfer

1994 - 2001 Scientist, UAB Comprehensive Cancer Center

1991 - 1994 Associate Scientist, UAB Comprehensive Cancer Center 

1997 - 2001 Scientist, UAB Center for AIDS Research

1997 - 2001 Scientist, UAB Center for Health Promotion

1996 - 2001 Scholar, John J. Sparkman Center for International Public Health Education

1995 - 2001 Associate Professor, Division of Geographic Medicine, Department of Medicine, School of 

Medicine

Adjunct Appointments 

2007-2012 Visiting Professor, Department of Hygiene and Preventive Medicine, University of Palermo, 

 Palermo, Italy

2003-2012 Adjunct Professor, Department of Epidemiology, Rollins School of Public Health. Emory 

 University, Atlanta, GA 

2003-Present Adjunct Professor, Department of Epidemiology, School of Public Health, UAB

2000-2011 Senior Fellow, WHO/CDC Collaborative Center on Reproductive Health

2000 Guest Professor, School of Public Health, Shandong University, Jinan, Shandong Province,

People’s Republic of China

Honors and Awards 

1979 Summa Cum Laude Graduation in Medicine and Surgery 

1979 Fellow, American College of Epidemiology 

1997, 1998 UAB President’s Award for Excellence in Teaching: Nominated

2006 33rd Annual Federal Employee of the Year– Outstanding Team Award (with the National 

 Assisted Reproductive Technology Surveillance System Team) – Nominated

2006 Charles C. Shepard Science Award for Assessment and Epidemiology 

2009 CDC/ATSDR Award for Employee Motivation and Development – Nominated

2009 American Fertility Association Illuminations Award 

C. Contribution to Science

1. I began my career in cancer epidemiology at the National Tumor Institute in Milan, Italy, where I gained 

experience in cancer registration and became interested in occupational carcinogenesis and in the etiology 

of neoplasms of the reproductive organs. With investigators in Italy and Canada, I worked on refining "jobexposure matrices." I also worked on breast cancer with clinical oncologists, and documented a relation 

between parity and younger age at diagnosis in a large case series. 

a) Macaluso M, Tamburini M, Massara G, Bertario L, Di Pietro S. Parity and breast cancer: confirmed 

evidence of an effect on age at diagnosis. Breast Cancer Res Treat. 1982; 2(3):257-60. 

b) Macaluso M, Vineis P, Continenza D, Ferrario F, Pisani P, Audisio R. Job/exposure matrices: 

experience in Italy. In Acheson ED (Ed.): Job exposure matrices. Conference Report. M.R.C. 

Environmental Epidemiology Unit Scientific Report No 2, Southampton 1983, 22-29.

c) Pisani P, Berrino F, Macaluso M, Pastorino U, Crosignani P, Baldasseroni A. Carrots, green 

vegetables and lung cancer: a case-control study. Int J Epidemiol. 1986 Dec;15(4):463-8.

d) Berrino F, Vigano' C, Gatta G, Crosignani P, Pisani P, Macaluso M. Italy, Lombardy Region, Varese 

Province. In Muir C, Waterhouse J, Mack T, Powell J, Whelan S, (Eds.): Cancer Incidence in Five 

Continents Vol. V. IARC Sci. publ. 88. International Agency for Research on Cancer, Lyon 1987, 560-

565.

2. At the University of Alabama at Birmingham (UAB) I worked in a series of cohort studies of the mortality 

of workers in chemical, petrochemical, and automobile manufacturing plants in the USA. These studies 

showed that workplace exposure to carcinogens makes subgroups of workers prone to developing 

malignant neoplasms. I developed methods for retrospective exposure assessment that were used in a 

study of workers employed in synthetic rubber manufacturing, potentially exposed to 1,2-butadiene and 

styrene. This research documented a dose-dependent association between exposure to butadiene and 

mortality from leukemia, providing the evidence base for lowering of the permissible exposure limit in the 

USA to 1 ppm. 

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 36
a) Delzell E, Macaluso M, Cole P. A follow-up study of workers at a dye and resin manufacturing 

plant. J Occup Med. 1989 Mar;31(3):273-8.

b) Macaluso M, Delzell E, Cole P, Wongsrichanalai C, Cowles S. Validity of a mortality study based 

on a corporate health surveillance system. J Occup Med. 1991 Nov;33(11):1180-6.

c) Macaluso M, Delzell E, Rose V, Perkins J. Use of organic solvents and potential worker exposure 

in the motor vehicle manufacturing industry. Am J Ind Med. 1993 Mar;23(3):449-60.

d) Macaluso M, Larson R, Delzell E, Sathiakumar N, Hovinga M, Julian J, Muir D, Cole P. Leukemia 

and cumulative exposure to butadiene, styrene and benzene among workers in the synthetic rubber 

industry. Toxicology. 1996 Oct 28;113(1-3):190-202.

e) Macaluso M, Larson R, Lynch J, Lipton S, Delzell E. Historical estimation of exposure to 1,3-

butadiene, styrene, and dimethyldithiocarbamate among synthetic rubber workers. J Occup 

Environ Hyg. 2004 Jun;1(6):371-90.

3. At UAB I also worked on collaborative research on the role of folic acid deficiency in the development of 

preneoplastic lesions of the uterine cervix. Human papillomavirus (HPV) was just beginning to be

recognized as a cause of cervical cancer. In a case-control study published in JAMA in 1992 we 

documented that low red blood cell folate levels greatly enhanced the ability of HPV-16 to produce cervical 

dysplasia. In the following two decades I collaborated with Dr. Piyathilake in a number of studies. In the 

aggregate, this research has produced evidence that methyl-donor micronutrients are associated with 

reduced risk of HPV infection, faster clearance, and reduced severity/progression of HPV-related cervical 

lesions. 

a) Butterworth CE Jr, Hatch KD, Macaluso M, Cole P, Sauberlich HE, Soong SJ, Borst M, Baker VV. 

Folate deficiency and cervical dysplasia. JAMA. 1992 Jan 22-29; 267:528-33.

b) Piyathilake CJ, Henao O, Frost AR, Macaluso M, Bell WC, Johanning GL, Heimburger DC, 

Niveleau A, Grizzle WE. Race- and age-dependent alterations in global methylation of DNA in 

squamous cell carcinoma of the lung (United States). Cancer Causes Control. 2003 Feb; 14:37-42

c) Piyathilake CJ, Henao OL, Macaluso M, Cornwell PE, Meleth S, Heimburger DC, Partridge EE. 

Folate is associated with the natural history of high-risk human papillomaviruses. Cancer Res. 2004 

Dec 1;64:8788-93. 

d) Piyathilake CJ, Macaluso M, Alvarez RD, Chen M, Badiga S, Edberg JC, Partridge EE, Johanning 

GL: A higher degree of methylation of the HPV 16 E6 gene is associated with a lower likelihood of 

being diagnosed with cervical intraepithelial neoplasia. Cancer, 2011 Mar 1; 117(5):957-63.

4. While at UAB, I took the scientific lead on a prospective study of barrier contraception for the prevention 

of sexually transmitted diseases funded by NICHD. As the HIV pandemic was rapidly growing, the 

development of effective barrier methods and of interventions to promote their use was very important for 

public health. I led a research program that encompassed the development and evaluation of behavioral 

interventions, the development of new methods to address the methodological limitations that plague 

condom effectiveness research, and studies of the acceptability, safety and efficacy of barrier methods. 

Some of the research funding came from the Division of Reproductive Health at CDC, which later selected 

me for the position of Chief, Women’s Health and Fertility Branch. At UAB and at the CDC, I pioneered the 

development of new objective biomarkers of sexual activity and condom failure, which today are 

increasingly recognized for their importance in evaluating new barrier methods by standard setting 

organizations like the International Standards Organization (ISO). 

a) Macaluso M, Lawson L, Akers R, Valappil T, Hammond K, Blackwell R, Hortin G. Prostate-specific 

antigen in vaginal fluid as a biologic marker of condom failure. Contraception. 1999 Mar; 59(3):195-

201

b) Macaluso M, Kelaghan J, Artz L, Austin H, Fleenor M, Hook EW 3rd, Valappil T. Mechanical 

failure of the latex condom in a cohort of women at high STD risk. Sex Transm Dis. 1999 Sep;

26(8):450-8 

c) Macaluso M, Demand MJ, Artz LM, Hook EW 3rd. Partner type and condom use. AIDS. 2000 Mar 

31; 14(5):537-46. 

d) Macaluso M, Blackwell R, Jamieson DJ, Kulczycki A, Chen MP, Akers R, Kim D-j, Duerr A. 

Efficacy of the male latex condom and of the female polyurethane condom as barriers to semen 

during intercourse: a randomized clinical trial. Am J Epidemiol, 2007; 166(1):88-96.

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 37
5. Children conceived using Assisted Reproductive Technology (ART) comprise 1.5% of U.S. children, but 

>15% of multiple births. Multiple birth is associated with poor infant and maternal health outcomes; there is 

evidence of increased risks for ART-conceived singletons. At the CDC, I oversaw the National ART 

Surveillance System, the publication of the Annual ART Success Rates Report, collaborated with state 

health departments in evaluating adverse outcomes of ART, and conducted research on ART effectiveness 

and safety. Infertility likely affects over 7 million U.S. couples, with medical costs likely exceeding $5 

billion. I formed and led a CDC-wide working group to improve coordination around reducing the burden of 

infertility in the US. With the working group I developed a white paper on the need for a national public 

health strategy for prevention, and diagnosis and management of infertility, coordinated a national 

symposium held in Atlanta in 2008, and drafted the “Outline of a National Action Plan for the Prevention, 

Detection and Management of Infertility” which made the basis for the National Action Plan released by the 

Department of Health and Human Services in 2014. 

a) Boulet SL, Schieve LA, Nannini A, Ferre C, Devine O, Cohen B, Zhang Z, Wright V, Macaluso M. 

Perinatal outcomes of twin births conceived using assisted reproduction technology: a populationbased study. Hum Reprod 2008; 23:1941-8.

b) Macaluso M, Wright-Schnapp TJ, Chandra A, Johnson R, Satterwhite CL, Pulver A, Berman SM, 

Wang RY, Farr SL, Pollack LA. A public health focus on infertility prevention, detection, and 

management. Fertil Steril 2010 Jan; 93(1):16.e1-10. 

c) Sauber-Schatz EK, Sappenfield W, Grigorescu V, Kulkarni A, Zhang Y, Salihu HM, Rubin LP, Kirby 

RS, Jamieson DJ, Macaluso M. Obesity, assisted reproductive technology, and early preterm birth-

-Florida, 2004-2006. Am J Epidemiol. 2012 Nov 15; 176(10):886-96. 

d) Kulkarni AD, Jamieson DJ, Jones HW, Jr., Kissin DM, Gallo MF, Macaluso M, Adashi EY. The 

Multiple Births Epidemic: Evolving Role of Assisted Reproductive Technology and Ovulation 

Induction and Ovarian Stimulation. N Engl J Med 2013; 369:2218-25.

Complete List of Published Work in MyBibliography: 

http://www.ncbi.nlm.nih.gov/sites/myncbi/1Z_FwlwSVl_5-

/bibliograpahy/47572367/public/?sort=date&direction=ascending

D. Research Support

ACTIVE

ULRRR026314 (Heubi) 07/01/2015 – 06/30/2020 

CCTST/UC 

“Clinical and Translational Science Award (BERD)” 

This is the national consortium of medical research institutions, funded through Clinical and Translational

Science Awards (CTSAs), which is working together to: 

- Improve the way biomedical research is conducted across the country

 - Reduce the time it takes for laboratory discoveries to become treatments for patients

 - Engage communities in clinical research efforts

 - Train the next generation of clinical and translational researchers

Role: Director/Co-Director of BioMetrics Core 

1R21OH010035-01A1 (Daraiseh) 09/1/2013 – 08/31/2016 

CDC NIOSH

Just-In-Time Methods for Understanding Near-Misses, Injuries and Risk Factors

Goal: The study’s objectives are to: determine the frequency and type of near-misses and injuries among PHCPs 

and assess the feasibility of using a real-time data collection method as the basis for active injury surveillance in 

healthcare organizations. A secondary objective is to assess the relationship of individual and work factors with 

these events.

Role: Co-Investigator

(Kim, Macaluso, Liu, Zou) 01/01/2015 – 12/31/2018 

PCORI 

Propensity Score-based Methods for CER Using Multilevel Data: What Works Best When

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 38
Goal: To investigate how to optimally extend the PS methodology and identify what works best when. An 

additional goal is to develop a novel imputation-based sensitivity analysis approach and to identify valid and 

most efficient PS methods for two existing CER studies.

Role: Co-Investigator

T32DK007695 (Devarajan) 07/01/2014 – 06/30/2019

Research Training in Pediatric Nephrology

Goal: To foster the development of outstanding clinical or basic science physician investigator and leaders 

who will meet the tremendously underserved academic workforce needs in Pediatric Nephrology.

Role: Mentor

K23 (Reed) 05/01/2014 – 04/30/2018

NIH

Decreasing teen STI prevalence through universal emergency department screening 

Goal: The objective of this proposal is to design and test the feasibility and effectiveness of a universal CT/GC 

screening program in the ED.

Role: Mentor

COMPLETED

Place Outcomes (Daraiseh) 09/01/2013 – 06/30/2014

CCHMC Place Outcomes

Surveillance of Psychiatric Patients to Improve Safety

Goal: We will evaluate patient and staff safety with a novel evidenced-based approach by introducing cameras 

in psychiatric patient’s rooms to monitor potentially harmful behavior.

Role: Co-Investigator 

Thrasher Research Fund (Ambroggio) 02/01/2012 – 01/31/2014

CCHMC 

Diagnostic Tools for Detecting Pneumonia in Children

Goal: The objective of the proposed study is to determine whether chest ultrasound is a more accurate 

diagnostic tool in detecting pneumonia in children than chest x-rays.

Role: Co-Investigator 

UL1TR000077 (Heubi-Tsevat) 04/03/2009 – 03/31/2015 

National Center for Research Resources 

“Center for Clinical and Translational Science and Training”

This is the national consortium of medical research institutions, funded through Clinical and Translational 

Science Awards (CTSAs). This NIH sponsored center supports clinical research on campus. 

- Improve the way biomedical research is conducted across the country

 - Reduce the time it takes for laboratory discoveries to become treatments for patients

 - Engage communities in clinical research efforts

 - Train the next generation of clinical and translational researchers

Role: Director of Biostatistics, Epidemiology and Research Design Core

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 39
Contact PD/PI: Ambroggio, Lilliam

OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018) 

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES.

NAME: Ruddy, Richard Michael

eRA COMMONS USER NAME (credential, e.g., agency login):

POSITION TITLE: Professor of Pediatrics, University of Cincinnati College of Medicine, Medical Director, 

Cincinnati Children’s Hospital – Liberty Campus

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, 

include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION DEGREE

(if applicable)

Completion 

Date

MM/YYYY

FIELD OF STUDY

University of Notre Dame BS 05/1972 Pre-Professional Studies

Georgetown University School of Medicine MD 05/1976 MD

Children’s Hospital of Philadelphia Resident

Chief Resident

06/1980 Pediatrics

A. Personal Statement

This past decade I have worked within the University of Cincinnati and Cincinnati Children’s Hospital Medical 

Center (CCHMC) to bring together three important interests: (a) leading our institution and Emergency Medicine 

(EM) in multi-center research through the Pediatric Emergency Care Applied Research Network (PECARN), (b) 

mentoring junior faculty and fellows and (c) advancing the content area of respiratory illness in infants and 

children. Within PECARN, my role has progressed from the CCHMC site PI for the first 10 years, to the PI for a 

three-hospital node comprised of CCHMC, Milwaukee Children’s Hospital and St. Louis Children’s Hospital, to 

Chair of the PECARN Steering Committee. The themes critical to our nodal success are our work on knowledge 

implementation and dissemination, new discovery to advance the health of children, mentoring the next 

generation of pediatric emergency researchers and partnership with the community in advancing children’s 

health. CCHMC has been one of the most productive sites in subject recruitment for network-wide studies and 

has made outstanding contributions to over 80 published manuscripts. We have strengthened our divisional 

improvement science work within CCHMC, and are well known for demonstrating high performance on improving 

the health care delivery system for children. Within the network we assembled a team of highly qualified clinicianscientists and mentors for junior faculty.

For the past three years I have been one of two senior mentors for Lilliam Ambroggio, PhD, MPH and Todd 

Florin, MD, MSCE on studies investigating lower respiratory tract infections. This team has been very successful 

at building a strong infrastructure in the ED and inpatient setting for patient enrollment, prospective clinical data 

collection and biological specimen collection to answer important questions regarding pneumonia etiology and 

severity. In addition to our work at CCHMC we are partnering with 6 children’s hospitals within Ohio funded by 

the Governor’s Fund of Ohio to expand our current pneumonia study and to propose a multicenter study through 

PECARN. As one of Dr. Ambroggio’s research mentors, I will provide oversight for her research and career 

development activities. Lastly, I believe that my commitment to partnerships within our academic and local 

community has helped to generate vital connections that improve the success of clinical research. The Division 

of EM has long supported work to improve the outcomes for children in our community and throughout the 

country and therefore we are supportive of Dr. Ambroggio and her proposal.

B. Positions and Honors

1980-81 Lecturer in Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA

1981-85 Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia

1985-89 Assistant Professor of Pediatrics, New York Medical College, Valhalla, NY

Biosketches Page 40
1989-91 Associate Professor of Pediatrics, New York Medical College, Valhalla, NY

1991-15 Director, Emergency Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

1991-96 Associate Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH

1996- Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH

2015- Medical Director, Cincinnati Children’s Hospital Medical Center – Liberty Campus

Other Experience and Professional Memberships

1975- Alpha Omega Alpha Honor Society

1986-92 Board Certification - American Board of Pediatrics; Subspecialty - Pediatric Pulmonology

1992- Board Certification - Subspecialty - Pediatric Emergency Medicine (Recertification 1998, 2006)

1992-97 Member, Emergency Medical Services Board, Ohio - Trauma Advisory Group Subcommittee. 

1993-2004 Member, American Academy of Pediatrics - Executive Committee

Section of Emergency Medicine, 1993-1995 and 1997-2000

Chair: 2000-2002, Past Chair: 2002-2004

1993-2003 Member, Academy of Medicine Emergency & Disaster Committee

1996-1997 Physician Leadership Program, Cincinnati Ohio

1997-2013 Medical Advisory Committee - Hamilton County Injury Surveillance System

Medical Director: 2002-2012

1998-2002 Chair, Pediatric Emergency Medicine Directors SIG, Ambulatory Pediatric Association

2004- Grant Reviewer, HRSA/MCHB, EMSC Targeted Issues Grants

2007-2008 Improvement Science Course completion, CCHMC

2007-2010 Member, City of Cincinnati Board of Health, Cincinnati, OH

2009- Member, American Pediatric Society

2010- Grant Reviewer – CCHMC Place Outcome Awards

2011- CCTST Community Grants and Research Committee

2009-2011 Society of Academic Emergency Medicine – Aging and Generational Issues in Academic 

Emergency Medicine Task Force

2011-2012 Office of Maternal and Infant Health and Infant Mortality Reduction Board

2011-2015 Vice Chair, Steering Committee, Pediatric Emergency Care Applied Research Network

2015- Chair, Steering Committee, PECARN

Honors 

1999, 00, 04, Division Teaching Award Pediatric Resident, CCHMC 

06, 10, 12, 15

2001 Mead Johnson Excellence in Teaching Award

2004 Pediatric Golden Apple Award – Faculty Teaching Award – UC Dept. of Emergency Medicine

2009 Cincinnati Pediatric Society – 2009 Founder’s Award Recipient

2010 AAP James Seidel Section of Emergency Medicine Distinguished Service Award

2016 CCHMC Faculty Service Award

C. Contribution to Science

1. Emergency Department Health Care Improvement – From 1991 until now, I have had a firm commitment 

to improve the quality of care provided to children in the ED. At Cincinnati Children’s, we strive to become the 

best pediatric health system at improving outcomes for children. As a Division Director, I sought to ensure that 

our emergency services could be at the core of that work, in both assessment of quality and variation of care 

and implementation of evidence-based guidelines. Within the Pediatric Emergency Care Applied Research 

Network (PECARN), I have been a senior investigator involved in helping to better understand safety in the ED 

and in the development of quality measures. Our work has led to important system-based improvements to the 

care provided, in addition to providing me an opportunity to mentor a generation of PEM providers who now 

are leaders in health care improvement science in pediatric emergency medicine. 

Perlstein PH, Lichtenstein P, Cohen MB, Ruddy RM, Schoettker PJ, Atheron HD, Kotagal U: Implementing an 

evidence-based acute gastroenteritis guideline at a children's hospital. Jt Comm J Qual Improv. 2002; 

28(1):20-30. PMID: 11787237

Alessandrini E, Varadarajan K, Alpern ER, Gorelick MH, Shaw K, Ruddy RM, Chamberlain JM, for the 

Pediatric Emergency Care Applied Research Network: Emergency Department Quality: An Analysis of Existing 

Pediatric Measures. Academic Emergency Medicine. 2011; 18(5):519-26. PMID: 21569170

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 41
Ruddy RM, Mace SE, Shaw K, Percelay J: Pediatric emergency care in community hospitals with nonpediatric emergency medicine providers. Pediatr Emerg Care. 2008; 24(8):582-5. PMID: 18708908

Timm NL, Ruddy RM: Demographics of patient visits during high daily census in a pediatric ED. Am J Emerg 

Med. 2010; 28(1):56-60. PMID: 20006202

2. Pediatric Respiratory Illnesses – In the early part of my career, my professional activities and interests 

included both Pediatric Pulmonology and Pediatric Emergency Medicine. This early exposure to both fields led 

to an academic interest and scholarly output in acute and chronic pediatric respiratory illness. My early 

experiences with the cystic fibrosis population at The Children’s Hospital of Philadelphia formed the basis for 

much of my subsequent work in the ED setting. One of my early clinical trials found nebulized metaproterenol 

more effective than subcutaneous epinephrine in acute asthma exacerbation, which contributed to the 

increased use of aerosolized medications for asthma that is now the standard of care. Since that trial, I have 

collaborated with investigators studying resource utilization and novel diagnostics and therapeutics in asthma, 

bronchiolitis, croup and pneumonia. 

Ruddy RM, Kolski G, Scarpa N, Wilmott R: Aerosolized metaproterenol compared to subcutaneous 

epinephrine in the emergency treatment of acute childhood asthma. Pediatr Pulmonol. 1986; 2(4):230-6. 

PMID: 3532010

Luria, JW, Gonzalez del Rey JA, DiGiulio GA, McAneney CM, Olson JJ, Ruddy RM: Effectiveness of oral or 

nebulized dexamethasone for children with mild croup. Arch Pediatr Adol Med. 2001; 155(12):1340-5. PMID: 

11732953

Stevenson MD, Heaton PC, Moomaw CJ, Bean JA, Ruddy RM. Inhaled corticosteroid use in asthmatic 

children receiving Ohio Medicaid: trend analysis, 1997-2001. Ann Allergy Asthma Immunol. 2008; 100(6):538-

44. PMID: 18592816

Florin TA, Byczkowski T, Ruddy RM, Zorc JJ, Test M, Shah SS: Variation in the Management of Infants 

Hospitalized for Bronchiolitis Persists after the 2006 American Academy of Pediatrics Bronchiolitis 

Guidelines. J Pediatr. 2014; 165(4):786-92. PMID: 25015578

Florin TA, Byczkowski T, Ruddy RM, Zorc JJ, Test M, Shah SS: Utilization of nebulized 3% saline in infants 

hospitalized with bronchiolitis. J Pediatrics 2015 May; 166(5): 1168-1174.e2 doi:10.1016/j.jpeds.2015.01.045. 

Epub 2015 Mar 4. PMID: 25747800

3. Diagnosis of the Febrile Child in the Emergency Department – Fever is one of the most common 

reasons for ED visits in infants and young children. Often, it is difficult to determine if a fever is the result of a 

benign viral infection or due to a potentially devastating bacterial illness, such as meningitis or bacteremia. In 

the era before the pneumococcal conjugate vaccine, invasive pneumococcal disease (IPD) was prevalent. 

Some of my early collaborative work in this area focused on diagnostics to detect S. pneumoniae. As vaccines 

were developed and IPD decreased, my focus in this area shifted to focusing testing on those with increased 

risk of serious infection, thereby decreasing resource use in those who are at low-risk. Some of this work is 

ongoing through my work in PECARN. I was the site PI of two R01 funded multicenter studies to determine the 

utility of biomarkers and RNA microarray technology in improving the diagnosis of serious bacterial infection in 

the febrile neonate. The second study just initiated funding and enrollment. 

Mahajan P, Kuppermann N, Suarez N et al and the Febrile Infant Working Group for the Pediatric Emergency 

Care Applied Research Network (PECARN). RNA transcriptional biosignatures analysis for identifying febrile 

infants with serious bacterial infections in the emergency department: a feasibility study. Pediatr Emerg Care. 

2015; 31(1):1-5. PMID: 25526020

Friedland LR, Menon AG, Reising SF, Ruddy RM, Hassett DJ: Development of a polymerase chain reaction 

assay to detect the presence of streptococcus pneumoniae DNA. Diagn Microbiol Infect Dis. 1994; 20(4):187-

93. PMID: 7705031

Strait RT, Ruddy RM, Friedland LR, Duncan KM, Wilmott RW: A pilot study of the predictive value of plasma 

tumor necrosis factor α and interleukin 1β for streptococcus pneumoniae bacteremia in febrile children. Acad 

Emerg Med. 1997; 4(1):44-51. PMID: 9110011

Iyer SB, Gerber MA, Pomerantz WJ, Mortensen JE, Ruddy RM. Effect of point-of-care influenza testing on 

management of febrile children. Acad Emerg Med. 2006; 13(12):1259-68. PMID: 17079787

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 42
4. Patient Safety in the Emergency Department – Both our safety efforts at CCHMC and a PECARN 

working group began to further focus our local and network efforts on patient safety in emergency services. 

With infrastructure support locally and the team’s efforts we began an important element of safety through ED 

infrastructure, culture change, crew resource management (through high fidelity simulation) to help us make 

the ED the safest they can be. This is a true team effort with high reliability organization characteristics and 

accountability to each other and more reliable systems in our departments. 

Ruddy RM, Patterson MD: Medical simulation: a tool for recognition of and response to risk. Pediatr Radiol. 

2008; 38(S4):S700-6. PMID: 18810414

Chamberlain JM, Shaw KN, Lillis KA, Mahajan PV, Ruddy RM, Lichenstein R, Olsen CS, Dean JM: Creating 

an Infrastructure for Safety Event Reporting and Analysis in a Multicenter Pediatric Emergency Department 

Network. Pediatr Emerg Care. 2013 Feb; 29(2):125-30. PMID: 23364372

Shaw KN, Lillis KA, Ruddy RM, Mahajan PV, Lichenstein R, Olsen CS, Chamberlain JM, for the Pediatric 

Emergency Care Applied Research Network (PECARN): Reported Medication Events in a Paediatric 

Emergency Research Network: Sharing to Improve Patient Safety. Emerg Med J. 2013 Oct: 30 (10):815-9. 

PMID: 23117714 

Shaw KN, Ruddy RM, Olsen CS, Lillis KA, Mahajan PV, Dean JM, Chamberlain JM: Pediatric patient safety in 

emergency departments: unit characteristics and staff perceptions. Pediatrics. 2009; 124(2):485-93.

Ruddy RM, Chamberlain JM, Mahajan PV, Funai T, O’Connell KJ, Blumberg S, R Lichenstein, HL Gramse, KN 

Shaw, Pediatric Emergency Care Applied Research Network (PECARN): Near Misses & Unsafe Conditions 

Reported in a Pediatric Emergency Research Network. BMJ Open 2015; 5:e007541. doi:10.1136/bmjopen-2014-

007541

5. Multicenter Pediatric Emergency Research – As a member of the Pediatric Emergency Medicine 

Collaborative Research Committee of the American Academy of Pediatrics I fostered research partnerships 

across many pediatric emergency medicine programs. An extension of that, in 2001 I was recruited to be the 

site PI of one of the original 25 sites in PECARN. As the PI for CCHMC, I became heavily focused on building 

the research infrastructure to produce quality work in the trials, as well as ensuring that junior faculty had 

sufficient mentoring to succeed in this important work. We were the leading site in the clinical trial evaluating 

the effectiveness of corticosteroids in bronchiolitis, published in the New England Journal of Medicine. Since

2011, I have been the nodal PI for the Midwest Emergency Node of CCHMC, Children’s Hospital of Wisconsin 

and St. Louis Children’s Hospital. Currently I serve as the Chair of the PECARN Steering Committee. The 

robust infrastructure that we built for clinical research also enabled us to collaborate outside of PECARN in 

other important studies, including the use of biomarkers helping to predict early appendicitis. 

Corneli HM, Zorc JJ, Majahan P, Shaw KN, Holubkov R, Reeves SD, Ruddy RM, et al. A multicenter, 

randomized, controlled trial of dexamethasone for bronchiolitis. NEJM. 2007; 357(4):331-9. PMID: 17652648

Stanley R, Lillis KA, Zuspan SJ, Lichenstein R, Ruddy RM, Gerardi MJ, Dean JM: Development and 

implementation of a performance measure tool in an academic pediatric research network. Contemp Clin 

Trials. 2010; 31(5):429-437. PMID: 29478406

Mills AM, Huckins DS, Kwok H, Baumann BM, Ruddy RM, Rohman RE, Schrock JW, Lovecchio F, Krief WI, 

Hexdall A, Caspari R, Cohen B, Lewis RJ: Diagnostic Characteristics of S100A8/A9 in a Multicenter Study of 

Patients with Acute Right Lower Quadrant Abdominal Pain. Acad Emerg Med. 2012 Jan; 19(1):48-55. PMID: 

22221415 

Ruddy RM, Chamberlain JM, Mahajan PV, Funai T, O’Connell KJ, Blumberg S, R Lichenstein, HL Gramse, KN 

Shaw, Pediatric Emergency Care Applied Research Network (PECARN): Near Misses & Unsafe Conditions 

Reported in a Pediatric Emergency Research Network. BMJ Open 2015;5 (9):e007541. PMID: 26338681. 

Glass T, Ruddy RM, Alpern E, Gorelick M, Callahan J, Lee L, Gerardi M, Melville K, Miskin M, Holmes J, 

Kuppermann N, Pediatric Emergency Care Applied Research Network (PECARN): Traumatic Brain Injuries and 

Computed Tomography Use in Pediatric Sports Participants. American Journ Emerg Med 2015; 33(10):1458-64. 

PMID: 26256635.

Complete List of Published Work in My 

Bibliography: http://www.ncbi.nlm.nih.gov/sites/myncbi/1FOK6BiuoIZAK/bibliography/48626594/public/?sort=

date&direction=ascending

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 43
Contact PD/PI: Ambroggio, Lilliam

D. Research Support

Ongoing Research Support

1 U03MC22684-01-00 Ruddy, RM (PI) 

09/01/15 – 08/31/19

HRSA

EMSC: Network Development Demonstration Project

This funding supports the Pediatric Emergency Care Applied Research (PECARN) Network. 

Role: PI

R01HD85233-01 Mahajan P (PI) Ruddy RM (site PI) 8/21/2015-5/30/2020

NICHD 

RNA Biosignatures: A Paradigm Change for the Management of Young Febrile Infants

This proposal will assess the impact of viral and bacterial infection on infants less than 60 days and assess the 

biosignature over time in-hospital. 

1R01HD071915-01A1 Schnadower (PI) 12/10/2013-11/30/2018

NICH

Impact of Emergency Department Probiotic Treatment of Pediatric Gastroenteritis

We propose to study the effectiveness and side effects of a probiotic, LGG, in treating children with 

gastroenteritis. If successful, this therapeutic intervention would be the first treatment that actually changes the 

disease process and would represent an enormous public health advance both in the US, and potentially, 

globally.

Completed Research Support:

1 U03MC22684-01-00 Ruddy, RM (PI) 09/01/11 – 08/31/15

HRSA

EMSC: Network Development Demonstration Project

This funding supports the Pediatric Emergency Care Applied Research (PECARN) Network. 

 

1 R01 HD062477 Mahajan, P (PI) 01/01/11 – 05/31/13

RNA Biosignatures in the Emergency Evaluation of Febrile Infants

The goal of this study is to change the paradigm of how young febrile infants are evaluated in the ED, and as a 

consequence improve their care. 

Role: Site PI

Biosketches Page 44
Contact PD/PI: Ambroggio, Lilliam

OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES.

NAME: STRINGER, KATHLEEN A

eRA COMMONS USER NAME (agency login):

POSITION TITLE: Professor of Clinical and Translational Pharmacy and Director, NMR Metabolomics

Laboratory

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,

include postdoctoral training and residency training if applicable.)

INSTITUTION AND

LOCATION

DEGREE

(if applicable)

Completion

Date 

MM/YYYY

FIELD OF STUDY

University of Michigan, Ann

Arbor, MI

PharmD 06/1985 Clinical Pharmacy

University of Michigan

Hospital, Ann Arbor, MI

Other training 05/1985 Internship

University of Illinois at

Chicago, Chicago, IL

Resident 06/1986 Clinical Pharmacy Practice Residency

State University of New York

at Buffalo, Buffalo, NY

Postdoctoral

Fellow

08/1988 Post-doctoral training in cardiovascular research

University of Colorado Health

Sciences Center, Denver, CO

Postdoctoral

Fellow

07/1996 American Foundation for Pharmaceutical

Education Post-PharmD Fellow in Experimental

Pulmonary Research

A. Personal Statement

The goal of the work proposed in this Mentored Research Scientist Development Award (K01) application is to

provide Dr. Ambroggio with protected time so that she can have an intensive, supervised career development

experience in pediatric infectious diseases epidemiology and metabolomics. In this regard, I will serve as her

metabolomics mentor and collaborator. In the preparation of this application, I have assisted and guided Dr.

Ambroggio in metabolomics study design including the construction of standard operating procedures for the

collection of urine samples for metabolomics assays. In this capacity as her metabolomics mentor, my

laboratory personnel and I will teach her the NMR metabolomics workflow “on site” at the University of

Michigan’s NMR Metabolomics Laboratory. She will learn sample preparation, NMR spectrum acquisition,

spectral processing, metabolite identification and quantification so that she can bring these skills back to her

own institution and function as an independent metabolomics investigator. She will also gain, in collaboration

with the study’s statisticians, experience in metabolomics data and pathway analysis. I am uniquely qualified to

serve in this capacity because I have successfully developed and led a productive metabolomics research

program. I have gained considerable experience in quantitative NMR metabolomics, employing both blood and

urine samples and have optimized sample collection, processing and analysis techniques. In particular, I have

gained expertise in the use of a number of commercially and publically available software platforms including

Chenomx (www.chenomx.com) and Metaboanalyst (www.metaboanalyst.ca) and I have forged productive

collaborations with a number of of internal and external investigators (Dr. John Younger and Dr. Vicki Ellingrod,

University of Michigan; and Dr. Alan Jones, University of Mississippi). In addition to my expertise in

metabolomics, I have a strong record of mentorship. I have mentored over 50 PharmD and PhD students and

several post-doctoral trainees. In addition, I have had the privilege and opportunity to mentor a number of

junior faculty. My capability and effectiveness as a mentor is evidence by my receipt of a Michigan Institute for

Clinical and Health Research Distinguished Mentor Award. Collectively, I will utilize my metabolomics and

effective mentorship skills to guide and assist in the training of Dr. Lilliam Ambroggio so that she may become

a successful independent investigator in epi-metabolomics.

1. Karnovsky A, Weymouth T, Hull T, Tarcea VG, Scardoni G, Laudanna C, Sartor MA, Stringer KA, 

Jagadish HV, Burant C, Athey B, Omenn GS. Metscape 2 bioinformatics tool for the analysis and

Biosketches Page 45
Contact PD/PI: Ambroggio, Lilliam

visualization of metabolomics and gene expression data. Bioinformatics. 2012 Feb 1;28(3):373-80.

PubMed PMID: 22135418; PubMed Central PMCID: PMC3268237. 

2. Lacy P, McKay RT, Finkel M, Karnovsky A, Woehler S, Lewis MJ, Chang D, Stringer KA. Signal

intensities derived from different NMR probes and parameters contribute to variations in quantification

of metabolites. PLoS One. 2014;9(1):e85732. PubMed PMID: 24465670; PubMed Central PMCID:

PMC3897511. 

3. Puskarich MA, Finkel MA, Karnovsky A, Jones AE, Trexel J, Harris BN, Stringer KA. 

Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock. Ann

Am Thorac Soc. 2015 Jan;12(1):46-56. PubMed PMID: 25496487; PubMed Central PMCID:

PMC4342803. 

4.

B. Positions and Honors

Positions and Employment

1982 - 1984 Pharmacy Intern, Sinai Hospital of Detroit, Detroit, MI

1984 - 1984 Research Assistant, Department of Pharmacology, University of Michigan Medical School, Ann

Arbor, MI

1988 - 1997 Assistant Professor, School of Pharmacy, University of Colorado Health Sciences Center,

Denver, CO

1997 - 2006 Associate Professor of Clinical Pharmacy (with tenure), Department of Clinical Pharmacy,

School of Pharmacy, Denver, CO

2003 - 2007 Associate Professor , Graduate Program in Toxicology and Pharmaceutical Sciences,

Graduate School, Denver, CO

2006 - 2007 Associate Professor of Clinical Pharmacy (with tenure), Department of Pharmaceutical

Sciences, School of Pharmacy, Denver, CO

2007 - 2012 Associate Professor of Clinical Pharmacy (with tenure), Department of Clinical Pharmacy,

College of Pharmacy, Ann Arbor, MI

2012 - Professor of Clinical & Translational Pharmacy, Department of Clinical Pharmacy, College of

Pharmacy, Ann Arbor, MI

2014 -

2016 - 

Director, NMR Metabolomics Laboratory, College of Pharmacy, University of Michigan, Ann

Arbor, MI

Associate Director, Michigan Center for Integrative Research in Critical Care, University of

Michigan, Ann Arbor, MI

Other Experience and Professional Memberships

1988 - Member, American College of Clinical Pharmacy

2003 - 2007 Associate Member, University of Colorado Cancer Center

2007 - Member, University of Michigan Comprehensive Cancer Center

2007 - Member, American Thoracic Society

2007 - Member, The American Physiological Society

2011 - Affiliate Member, University of Michigan Center for Computational Medicine and Bioinformatics

2014 - Member, The Metabolomics Society

Honors

1989 Young Investigator's Award, American Association of Colleges of Pharmacy

1994 Gustavus A. Pfeiffer Clinical Pharmacy Post-PharmD Fellowship, American Foundation for

Pharmaceutical Education

2014 Distinguished Clinical and Translational Research Mentor, Michigan Institute for Clinical and

Biosketches Page 46
Health Research

C. Contribution to Science

1. Metabolomics: I have been involved in conducting metabolomics studies for nearly 8 years. I directed

and published some of the first metabolomics studies in sepsis and acute respiratory distress

syndrome. I continue to pioneer the development and application of NMR metabolomics approaches to

further knowledge of disease mechanism, the identification of drug target opportunities and to

metabolically phenotype drug response.

a. Serkova NJ, Van Rheen Z, Tobias M, Pitzer JE, Wilkinson JE, Stringer KA. Utility of magnetic

resonance imaging and nuclear magnetic resonance-based metabolomics for quantification of

inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L152-61. PubMed

PMID: 18441091; PubMed Central PMCID: PMC2494785. 

b. Stringer KA, Serkova NJ, Karnovsky A, Guire K, Paine R 3rd, Standiford TJ. Metabolic

consequences of sepsis-induced acute lung injury revealed by plasma 1H-nuclear magnetic

resonance quantitative metabolomics and computational analysis. Am J Physiol Lung Cell Mol

Physiol. 2011 Jan;300(1):L4-L11. PubMed PMID: 20889676; PubMed Central PMCID:

PMC3023293. 

c. Evans CR, Karnovsky A, Kovach MA, Standiford TJ, Burant CF, Stringer KA. Untargeted LC-MS

metabolomics of bronchoalveolar lavage fluid differentiates acute respiratory distress syndrome

from health. J Proteome Res. 2014 Feb 7;13(2):640-9. PubMed PMID: 24289193; PubMed Central

PMCID: PMC4068805. 

d. Stringer KA, Younger JG, McHugh C, Yeomans L, Finkel MA, Puskarich MA, Jones AE, Trexel J, 

Karnovsky A. Whole Blood Reveals More Metabolic Detail of the Human Metabolome than Serum

as Measured by 1H-NMR Spectroscopy: Implications for Sepsis Metabolomics. Shock. 2015

Sep;44(3):200-8. PubMed PMID: 26009817; PubMed Central PMCID: PMC4537695. 

2. Drug development: I have directed the development and tested the feasibility of tissue plasminogen

activator (tPA) for inhalation. This effort has advanced knowledge of the safety and efficacy of tPA for

the treatment of pediatric plastic bronchitis. In addition, it resulted in FDA approval of its orphan drug

status and the investigational new drug (IND) application for the use of inhaled tPA for the treatment of

pediatric plastic bronchitis. Collectively, this work serves as the basis for a planned phase II clinical trial

which will permit its translation into the clinic.

a. Dunn JS, Nayar R, Campos J, Hybertson BM, Zhou Y, Manning MC, Repine JE, Stringer KA. 

Feasibility of tissue plasminogen activator formulated for pulmonary delivery. Pharm Res. 2005

Oct;22(10):1700-7. PubMed PMID: 16180128; PubMed Central PMCID: PMC2040297. 

b. Stringer KA, Tobias M, Dunn JS, Campos J, Van Rheen Z, Mosharraf M, Nayar R. Accelerated

dosing frequency of a pulmonary formulation of tissue plasminogen activator is well-tolerated in

mice. Clin Exp Pharmacol Physiol. 2008 Dec;35(12):1454-60. PubMed PMID: 18671720; PubMed

Central PMCID: PMC2779770. 

c. Lackowski NP, Pitzer JE, Tobias M, Van Rheen Z, Nayar R, Mosharaff M, Stringer KA. Safety of

prolonged, repeated administration of a pulmonary formulation of tissue plasminogen activator in

mice. Pulm Pharmacol Ther. 2010 Apr;23(2):107-14. PubMed PMID: 19879371; PubMed Central

PMCID: PMC2821999. 

d. Heath L, Ling S, Racz J, Mane G, Schmidt L, Myers JL, Tsai WC, Caruthers RL, Hirsch JC,

Stringer KA. Prospective, longitudinal study of plastic bronchitis cast pathology and

responsiveness to tissue plasminogen activator. Pediatr Cardiol. 2011 Dec;32(8):1182-9. PubMed

PMID: 21786171; PubMed Central PMCID: PMC3207025. 

3. Drug discovery, drug action and transport: I have directed, led, and intellectually contributed to

studies that identified new drug actions, mechanisms of drug transport and identified potential new drug

candidates. This includes work with the drug clofazimine and tissue plasminogen activator.

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 47
Contact PD/PI: Ambroggio, Lilliam

a. Stringer KA, Dunn JS, Gustafson DL. Administration of exogenous tissue plasminogen activator

reduces oedema in mice lacking the tissue plasminogen activator gene. Clin Exp Pharmacol

Physiol. 2004 May-Jun;31(5-6):327-30. PubMed PMID: 15191406. 

b. Min KA, Talattof A, Tsume Y, Stringer KA, Yu JY, Lim DH, Rosania GR. The extracellular

microenvironment explains variations in passive drug transport across different airway epithelial cell

types. Pharm Res. 2013 Aug;30(8):2118-32. PubMed PMID: 23708857; PubMed Central PMCID:

PMC3706189. 

 

d.

Complete List of Published Work in My Bibliography:

http://www.ncbi.nlm.nih.gov/myncbi/kathleen.stringer.1/bibliography/40956426/public/?sort=date&dire

ction=ascending

D. Research Support

Ongoing Research Support

2016/04/01-2020/01/31

R01GM111400, NIH

Stringer (PI)

L-Carnitine Pharmacometabolomics in Sepsis (CaPS)

The goal of this project is to determine to what extent L-carnitine utilization is directly linked to metabolic

adaptiveness and mortality in patients with severe sepsis. 

Role: Principal Investigator

2012/07/12-2016/06/30

R01GM078200, NIH

Rosania (PI) 

Chemical Address Tags: A chemoinformatics & image data management and analysis plan

The goal of this project is to develop machine vision and image analysis tools to identify chemical address tags

by relating the chemical structure of small molecules to their subcellular localization as apparent in image data.

Role: Co-Investigator

2015/07/01-2016/06/30

R01GM103799-S1, NIH

Jones (PI) 

L-carnitine Treatment for Vasopressor Dependent Septic Shock

This is a phase II randomized clinical trial of carnitine efficacy and safety in septic shock. The supplement will

fund the metabolomics assay of serum samples collected as part of the phase I tri-al in order to inform a 

targeted metabolomics approach for the phase III study.

Role: Co-Investigator

Completed Research Support

2013/06/01-2015/12/31 (no cost extension)

Biosketches Page 48
R01GM069438-07S1, NIH

Younger (PI) 

Complement C5a in Human Sepsis- Metabolomics Supplement

The goal of this project is to use novel assays of host bactericidal activity and C5a generation and to measure

function in a subset of sepsis patients. The supplement funds the metabolomics portion of this study.

Role: Co-Investigator

2010/07/15-2013/06/30

R15 HD065594-01, Eunice Kennedy Shriver National Institute of Child Health and Human Development

(NICHD)

Stringer (PI) 

Pulmonary Formulation of tPA for Plastic Bronchitis

Role: PI

2014/06/01-2015/05/31

MH082784-07S3, NIH

Ellingrod (PI) 

Antipsychotic and folate pharmacogenetics- Sex differences Metabolomics Supplement

The goal of this project is to genetically phenotype patients who respond and do not respond to folate

supplementation and to characterize risk of metabolic syndrome. This supplement funds the characterization of

sex-differences in the metabolomics data.

Role: Co-Investigator

2014/06/01-2015/05/31

R01MH082784-07S2, NIH

Ellingrod (PI) 

Antipsychotic and folate pharmacogenetics- Metabolomics Supplement

The goal of this project is the genetic phenotyping of patients who respond and do not respond to folate

supplementation and to characterize risk of metabolic syndrome. This supplement funds the metabolomics

component of the work.

Role: Co-Investigator

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 49
Contact PD/PI: Ambroggio, Lilliam

OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018) 

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES.

NAME: Sucharew, Heidi

eRA COMMONS USER NAME (credential, e.g., agency login):

POSITION TITLE: Assistant Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, 

include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION

DEGREE

(if 

applicable)

Completion 

Date

MM/YYYY

FIELD OF STUDY

The College of New Jersey, Ewing, NJ B.A. 05/2000 Statistics

University of Washington, Seattle, WA M.S. 08/2002 Biostatistics

University of Cincinnati, Cincinnati, OH Ph.D. 12/2009 Biostatistics

A. Personal Statement

The objective of this study is to improve our understanding of the role of urine metabolites in relation to viral or 

bacterial community acquired pneumonia and to evaluate the impact of antibiotic treatment on changes in the 

urine metabolite profile. My academic specialty is in biostatistics with methodology interests in latent variable 

models and structural equation modeling. My recent areas of application include latent profile analysis of infant 

neurobehavior and latent class analysis of individual NIH stroke scale scores for mortality prediction. I am an 

assistant professor in the Division of Biostatistics and Epidemiology at Cincinnati Children’s Hospital Medical 

Center. I currently provide statistical support for researchers and faculty in the Hospital Medicine division within 

Cincinnati Children’s Hospital and the Department of Neurology at the University of Cincinnati. I have an 

established working collaboration with Dr. Lilliam Ambroggio and am excited to share my expertise with her to 

accomplish the goals of the research plan. I am also excited about the research/mentoring team, as Lilliam has 

brought together the expertise from multiple dimensions that will ensure the successful completion of the 

proposed research work. I have the expertise, leadership, training, and passion necessary to serve as 

statistician for this application. I’m a biostatistician for the ongoing Epidemiology of Stroke study and have 

served as associate director for the Biostatistical Core of the Special Program on Translational research in 

Acute Stroke (SPOTRIAS) grant for Cincinnati and therefore provided statistical support for three NIH-funded, 

multicenter clinical trials. My methodologic training allows me to apply my skills across a diverse set of 

research topics. I have a highly productive track record not only in my personal research field, but also on a 

diverse set of research teams. As a member of this research team, I am committed to the success of this 

important research work.

a. Sucharew H, Khoury JC, Xu Y, Succop P, Yolton K. NICU Network Neurobehavioral Scale profiles predict 

developmental outcomes in a low-risk sample. Paediatr Perinat Epidemiol. 2012 Jul;26(4):344-52. PMID: 

22686386; PMCID: PMC3376022.

b. Sucharew H, Khoury J, Moomaw CJ, Alwell K, Kissela BM, Belagaje S, Adeoye O, Khatri P, Woo D, 

Flaherty ML, Ferioli S, Heitsch L, Broderick JP, Kleindorfer D. Profiles of the National Institutes of 

Health Stroke Scale items as a predictor of patient outcome. Stroke. 2013, 44(8):2182-7. PMID: 

23704102; PMCID: PMC4190834. 

c.

Biosketches Page 50
B. Positions and Honors

Positions and Employment

2000-2001 Teaching Assistant, Department of Biostatistics, University of Washington, Seattle, WA

2001-2002 Research Assistant, Southwest Oncology Group, Seattle, WA

2002-2005 Statistician, CF Therapeutics Development Network Coordinating Center, Seattle, WA

2005-2009 Research Assistant, Department of Environmental Health, University of Cincinnati, 

 Cincinnati, OH

2010-2011 Research Associate, Division of Biostatistics and Epidemiology, Cincinnati Children’s 

 Hospital Medical Center, Cincinnati, OH 

2011-2013 Instructor, Division of Biostatistics and Epidemiology, Cincinnati Children’s 

 Hospital Medical Center, Cincinnati, OH

2013-present Assistant Professor, Division of Biostatistics and Epidemiology, Cincinnati Children’s 

Hospital Medical Center, Cincinnati, OH

Professional Memberships and Honors

2006-2008 Fellow, Molecular Epidemiology in Children’s Environmental Health Training Program, 

 National Institute of Environmental Health Sciences

2010-present American Statistical Association (ASA)

2013-present American Heart Association

2013-present Eastern North American Region (ENAR) of the International Biometric Society

C. Contribution to Science

1. Cystic Fibrosis Therapeutic Studies. My early research and publications were focused on improving 

outcomes for children with cystic fibrosis (CF). Cystic fibrosis is one of the most common inherited fatal 

diseases in Caucasians. Improving the care of patients with CF requires the continued search for more 

efficacious treatments that can potentially modify the natural history of the disease and improve symptom 

control and prognosis. The clinical trial has been a vital tool for expanding our knowledge of disease and 

response to therapies and is considered the gold standard for assessing the effectiveness of various 

therapies and interventions. We were the first study to show the correlation between computed tomography 

(CT) scores and the clinical outcome of respiratory tract exacerbations in CF patients; providing support for 

CT use as a surrogate outcome in CF therapeutic studies. This finding is important because using 

outcome surrogates can decrease both study duration and sample size and has particular relevance in the 

field of adaptive study design. Because subjects with CF frequently have adverse events (AEs) during 

clinical trials, interpretation of the safety profile of the therapy being tested, especially for small phase 1 and 

2 trials, can be very challenging. In clinical trials, it is critical to know background AE rates in the CF clinical 

trial population in order to have a reference for determining safety. We presented tables of AE rates for 

both pediatric (5–17 years old) and adult (≥ 18 years old) placebo subjects for short-term and long-term 

inhaled therapy trials, and described how these tables can be used for interpreting safety data and study 

planning. These data have improved safety monitoring in CF clinical trials involving novel inhaled drugs.

a. Brody AS, Sucharew H, Campbell JD, Millard SP, Molina PL, Klein JS, Quan J. Computed tomography 

correlates with pulmonary exacerbations in children with cystic fibrosis. Am J Respir Crit Care Med. 

2005; 172(9), 1128-32, PMID 16100015.

b. Sucharew H, Goss CH, Millard SP, Ramsey BW; Cystic Fibrosis Therapeutics Development Network. 

Respiratory adverse event profiles in cystic fibrosis placebo subjects in short- and long-term inhaled 

therapy trials. Contemp Clin Trials. 2006;27(6):561-70. PMID: 16875884.

2. Environmental Exposures and Child Health. Exposure to air pollution has been consistently associated 

with poor respiratory outcomes in children including wheezing, bronchitis, and asthma. Few studies, 

however, have evaluated the etiology for dry night cough despite cough being among the most common 

symptoms of pediatric asthma presented to family physicians. I was able to combine my research interest 

in structural equation modelling techniques and environmental exposures to simultaneously evaluate 

family, home, health, and environmental factors for association with recurrent dry night cough during early 

childhood. We found that children who were exposed to the highest tertile of traffic exhaust had 45% 

increased risk of night cough compared with children less exposed, adding to the body of literature on the 

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 51
respiratory symptoms. Next, we evaluated the potential effect of traffic exposure on the developing brain 

and found that traffic exhaust exposure during infancy was associated with higher hyperactivity scores at 

age 7. When defining allergic outcomes in epidemiology studies, results of the skin prick test (SPT) panel 

are often dichotomized as positive/negative or categorized based on the number of positive responses. In a 

novel application of Item Response Theory to SPT responses, we showed the benefits of this method over 

traditional approaches for evaluating atopy. Essential elements play a challenging role in child health and 

development, as both high and low levels may exert a poor impact. Manganese (Mn) is an example of 

such and while it plays a vital role in brain growth and development, excessive exposure can result in 

neurotoxicity. Using penalized splines, we found that both low and high Mn concentrations in blood and 

hair were negatively associated with child IQ scores.

a. Sucharew H, Ryan PH, Bernstein D, Succop P, Khurana Hershey GK, Lockey J, Villareal M, Reponen 

T, Grinshpun S, LeMasters G. Exposure to traffic exhaust and night cough during early childhood: the 

CCAAPS birth cohort. Pediatr Allergy Immunol. 2010; 21(2), 253-9, PMID 19824943, PMC

b. Newman NC, Ryan P, Lemasters G, Levin L, Bernstein D, Hershey GK, Lockey JE, Villareal M, 

Reponen T, Grinshpun S, Sucharew H, Dietrich KN. Traffic-related air pollution exposure in the first 

year of life and behavioral scores at 7 years of age. Environ Health Perspect. 2013;121(6):731-6.

PMCID: PMC3672910.

c. Sucharew H, Khoury JC, Rao MB, Succop P, Bernstein D, Ryan PH, LeMasters G. Predicting allergic 

disease at age four using an atopy predisposition score at age two: the application of Item Response 

Theory. Pediatric Allergy and Immunology. 2012; 23 (2): 195-201. PMID 22192382. [Selected for 

Editor’s Choice March 2012 issue]

d. Haynes EN, Sucharew H, Kuhnell P, Alden J, Barnas M, Wright RO, Parsons PJ,Aldous KM, 

Praamsma ML, Beidler C, Dietrich KN. Manganese Exposure and Neurocognitive Outcomes in Rural 

School-Age Children: The Communities Actively Researching Exposure Study (Ohio, USA). Environ 

Health Perspect. 2015 Apr 22. PMID: 25902278.

3. Stroke Research. Initial National Institutes of Health Stroke Scale (NIHSS) score is highly predictive of 

outcome after ischemic stroke. The total score (range 0 to 42) is comprised of 15 items with individual 

scores ranging between 0 and 4. We examined whether grouping strokes by presence of individual NIHSS 

symptoms could provide prognostic information additional or alternative to the NIHSS total score. This

study showed that the latent class analysis method of analyzing NIHSS items provides an alternative 

approach for summarizing prognostic information for forecasting functional outcome and death compared 

with using the raw NIHSS total score. In particular, two symptom profiles with identical median NIHSS total 

scores but with widely disparate outcomes were identified. These profiles were recently validated in an 

acute cohort suggesting a reliable approach to capture the true response patterns that are associated with 

functional outcome and mortality post stroke. With the recent findings that timely endovascular therapy may 

improve outcomes in ischemic stroke patients with confirmed large vessel occlusions (LVO), there is now a 

clinical need for accurate initial triage of patients to hospitals where these therapies are available. To 

address this need, we derived and validated a new practical neurologic scale, the Cincinnati Prehospital 

Stroke Severity Scale (CPSSS), in prediction of severe ischemic stroke and LVO.

a. Sucharew H, Khoury J, Moomaw CJ, Alwell K, Kissela BM, Belagaje S, Adeoye O, Khatri P, Woo D, 

Flaherty ML, Ferioli S, Heitsch L, Broderick JP, Kleindorfer D. Profiles of the National Institutes of 

Health Stroke Scale items as a predictor of patient outcome. Stroke. 2013, 44(8):2182-7. PMCID: 

PMC4190834.

b. Abdul-Rahim AH, Fulton RL, Sucharew H, Kleindorfer D, Khatri P, Broderick JP, Lees KR; VISTA 

Collaborators. National institutes of health stroke scale item profiles as predictor of patient outcome: 

external validation on independent trial data. Stroke. 2015;46(2):395-400. PMID: 25503546.

c. Abdul-Rahim AH, Fulton RL, Sucharew H, Kleindorfer D, Khatri P, Broderick JP, Lees KR; SITS-MOST 

Steering Committee. National Institutes of Health Stroke Scale Item Profiles as Predictor of Patient 

Outcome: External Validation on Safe Implementation of Thrombolysis in Stroke-Monitoring Study 

Data. Stroke. 2015;46(10):2779-85. PMID: 26359360.

d. Katz BS, McMullan JT, Sucharew H, Adeoye O, Broderick JP. Design and Validation of a Prehospital 

Scale to Predict Stroke Severity: Cincinnati Prehospital Stroke Severity Scale. Stroke. 2015. PubMed 

PMID: 25899242.

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 52
Complete List of Published Work in 

MyBibliography: http://www.ncbi.nlm.nih.gov/sites/myncbi/10mIFUdkMgkA2/bibliography/47756713/public/?sort=date&direction=a

scending. 

D. Research Support

Active:

PFA-072313 Shah (PI) 07/01/2014 – 06/30/2017 

PCORI 

Improving post-discharge outcomes by facilitating family-centered transitions from hospital to home

Role: Biostatistician

Shah (PI) 01/04/2016 – 04/28/2017

PCORI - Supplement 

Improving post-discharge outcomes by facilitating family-centered transitions from hospital to home

Goal: Our overarching goal is to improve the outcomes of hospital to home transitions for acutely ill 

hospitalized children and their families. The goal of this supplement is to evaluate a phone call shortly after 

discharge in improving patient outcomes.

Role: Biostatistician

R34 MH101155-01 Brinkman (PI) 04/01/2014 – 03/31/2017 

NIMH

Developing New Technologies to Improve ADHD Mediation Continuity

Role: Biostatistician

R01 (Kleindorfer/Khoury) 04/01/2015 – 03/31/2020 

NIH - Resubmission 

Comparison of Hemorrhagic & Ischemic Stroke Among Blacks and Whites

Goal: Tracking of population-based stroke incidence in the Greater Cincinnati and Northern Kentucky region, 

with special emphasis on stroke in the young and stroke recurrence. 

Role: Co-I 

Place Outcomes Research Award Brady/Heather (PIs) 07/01/2014 – 06/30/2016

Internal Grant

Develop and Evaluate Supplemental Oxygen Data Displays in the Clinical Setting

Role: Biostatistician

Shah (PI) 03/01/2016 – 02/28/2017

APA

Effect of Parental Adverse Childhood Experiences and Resilience on Outcomes After Pediatric Discharge

Goal: The objectives of this proposal are to determine the prevalence of ACEs and levels of resilience among 

the parents of hospitalized children, their association with a parent’s post-discharge coping, and their 

association with their child’s rate of unplanned post discharge utilization.

ARC Lilliam Abroggio (PI) 01/01/2016 – 12/31/2017

Catalyzing Ambulatory Research in Pneumonia Etiology and Diagnostic Innovations in Emergency medicine 

(CARPE DIEM)”

Role: Biostatistician

Completed: 

P50 NC 44283 Broderick/Khoury (PI/Core B PI) 07/01/2008 – 04/30/2016

NINDS

Recanalization Therapies and Markers of Stroke Outcome

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 53
The long-term goal of this program project grant (an application to the SPOTRIAS program – Specialized 

Program of Translational Research in Acute Stroke) is to improve the early recanalization of occluded

arteries in patients with acute ischemic stroke without compromising safety. 

Role: Co-I 

R21ES021106 Haynes/Sucharew (PI/subsite PI) 07/09/2012 – 06/30/2015 

CCHMC/UC 

Multiple Risk Factors and Neurodevelopment Deficits in Rural Appalachian Children

Goal: The goal of this study is to assess the impact of Mn exposure on neurocognition in an Appalachian 

American cohort of school-aged children.

Role: PI of subsite

U19HS021114 Brady (PI) 09/01/2013 – 08/31/2015 

Agency for Healthcare Research and Quality 

Centers for Education and Research on Therapeutics (CERTs)

Evaluating Huddle Effectiveness

Role: Biostatistician 

K23 MH083027 Brinkman (PI) 01/01/2010 – 03/16/2015 

NIMH

Medication Continuity in Children Treated for ADHD 

The primary goal of this project is to develop expertise for becoming an independent investigator in the study of 

medication continuity in children with ADHD cared for in primary care settings.

Role: Biostatistician

R01 NS30678 Kissela/Kleindorfer (PIs) / Khoury (Subsite PI) 07/01/2009 – 06/30/2014

NINDS/NIH 

Hemorrhagic and Ischemic Stroke Among Blacks and Whites

Some of the major goals of this project are to study temporal trends in the incidence rate, causes, treatment 

and outcome of stroke in a biracial metropolitan population of 1.3 million of whom 15% are black (2000 

Census), and compare these data with those collected using the same methodology during earlier years of the 

study. 

Role: Biostatistician

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 54
Contact PD/PI: Ambroggio, Lilliam

OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018) 

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES.

NAME: Romick-Rosendale, Lindsey

eRA COMMONS USER NAME (credential, e.g., agency login):

POSITION TITLE: Assistant Professor, Pathology

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, 

include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION

DEGREE

(if 

applicable)

Completion 

Date

MM/YYYY

FIELD OF STUDY

Marietta College, Marietta, Ohio BS 05/2007 Chemistry

Miami University, Oxford, Ohio PHD 12/2011 Chemistry

Cincinnati Children's Hospital Medical Center, 

Cincinnati, Ohio

Postdoctoral 

Fellow

03/2014 Hematology/Oncology

University of Cincinnati, Cincinnati, Ohio NIH training 

grant

03/2014 NRSA-T32 NIH Training 

Grant: Environmental 

Carcinogenesis

A. Personal Statement

I am the Director of the NMR-Based Metabolomics Core with core responsibilities and research focusing on the 

use of NMR and MS-based metabolomics as a tool in the study of disease diagnostics and drug surveillance, 

both in the areas of clinical medicine and basic research. My graduate career focused on the use of NMRbased metabolic profiling to evaluate mouse models of human disease, as well as the effects of various 

diseases and disorders on metabolic pathways through the analysis of human biological fluids (urine, feces, 

blood, etc.). My experiences at Miami University under the guidance of Dr. Michael Kennedy, Ohio Eminent 

Scholar, coupled with my postdoctoral training under Dr. Susanne Wells prepared me to take on a leadership 

role in the field of metabolomics at Cincinnati Children’s Hospital. My close proximity to pediatric 

hematologists, oncologists and pathologists has allowed me to establish collaborations with them, in which I 

utilize biological fluids and tissue biopsies from their patients in an effort to identify markers of the diseases and 

drug treatment regimens that they are studying. My goal is to demonstrate the power of metabolomics as a 

desirable tool to allow clinicians and basic scientists to better understand the biochemical pathways that are at 

play during disease onset, disease progression and therapeutic intervention. With this goal in mind, I am 

excited for the opportunity to collaborate with Dr. Ambroggio on her proposal. As such I will provide guidance 

and the necessary resources for Dr. Ambroggio to be successful in her application of NMR metabolomics to 

the field of pediatric pneumonia.

1. Romick-Rosendale LE, Hoskins EE, Privette Vinnedge LM, Foglesong GD, Brusadelli GD, et al.

Defects in the fanconi anemia pathway in head and neck cancer cells stimulate tumor cell invasion

through DNA-PK and Rac1 signaling. Clin Cancer Res. 2015 Nov 24. PubMed PMID 26603260. 

2. Romick-Rosendale LE, Brunner HI, Bennett MR, Mina R, Nelson S, et al. Identification of urinary

metabolites that distinguish membranous lupus nephritis from proliferative lupus nephritis and focal

segmental glomerulosclerosis. Arthritis Res Ther. 2011; 13(6):R199. PubMed PMID: 22152586; 

PubMed Central PMCID: PMC3334650. 

3. Romick-Rosendale LE, Schibler KR, Kennedy MA. A Potential Biomarker for Acute Kidney Injury in

Preterm Infants from Metabolic Profiling. J Mol Biomark Diagn. 2012 Feb; Suppl 3PubMed PMID:

25035813; PubMed Central PMCID: PMC4096988. 

Biosketches Page 55
4. Romick-Rosendale LE, Lui VW, Grandis JR, Wells SI. The Fanconi anemia pathway: repairing the link

between DNA damage and squamous cell carcinoma. Mutat Res. 2013 Mar-Apr; 743-744:78-88.

PubMed PMID: 23333482; PubMed Central PMCID: PMC3661751. 

5. Romick-Rosendale LE, Legomarcino A, Patel NB, Taft D, Morrow AL, et al. Prolonged antibiotic use

induces intestinal injury in mice that is repaired after removing antibiotic pressure: Implications for

empiric antibiotic therapy. Metabolomics. 2014 February; 10(1):8-20. PubMed PMID: 26273236; 

PubMed Central PMCID: PMC4532301 

My NCBI Bibliography 

B. Positions and Honors

Positions and Employment

2007 - 2011 Graduate Teaching Assistant, Miami University, Oxford, OH

2012 - 2014 Postdoctoral Fellow, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

2014 - Assistant Professor, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

2014 - Assistant Professor, University of Cincinnati College of Medicine, Cincinnati, OH

Other Experience and Professional Memberships

2006 - Member, American Chemical Society

2014 - Member, National Association of Professional Women

2014 - Member, Metabolomics Society

Honors

2005 The Ellis L. and Jennie Mae Krause Memorial Scholarship, Marietta College

2006 The LaVallee Award in Chemistry, Marietta College

2007 Miami University Charcher’s Summer Research Scholarship, Miami University

2010 Experimental Nuclear Magnetic Resonance Conference Travel Award, Experimental Nuclear 

Magnetic Resonance Conference

2010 Miami University Research Graduate Assistantship (RGA), Miami University

C. Contribution to Science

1. Metabolomics was first defined as “the quantitative measurements of the multi-parametric metabolic

response of a living system to pathophysiological stimuli or genetic modifications”. The technique has been

minimally utilized thus far in studies of human disease due to the complexity of the organism; however, it

has shown to be a potentially useful tool in the area of biomarker identification in a select number of

diseases. Metabolomics is the study of an organism’s metabolome, which makes this a powerful “omics” 

technique because the metabolome is downstream of both the genome and proteome and is

complementary to other “omic” methods. Metabolomics has been employed in drug surveillance as well as

disease diagnosis, identification of changes in metabolites associated with cell apoptosis, cancer cell

growth, proliferation rates and metabolic effects related to the Warburg hypothesis of modified energy

production. My colleagues and I were able to utilize NMR-based metabolomics to identify potential markers

of acute kidney injury (AKI) in preterm infants, which is an otherwise difficult preterm complication to

diagnose using conventional methods. Employing the same NMR techniques, we were also able to identify

key metabolic changes resulting from the development of lupus nephritis that may lead to improved

personalized care in this patient population. Defining changes in the metabolome related to disease onset

and progression in any patient population would provide significant information about regulatory pathways

in disease in general, and should drive the identification of novel disease biomarkers and therapeutic

targets.

a. Romick-Rosendale LE, Brunner HI, Bennett MR, Mina R, Nelson S, et al. Identification of urinary

metabolites that distinguish membranous lupus nephritis from proliferative lupus nephritis and focal

segmental glomerulosclerosis. Arthritis Res Ther. 2011; 13(6): R199. PubMed PMID: 22152586; 

PubMed Central PMCID: PMC3334650. 

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 56
b. Romick-Rosendale LE, Schibler KR, Kennedy MA. A Potential Biomarker for Acute Kidney Injury in

Preterm Infants from Metabolic Profiling. J Mol Biomark Diagn. 2012 Feb; Suppl 3 PubMed PMID:

25035813; PubMed Central PMCID: PMC4096988. 

2. Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure (BMF),

and increased susceptibility to cancers. The two predominant cancers are acute myeloid leukemia (AML)

and head and neck squamous cell carcinoma (HNSCC). Although FA as a disease is rare, by utilizing

whole-exome sequencing data taken from HNC tumors from patients in the general population I was able

to show that a subset of primary, therapy-naïve HNSCCs harbor mutations in important DNA repair

pathways including FA. As stated previously, individuals with FA have an astonishing probability of 1 in 3 

for developing solid tumors, most commonly HNSCC, by age 48. Unfortunately, a concrete explanation for

the high HNSCC susceptibility in this disease population had yet to be uncovered. My colleagues and I 

were able to determine that perturbation of a number of components of the FA pathway lead to increased

cancer cell invasion and migration that was at least in part mediated by a Rac1 and DNA-PK signaling

cascade. These findings may allow for therapies directed at these signaling networks to improve not only

survival of FA HNSCC patients, but also HNSCC patients in the general population harboring tumors with

mutations in FA-related genes. 

a. Romick-Rosendale LE, Lui VW, Grandis JR, Wells SI. The Fanconi anemia pathway: repairing the link

between DNA damage and squamous cell carcinoma. Mutat Res. 2013 Mar-Apr; 743-744:78-88.

PubMed PMID: 23333482; PubMed Central PMCID: PMC3661751. 

b. Romick-Rosendale LE, Hoskins EE, Privette Vinnedge LM, Foglesong GD, Brusadelli GD, et al.

Defects in the fanconi anemia pathway in head and neck cancer cells stimulate tumor cell invasion

through DNA-PK and Rac1 signaling. Clin Cancer Res. 2015 Nov 24. PubMed PMID 26603260. 

3. The human gastrointestinal tract is home to hundreds of species of bacteria and the balance between

beneficial and pathogenic bacteria plays a critical role in human health and disease. The human infant,

however, is born with a sterile gut and the complex gastrointestinal host/bacterial ecosystem is only

established after birth by rapid bacterial colonization. Imbalance in normal, healthy gut flora contributes to

several adult human diseases including inflammatory bowel (ulcerative colitis and Crohn's disease) and

Clostridium difficile associated disease, and early childhood diseases such as necrotizing enterocolitis. As

a first step towards characterization of the role of gut bacteria in human health and disease, my colleagues

and I conducted an 850 MHz 1H nuclear magnetic resonance spectroscopy study to monitor changes in

metabolic profiles of urine and fecal extracts of 15 mice following gut sterilization by the broad-spectrum

antibiotic enrofloxacin (also known as Baytril). We believe that metabolic profiling of mice sterilized by a 

broad-spectrum antibiotic offers many possibilities for future studies enabling characterization and

monitoring of the metabolic signature of specific pathogenic bacteria as they are reintroduced into the host.

Obtaining metabolic profiles that can be attributed to specific bacterial species in host biological fluids and

analyzing the changes that occur may lead to a better understanding of how certain inflammatory bowel

diseases are initiated.

a. Romick-Rosendale LE, Goodpaster AM, Hanwright PJ, Patel NB, Wheeler ET, et al. NMR-based

metabonomics analysis of mouse urine and fecal extracts following oral treatment with the broadspectrum antibiotic enrofloxacin (Baytril). Magn Reson Chem. 2009 Dec; 47 Suppl 1: S36-46. PubMed

PMID: 19768747. 

b. Romick-Rosendale LE, Legomarcino A, Patel NB, Taft D, Morrow AL, et al. Prolonged antibiotic use

induces intestinal injury in mice that is repaired after removing antibiotic pressure: Implications for

empiric antibiotic therapy. Metabolomics. 2014 February; 10(1):8-20. PubMed PMID: 26273236; 

PubMed Central PMCID: PMC4532301 

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 57
D. Research Support

Current Research Support

2015/05/01-2016/05/01

CCHMC Research Innovations Program (RIP) Funding

Title: Identification of Biomarkers of Fanconi Anemia and Head and Neck Cancer by NMR-Based

Metabolomics and MS-Based Lipidomics

Role: PI

Completed Research Support

1988/07/01-2014/03/31

T32 ES007250-24, National Institute of Environmental Health Sciences (NIEHS)

STAMBROOK, PETER J. (PI) 

Environmental Carcinogenesis and Mutagenesis 

Role: TA

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 58
Contact PD/PI: Ambroggio, Lilliam

OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018) 

BIOGRAPHICAL SKETCH

Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES.

NAME: Ziady, Assem Galal

eRA COMMONS USER NAME (credential, e.g., agency login):

POSITION TITLE: Associate Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, 

include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION

DEGREE

(if 

applicable)

Completion 

Date

MM/YYYY

FIELD OF STUDY

Boston College, Boston, MA B.S. 05/1993 Biochemistry

Physiology & Biophysics, Case Western Reserve 

University, Cleveland, OH

Ph.D. 01/1999 Cell Physiology

Pediatrics, Case Western Reserve University, 

Cleveland, OH

Fellow 01/2002 Gene transfer/ delivery

Mass Spectrometry Center, The Cleveland Clinic 

Foundation, Cleveland, OH

Visiting 

Fellow

9/2003 Protein Mass 

Spectrometry

A. Personal Statement

The goal of this application is to provide training for the career development of Dr. Lilliam Ambroggio’s into an 

independent investigator with an expertise in delineating the molecular basis of childhood pneumonia using 

metabolomics. I am a NIH R01 funded investigator and I recently joined the CCHMC Cystic Fibrosis Center. I 

am an expert in the use of liquid chromatography mass spectrometry to analyze disease pathways based on 

protein and metabolite profiles. I have trained a number of researchers and academic clinicians that now 

serve at the rank of Assistant to Associate professor and have performed similar studies to those proposed in 

Lilliam’s proposal but in the study of cystic fibrosis. Furthermore, I direct the CF biomarker analysis core at 

CCHMC, and I have previously served as Associate Director of Translational Research for 3 years at Emory 

University. I have also authored a number of reviews and book chapters on the use of mass spectrometry for 

the study of lung disease. 

B. Positions and Honors

Positions and Employment

10/2003-11/2003 Research Associate, Department of Pediatrics, CWRU, Cleveland, OH

12/2003-10/2011 Assistant Professor, Department of Pediatrics, CWRU, Cleveland, OH

08/2006-10/2011 Assistant Professor, Department of Physiology & Biophysics, CWRU, Cleveland, OH

03/2008-10/2011 Assistant Professor, Department of Biomedical Engineering, CWRU, Cleveland, OH

10/2011-10/2014 Associate Professor, Department of Pediatrics, Emory University, Atlanta, GA

04/2012-10/2014 Associate Professor, Department of Pharmacology, Emory University, Atlanta, GA

06/2012-10/2014 Associate Director of CF Basic & Translational Research, Emory University, Atlanta, GA

11/2012-present Associate Professor, University of Cincinnati School of Medicine, Cincinnati, OH

11/2014-present Associate Professor, Department of Pediatrics, Cincinnati Children’s Hospital Medical 

Center, Cincinnati, OH

Other Experience and Professional Memberships

1999-present American Society of Gene Therapy

1999-2000 Board member of the March For A Cure in Cleveland, OH (CF Foundation)

1999-2006 Technical and scientific consultant for Copernicus Therapeutics, Inc. (Cleveland, OH) Biosketches Page 59
2004-present American Society of Mass Spectrometry

2007-2011 Member, Institutional Animal Care and Use Committee (IACUC) of CWRU

2006 Member, conference committee for Ohio Collaborative Conference on Bioinformatics

2005-2008 Case Western Reserve University representative to the Ohio Supercomputer Center

2005-2007 Member, Advisory Committee for the CWRU Center of Mass Spectrometry and Proteomics

2010-present Member, Cystic Fibrosis Foundation Biomarker Consortium

2013-present Member, Chemical Gene & Cell Therapy Committee, American Society of Gene & Cell 

Therapy

Honors and Awards

1993 Scholar of the College, Boston College, Boston, MA

1999 Cystic Fibrosis Foundation fellow award

2000 Cystic Fibrosis Foundation fellow award

2000 American Society of Gene Therapy Merit award

2001 Cystic Fibrosis Foundation fellow award

2002 American Society of Gene Therapy, Research Merit award

2002 American Society of Gene Therapy, Excellence In Research award

2003 Cold Spring Harbor Laboratory merit travel award (Vector targeting meeting)

2012 Best scientific publication of the year Award 2012, Department of Pediatrics, Emory University

Patents

2009 Co-inventor on patent EP Patent 2,025,757

2002 Co-inventor on patent EP Patent 1,200,616

2001 Co-inventor on patent WO 1,997,046,100

2001 Co-inventor on patent US 6,200,801

1999 Co-inventor on patent US 5,972,901

C. Contribution to Science (* Corresponding author)

1. Understanding redox mediated regulation of inflammation in cystic fibrosis. We have played a 

significant role in the field studying the mechanism of the dysfunction of cellular redox balance in CF, 

chiefly centered on the behavior of Nrf2, a key transcription factor in the antioxidant response element. 

My research on the dysfunction of antioxidant responses in CF epithelia was the first to report a 

dysfunction of the ARE that resulted in elevation of steady state H2O2 that contributes to inflammation 

in CF. Inflammation in CF is the chief cause of mortality and morbidity. Therefore, our findings of a 

pathway that can be modulated to reduce inflammation were very significant. However, the work was 

not immediately accepted by the community back in 2008. In the past 2 years the work has become 

more appreciated as others have shown similar findings. Our more recent work on the mechanism of 

Nrf2 dysregulation that link it to CFTR dysfunction has been completed at a time when our hypothesis 

is becoming more widely accepted, and the topic of discussions and presentations at national and 

international CF meetings. Translationally, our work has increased the interest of the CF foundation 

and our department to target Nrf2 with activators as an anti-inflammatory approach.

a. A.G. Ziady* and J. Hansen. Redox balance in Cystic Fibrosis. Int J Biochem Cell Biol. 

2014. 52C:113-123. PMCID: PMC4035434

b. A.G. Ziady*, A. Sokolow, S. Shank, D. Corey, R. Myers, S. Plafker, T.J. Kelley. Interaction with 

CREB binding protein modulates the activities of Nrf2 and NF-κB in Cystic Fibrosis Airway 

epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2012. 302(11):L1221-1231. PMCID: 

PMC3379036

c. A.G. Ziady,* P.B. Davis. Methods for evaluating inflammation in cystic fibrosis. Methods Mol

Biol. 2011. 742:51-76.

d. D.P. Nichols, A.G. Ziady, S.L. Shank, J.F. Eastman, P.B. Davis. The triterpenoid CDDO limits 

inflammation in preclinical models of cystic fibrosis lung disease. Am J Physiol Lung Cell Mol 

Physiol. 2009. 297(5):L828-836. PMCID: PMC2777499

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 60
e. J. Chen, M. Kinter, S. Shank, C. Cotton, T.J. Kelley, A.G. Ziady*. Dysfunction of Nrf-2 in

CF epithelia leads to excess intracellular H2O2 and inflammatory cytokine production. PLoS

ONE. 2008. 3(10): e3367 doi:10.1371/journal.pone.0003367. PMCID: PMC2563038

2. Nanoparticle-mediated gene transfer and nucleic acid delivery. We have focused our on

developing, optimizing, and examining the biology of nucleic acid nanoparticles. For our DNA

nanoparticles have set a paradigm for non-viral gene delivery in vivo, and have played a key

role in testing them in the clinic. They are also the subject of 6 patents on which I am inventor.

In my lab, we have developed imaging techniques that allow us to examine the activity and

distribution of this gene delivery agent in vivo using real-time measurements and have made

inroads on translating these experiments to human studies. These studies have allowed us to

more efficiently examine the effects of repeated administration over time, as this is needed for a 

non-viral and non-integrating gene expression system. In recent years we have focused on the

biology of the nanoparticles in cells by examining the interactome of the particles. We have

defined a number of proteins and cellular pathways responsible for the uptake and nuclear

delivery of the particles. This is the first time the biology of the particles has been examined. Our

goal is to better understand the determinants of successful gene delivery by the particles and

manipulate these pathways to enhance the utility of this vector in humans. The long-term goal for

the gene therapy work in our lab is to develop DNA nanoparticles that can target specific cell

types, including respiratory airway epithelia, hepatocytes, or neurons.

a. D.M. Yurek, A.M. Fletcher, M. McShane, T.H. Kowalczyk, L. Padegimas, M.R. Weatherspoon,

M.D. Kaytor, M.J. Cooper, A.G. Ziady*. DNA Nanoparticles: Detection of long-term transgene

activity in brain using bioluminescence imaging. Mol Imaging. 2011. 10(5):327-339. PMCID:

PMC3173525

b. X. Chen, S. Shank, P.B. Davis, A.G. Ziady*. Nucleolin-mediated cellular trafficking of DNA

nanoparticle is lipid raft and microtubule dependent and can be modulated by glucocorticoid.

Mol Ther. 2011. 19(1):93-102. PMCID: PMC3017445

c. A.G. Ziady*, M. Kotlarchyk, L. Bryant, M. McShane, Z. Lee. Bioluminescent imaging of reporter

gene expression in the lungs of wildtype and model mice following the administration of

PEG- stabilized DNA nanoparticles. Microsc Res Tech. 2010. 73(9):918-928.

d. A.G. Ziady, C.R. Gedeon, O. Muhammad, V. Stillwell, S. Oette, T. Fink, W. Quan, T.

Kowalczyk, S.L. Hyatt, A. Peischl, J.E. Seng, R. Moen, M.J. Cooper, P.B. Davis. Minimal

toxicity of stabilized compacted DNA in the murine lung. Mol. Ther. 2003. 8(6): 948-956. 

PM:14664797

e. A.G. Ziady*, C.R. Gedeon, T. Miller, W. Quan, J.M. Payne, S.L. Hyatt, T. Fink, O. Muhammad,

S. Oette, T. Kowalczyk, M.K. Pasumarthy, R. Moen, M.J. Cooper, P.B. Davis. Transfection of

airway epithelium by stable PEGylated Poly-L-lysine DNA nanoparticles in vivo. Mol. Ther. 

2003. 8(6): 936-947. PM:14664796

3. Understanding the molecular basis of CF and other inflammatory diseases. We have developed a line

of work in the lab based on our expertise with proteomics, where we use analyses to examine the

proteome of disease severity and progression. In non-bias analyses that are not targeted, we have

used high throughput proteomics to discover biomarkers of disease. We have also used targeted

approaches to look at changes in protein, for example, the modification of albumin with mold toxins or

protein changes that make mycobacterium more virulent. Our chief focus lately is the examination of

the proteomic underpinnings of CF disease severity and markers of disease progression.

a. C. Sinha, A. Ren, K. Arora, C.S. Moon, S. Yarlagadda, K. Woodrooffe, S. Lin, J.D. Schuetz,

A.G. Ziady, and A.P. Naren. PKA and actin play critical roles as downstream effectors in

MRP4- mediated regulation of fibroblast migration. Cell Signal. 2015, 27(7):1345-1355. PMID:

25841995

b. Q. Li, X. Ding, J.J. Thomas, C.V. Harding, N.D. Pecora, A.G. Ziady, S. Shank, W.H. Boom,

C.L. Lancioni, R.E. Rojas. Rv2468c, a novel Mycobacterium tuberculosis protein that costimulates human CD4+ T cells through VLA-5. J Leukoc Biol. 2012. 91(2):311-320. PMCID:

PMC3290430

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 61
c. C.L. Lancioni, Q. Li, J.J. Thomas, X. Ding, M.G. Drage, N.D. Pecora, A.G. Ziady, S. Shank,

C.V. Harding, W.H. Boom, R.E. Rojas. Mycobacterium tuberculosis lipoproteins induce human

memory CD4+ T cell activation via toll-like receptors 1 and 2. Infect and Immun 2011. 79(2):663-

673. PMCID: PMC3028837 

d. I. Yike, A.M. Distler, A.G. Ziady, D.G. Dearborn. Mycotoxin Adducts on Human Serum Albumin: 

Biomarkers of Exposure to Stachybotrys chartarum. Environ Health Perspect. 2006. 114(8):1221- 

1226. PMCID: PMC1552036

D. Research Support

Ongoing Research Support 

CFF CCHMC Research Development Program (Clancy) 07/1/2015-06/30/2019

Cystic Fibrosis Foundation 

The Biomarkers Analysis and Assay Development Core of the CCHMC RDP encompasses the assays for the 

center grant. The Core conducts the examination of CFTR responses to available and future potentiators and 

correctors, the examination of the links between CFTR and the various pathologies of the disease, and the 

detailed examination of protein interactions that modulate CFTR localization and function.

Role: Biomarker Analysis and Assay Development Core PI

Gilead Sciences Grant (Nichols, Ziady) 07/1/2015-06/30/2016

Testing the effects of azithromycin exposure on established antibiotic resistance pathways in P. aeruginosa CF 

clinical isolates. We plan to study the proteome of P. aeruginosa following long term exposure to azithromycin.

Role: Contract PI

1R01HL109362-01 (Ziady) 07/1/11- 04/30/16

NIH/NHLBI

Nrf2 dysfunction in CF epithelia. We plan to examine the mechanisms of the dysregulation of Nrf2 in CF 

airway epithelial cells using proteomic and biochemical approaches.

Role: PI

1R01HL116226-01 (Clancy, Ziady) 09/26/12-06/30/16

NIH/NHLBI

MR predictors of infection, inflammation, and structural lung damage in CF. We aim to use imaging modalities 

to study early infection and inflammation in the lungs of CF patients.

Role: Co-PI

Contact PD/PI: Ambroggio, Lilliam

Biosketches Page 62
Contact PD/PI: Ambroggio, Lilliam

 

For New and Renewal Applications (PHS 398) – DO NOT SUBMIT UNLESS REQUESTED

PHS 398 OTHER SUPPORT

Provide active and pending support for all senior/key personnel. Other Support includes all financial resources, whether Federal, non-Federal, 

commercial or institutional, available in direct support of an individual's research endeavors, including but not limited to research grants, 

cooperative agreements, contracts, and/or institutional awards. Training awards, prizes, or gifts do not need to be included.

There is no "form page" for other support. Information on other support should be provided in the format shown below, using continuation pages as 

necessary. The sample below is intended to provide guidance regarding the type and extent of information requested. 

For instructions and information pertaining to the use of and policy for other support, see Other Support in the Supplemental Instructions, Part III, 

Policies, Assurances, Definitions, and Other Information. 

Effort devoted to projects must be measured using person months. Indicate calendar, academic, and/or summer months associated with each project.

SHAH, Samir S.

Active

R01 HL122261 Sara K. Pasquali (PI) 04/01/2014-03/31/2019 0.6 calendar

National Heart Lung Blood Institute $

Understanding quality and costs in congenital heart surgery

Role: Co-Investigator

Goal: The objective is to determine better methods of evaluating quality and cost in children undergoing 

congenital heart surgery.

Octavio Ramilo (PI) 07/01/2015-6/31/2017 0.2 calendar

Governor’s Office, State of Ohio $ 

Children’s Hospitals Research Initiative in Pneumonia (CHIRP)

Role: Site Principal Investigator

Goal: To focus on improving the etiologic diagnosis of children with pneumonia.

IHS-1306-00811 Samir S. Shah (PI) 05/01/2014-04/30/2017 2.4 calendar

Patient-Centered Outcomes Research Institute $

Improving post-discharge outcomes by facilitating family-centered transitions from hospital to home

Role: Principal Investigator

Goal: The objective is to determine the efficacy of a nurse home visit in improving patient and family 

outcomes following a child's hospitalization for acute illness.

IHS-1306-00811 Samir S. Shah (PI) 01/04/2016-04/28/2017 0.4 calendar

Patient-Centered Outcomes Research Institute $ 

Supplemental Funding: Improving post-discharge outcomes by facilitating family-centered transitions from 

hospital to home

Role: Principal Investigator

Goal: The objective is to determine the efficacy of a nurse home visit in improving patient and family 

outcomes following a child's hospitalization for acute illness.

Pending 

David Kimberlin (PI) 07/01/2016-06/30/2018 1.2 calendar

National Institute of Allergy and Infectious Diseases $

Burden of neonatal herpes simplex virus infections: disease incidence, adequacy of diagnostic assessment 

and societal costs

Role: Co-Investigator; disease incidence and diagnostic assessment project lead

Goal: The objective is to determine incidences of neonatal herpes simplex virus (HSV) (KID and MDD), 

quantifying hospital level variation in evaluation of neonates suspected of having HSV (PHIS), determining 

Current and Pending Support Page 63
Contact PD/PI: Ambroggio, Lilliam

 

the prevalence of mortality among neonates with HSV (KID), and determining the index hospitalization costs 

and the post-hospitalization costs, including outpatient and subsequent inpatient utilization costs, for neonates 

with HSV (MDD).

Karen Wilson (PI) 09/01/2016-06/30/2021 1.2 calendar

National Heart, Lung and Blood Institute $ 

Modifiable risk factors for asthma after bronchiolitis

Role: Site Principal Investigator

Goal: The objective is to understand the modifiable risk factors for asthma after bronchiolitis, and to identify 

targets for personalized preventive interventions to stop asthma from developing in these patients.

Current and Pending Support Page 64
Contact PD/PI: Ambroggio, Lilliam

OTHER SUPPORT 

Maurizio Macaluso, Ph.D. 

ACTIVE

ULRRR026314 (Heubi) 07/1/2015 – 06/30/2020 3.6 cal months

CCTST/UC $

Clinical and Translational Science Award (BERD)

This is the national consortium of medical research institutions, funded through Clinical and Translational 

Science Awards (CTSAs), which is working together to: 

 - Improve the way biomedical research is conducted across the country

 - Reduce the time it takes for laboratory discoveries to become treatments for patients

 - Engage communities in clinical research efforts

 - Train the next generation of clinical and translational researchers

Role: Director/Co-Director of BioMetrics Core

P30 DK078392 (Bezerra) 08/1/2007 - 05/31/2017 0.54 cal months

NIH/NIDDK $

Digestive Health Center: Bench to Bedside Research in Pediatric Digestive Disease

The major goal is to provide core services to advance digestive disease research at Cincinnati Children's 

Hospital Medical Center and the University of Cincinnati.

Role: Co-Investigator

T32DK007695 (Devarajan) 07/1/2014 – 06/30/2019 0.6 cal months

Research Training in Pediatric Nephrology $ No salary support

Goal: To foster the development of outstanding clinical or basic science physician investigator and leaders 

who will meet the tremendously underserved academic workforce needs in Pediatric Nephrology.

Role: Mentor

K23 (Reed) 05/1/2014 – 04/30/2018 0.6 cal months

NIH $ No salary support

Decreasing teen STI prevalence through universal emergency department screening 

Goal: The objective of this proposal is to design and test the feasibility and effectiveness of a universal CT/GC 

screening program in the ED.

Role: Co-Investigator

U18HS016957 Lannon (PI) 09/30/2011 – 08/31/2016 0.72 cal months

CERTs (Agcy for Healthcare Research and Quality) $

Pursuing Perfection in Pediatric Therapeutics

The CERTs Research Center (RC) will focus on improving outcomes for children by optimizing the use of 

therapeutics. Additional sub-themes, with expected impact beyond pediatrics, are pharmacogenomics and 

personalized medicine, patient safety, and quality improvement methodology. 

Role: Co-Investigator

OPQC Anderson Center 07/01/2015 – 06/30/2016 0.72 cal months

NAS – Federal $

On behalf of the Ohio Perinatal Quality Collaborative, the Anderson Center at Cincinnati Children's Hospital 

Medical Center will provide the project management, QI design and dissemination oversight, and data 

management and analysis support for the four years of the proposed project.

Role: Co-Investigator

(Kim, Macaluso, Liu, Zou) 01/01/2015 – 12/31/2018 0.36 cal months

PCORI $

Propensity Score-based Methods for CER Using Multilevel Data: What Works Best When

Current and Pending Support Page 65
Goal: The goal of this project is to investigate how to optimally extend the PS methodology and identify what 

works best when. An additional goal is to develop a novel imputation-based sensitivity analysis approach and

to identify valid and most efficient PS methods for two existing CER studies.

Role: Co-Investigator 

1KL2TR001426-01 (Tsevat) 08/14/2015 – 03/31/2019 1.2 cal months

NIH/CCTST $

The goal of the Institutional CTSA is to create a research environment that facilitates translating discoveries to 

clinical application. The KL2 is the mentored career development portion of the CTSA.

Role: Site PI

PENDING

(Piyathilake) 07/1/2016 – 06/30/2021 1.8 cal months

UAB $

(PQ 10) Interplay between cervical microbiome and HPV and risk of CIN risk after LEEP

Goal: The goal is to lead the analysis of the microbial 16S and whole metagenome shotgun DNA sequencing 

data and coordinate all analytic work. Also, to provide expertise in epidemiology, biostatistics and clinical data 

management in support of this project

Role: PI/CCHMC Sub

K23 (Nehus) 02/12/2016 – 01/31/2021 no salary support

NIH $

Early Kidney Injury and Adipokine Dysregulation in Severe Obesity

Goal: The proposed study will investigate the association of adipokine abnormalities with early kidney disease 

in severely obese adolescents undergoing weight reduction surgery. Improved understanding of obesitymediated kidney disease will support future studies that identify, treat, and prevent kidney disease in children 

with severe obesity.

Role: Mentor

U24OD023376-01 (Macaluso/White) 09/1/2016 – 08/31/2023 4.8 cal months

NIH $

The ECHO Data Analysis Center at Cincinnati Children's

Goal: The Environmental Influences on Child Health Outcomes (ECHO) program has been established to 

investigate the longitudinal impact of prenatal, perinatal, and postnatal environmental exposures (physical, 

chemical, biological, behavioral, social) on pediatric health outcomes with high public health impact in the 

following four areas: 1) upper and lower airway, 2) obesity, 3) pre-, peri-, and postnatal outcome, and 4) 

neurodevelopment.

Role: PI

OVERLAP

None

Contact PD/PI: Ambroggio, Lilliam

Current and Pending Support Page 66
Contact PD/PI: Ambroggio, Lilliam

For New and Renewal Applications (PHS 398) – DO NOT SUBMIT UNLESS REQUESTED

PHS 398 OTHER SUPPORT

Provide active and pending support for all senior/key personnel. Other Support includes all financial resources, whether Federal, non-Federal, 

commercial or institutional, available in direct support of an individual's research endeavors, including but not limited to research grants, 

cooperative agreements, contracts, and/or institutional awards. Training awards, prizes, or gifts do not need to be included.

There is no "form page" for other support. Information on other support should be provided in the format shown below, using continuation pages as 

necessary. The sample below is intended to provide guidance regarding the type and extent of information requested. 

For instructions and information pertaining to the use of and policy for other support, see Other Support in the Supplemental Instructions, Part III, 

Policies, Assurances, Definitions, and Other Information. 

Effort devoted to projects must be measured using person months. Indicate calendar, academic, and/or summer months associated with each project.

Ruddy, RM

ACTIVE/PENDING

1 U03MC22684 (Ruddy) 9/01/2011 – 08/31/2019 2.4 Cal

HRSA $ 

EMSC: Network Development Demonstration Project

This funding supports the Pediatric Emergency Care Applied Research (PECARN) Network. 

Role: PI

Gerber Pediatric Research Grant 1/2014 – 12/2016 0.3 cal

Gerber Foundation $ 

Clinical prediction model for community-acquired pneumonia

This project will use clinical data and the biomarker procalcitonin to develop a severity score used to predict 

the development of severe disease and complications in children with community-acquired pneumonia, the 

most common serious bacterial infection children and leading killer of children worldwide.

Role: Co-I

1R01HD071915-01 (Schnadower) 12/10/2013-11/30/2018 0.2 cal

NIH/NICHD $ 

Impact of Emergency Department Probiotic Treatment of Pediatric Gastroenteritis

We propose to study the effectiveness and side effects of a Probiotic, LGG, in treating children with 

Gastroenteritis. If successful, this therapeutic intervention would be the first Treatment that actually changes 

the disease process and would represent an enormous public health advance both in the US, and potentially, 

globally.

Role: Co-I

R21 (Mahajan) 8/21/2015-4/30/2020 0.6 cal

NIH $ 

RNA Biosignatures: A Paradigm Change for the Management of Young Febrile Infants

This project will study how to: (1) improve the precision and narrow the confidence intervals around the 

diagnostic accuracy of RNA biosignatures in this population; (2) assure that the discriminatory expression 

profiles among febrile infants in the studied categories remain stable over time and understand the impact of 

antipyretics and/or antibiotics on the biosignatures; (3) utilize the technology efficiently at the bedside.

Role: Co-I

1 U03 Admin Supplement (Ruddy) 09/01/15 – 08/31/16 1.8 cal

HRSA $ 

EMSC: Network Development Demonstration Project

This funding supports Dr. Ruddy’s role as the CHAIR of the Pediatric Emergency Care Applied Research 

(PECARN) Network

Role: PI

1 U03 Admin Supplement (Ruddy) 09/01/15 – 08/31/16 0.0 cal

HRSA $ 

EMSC: Network Development Demonstration Project

This funding supports meetings costs for the PECARN network

Role: PI

Current and Pending Support Page 67
OVERLAP 

None

Contact PD/PI: Ambroggio, Lilliam

Current and Pending Support Page 68
Contact PD/PI: Ambroggio, Lilliam

 

For New and Renewal Applications (PHS 398) – DO NOT SUBMIT UNLESS REQUESTED

For Non-competing Progress Reports (PHS 2590) – Submit only Active Support for Key Personnel

PHS 398/2590 OTHER SUPPORT

Provide active support for all key personnel. Other Support includes all financial resources, whether Federal, non-Federal, commercial or 

institutional, available in direct support of an individual's research endeavors, including but not limited to research grants, cooperative 

agreements, contracts, and/or institutional awards. Training awards, prizes, or gifts do not need to be included.

There is no "form page" for other support. Information on other support should be provided in the format shown below, using continuation pages as 

necessary. Include the principal investigator's name at the top and number consecutively with the rest of the application. The sample below is 

intended to provide guidance regarding the type and extent of information requested. 

For instructions and information pertaining to the use of and policy for other support, see Other Support in the PHS 398 Part III, Policies, Assurances, 

Definitions, and Other Information. 

Note effort devoted to projects must now be measured using person months. Indicate calendar, academic, and/or summer months associated with each 

project.

Format

NAME OF INDIVIDUAL

ACTIVE/PENDING 

Project Number (Principal Investigator) 

Source

Title of Project (or Subproject)

The major goals of this project are...

Dates of Approved/Proposed Project

Annual Direct Costs

Person Months

(Cal/Academic/

Summer)

OVERLAP (summarized for each individual)

STRINGER, KATHLEEN

ACTIVE

R01 GM078200 (Rosania, PI) 9/1/12-7/31/16 0.6 CM

NIH $ 

Chemical Address Tags: A Cheminformatics & Image Data Management and Analysis Plan

The goal of this project is to develop machine vision and image analysis tools to relate the chemical 

structure of small molecules to their subcellular localization as apparent in image data.

Role: Co-Investigator

No number (Stringer, PI) 6/30/15-6/30/16 0.0 CM

American Foundation of Pharmaceutical Education $

Pulmonary Delivered Tissue Plasminogen Activator (tPA) Drug Action in the Lungs

The goal of this research is to advance understanding of the molecular mechanisms of tPA drug action in the 

lungs when given for the treatment of the complex pediatric illness, plastic bronchitis (PB).

Role: PI

R01 GM111400 (Stringer, PI) 4/1/16-1/31/20 2.4 CM

NIH $ 

L-Carnitine Pharmacometabolomics in Sepsis (CaPS)

This project will introduce a personalized medicine approach called pharmacometabolomics to sepsis treatment 

in an effort to determine which patients are more likely to respond to a new therapy.

Role: PI

PENDING

No number (Stringer, PI) 11/1/16-10/31/20 1.8 CM

FDA $ 

IND119678 Phase II Safety & Efficacy of Inhaled Activase for Acute Plastic Bronchitis

The goal of this project is to test the safety and effectiveness of the designated orphan drug, inhaled tPA, for the 

treatment of acute exacerbations of plastic bronchitis (PB). 

Role: PI

R01 (Rosania, PI) 9/1/16-8/31/21 1.2 CM

Current and Pending Support Page 69
Contact PD/PI: Ambroggio, Lilliam

 

NIH $ 

Intracellular Drug Inclusions: Unwanted Side Effect or Active Therapeutic Agent? 

The goal of this project is to develop strategies for reducing the incidence of systemic off-target 

side-effects through improved understanding of drug transport properties; this will be of great benefit to 

patients across all therapeutic areas.

Role: Co-Investigator

R01 GM078200 (Rosania, PI) 9/1/16-8/31/20 (renewal) 1.2 CM

NIH $ 

Chemical Address Tags: A Cheminformatics & Image Data Management and Analysis Plan

The goal of this project is to develop machine vision and image analysis tools to relate the chemical 

structure of small molecules to their subcellular localization as apparent in image data.

Role: Co-Investigator

No number (Ambroggio, PI) 11/1/16-10/31/19 1.2 CM

Thrasher Research Fund $ 

Using Metabolite Signatures to Distinguish Viral and Bacterial Pneumonia in Children

We hypothesize that pathogen-specific metabolite profiles can be quantified using NMR which will result in the 

development of a diagnostic test for timely and accurate diagnosis to permit targeted and effective management 

of pneumonia. 

Role: Co-Investigator

OVERLAP

None

Current and Pending Support Page 70
Contact PD/PI: Ambroggio, Lilliam

Other Support 

SUCHAREW, HEIDI

ACTIVE

IHS -1306-00811 (Shah) 07/01/2014 – 06/30/2017 2.4 calendar months

PCORI $ 

Improving post-discharge outcomes by facilitating family-centered transitions from hospital to home

Goal: Our overarching goal is to improve the outcomes of hospital to home transitions for acutely ill hospitalized 

children and their families.

Role: Co-I 

Place Outcomes (Brady) 07/01/2014 – 06/30/2016 0.72 calendar months

CCHMC $

Developing and Evaluating User-Designed Data Displays

Goal: Our long term objective is to partner with end-users to develop data visualizations that organize and 

display data in a way that informs common decisions made on the frontlines of clinical care.

Role: Co-I 

R01NS030678 (Kleindorfer/Khoury) 04/01/2015 – 07/31/2018 4.8 calendar months

NIH - Resubmission $ 

Comparison of Hemorrhagic & Ischemic Stroke Among Blacks and Whites

Goal: Tracking of population-based stroke incidence in the Greater Cincinnati and Northern Kentucky region, 

with special emphasis on stroke in the young and stroke recurrence.

Role: Co-I 

R34 MH101155-01 (Brinkman) 04/01/2014 – 03/31/2017 0.6 calendar months

NIMH $

Developing New Technologies to Improve ADHD Mediation Continuity

Role: Biostatistician

IHS -1306-00811 (Shah) 01/04/2016 – 04/28/2017 0.48 calendar months

PCORI - Supplement $

Improving post-discharge outcomes by facilitating family-centered transitions from hospital to home

Goal: Our overarching goal is to improve the outcomes of hospital to home transitions for acutely ill hospitalized 

children and their families.

Role: Co-I 

Shah, Anita 03/01/2016 – 02/28/2017 0.48 calendar months

APA $

Effect of Parental Adverse Childhood Experiences and Resilience on Outcomes After Pediatric Discharge

Goal: The objectives of this proposal are to determine the prevalence of ACEs and levels of resilience among 

the parents of hospitalized children, their association with a parent’s post-discharge coping, and their 

association with their child’s rate of unplanned post discharge utilization.

Role: Biostatistician

Academic Res Committee Funding (Ambroggio) 1/12/2016 – 1/11/2018 1.8 calendar months

CCHMC $

Catalyzing Ambulatory Research in Pneumonia Etiology and Diagnostic Innovations in Emergency medicine 

(CARPE DIEM)

Goal: The objective of this study is to identify distinct metabolite profiles for the major classes of pathogens that 

cause CAP in children (e.g. virus, typical and atypical bacteria). Urine, blood samples, and nasopharyngeal 

swabs will be collected from children diagnosed with CAP in the Emergency Department or who are 

hospitalized at Cincinnati Children’s Hospital Medical Center. All urine samples will then be evaluated using 

Current and Pending Support Page 71
Contact PD/PI: Ambroggio, Lilliam

quantitative 1H-nuclear magnetic resonance. Advanced statistical methods such as partial least squaresdiscriminant analysis will be applied to the identified metabolite dataset to determine unique metabolite profiles. 

Role: Co-I 

PENDING

UC CARES (Cecil) 09/01/2016 – 06/30/2021 1.8 calendar months

NIH/UC (sub) $ 

Developmental Effects of Manganese Exposure in Rural Adolescents: The CARES Cohort Comes of Age

Goal: This project will innovatively examine the impact of manganese exposure along with other known 

neurotoxicants, including lead and tobacco smoke, in a follow-up study of a rural, Appalachian cohort. We will 

examine the impact of these exposures on neurobehavior, postural balance and gait, brain anatomy and 

physiology.

Role: Biostatistician

U24OD023376-01 (Macaluso/White) 09/01/2016 – 08/31/2023 1.2 cal months

NIH $ YRS 3-7 only

The ECHO Data Analysis Center at Cincinnati Children's

Goal: The Environmental Influences on Child Health Outcomes (ECHO) program has been established to 

investigate the longitudinal impact of prenatal, perinatal, and postnatal environmental exposures (physical, 

chemical, biological, behavioral, social) on pediatric health outcomes with high public health impact in the 

following four areas: 1) upper and lower airway, 2) obesity, 3) pre-, peri-, and postnatal outcome, and 4) 

neurodevelopment.

Role: Co-I 

R34 (Brinkman) 04/01/2017 – 03/31/2019 0.72 cal months

NIH $ YR3 only

Improving Medication Continuity among Adolescents with ADHD

Goal: The overall objective of this application is to develop and test a multi-component intervention that 

systematically identifies and targets aspects of the UTBC model most

relevant for each adolescent with poor ADHD medication continuity.

Role: Co-I

Current and Pending Support Page 72
OMB Number: 4040-0001

Expiration Date: 06/30/2016

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date: 2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  1

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2017 End Date*: 03-31-2018 Budget Period: 1

A. Senior/Key Person

# Prefix First Name* Middle

Name

Last Name* Suffix Project Role* Base

Salary ($)

Calendar

Months

Academic

Months

Summer

Months

Requested

Salary ($)*

Fringe

Benefits ($)*

Funds Requested ($)*

1 . Lilliam Ambroggio PD/PI 9 0 0

Total Funds Requested for all Senior Key Persons in the attached file 0.00

Additional Senior Key Persons: File Name: Total Senior/Key Person

Mime Type:

B. Other Personnel

Number of

Personnel*

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)*

Post Doctoral Associates

Graduate Students

Undergraduate Students

Secretarial/Clerical

0 Total Number Other Personnel Total Other Personnel 0.00

Total Salary, Wages and Fringe Benefits (A+B)

RESEARCH & RELATED Budget {A-B} (Funds Requested)

Contact PD/PI: Ambroggio, Lilliam

 Page 73
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 1

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2017 End Date*: 03-31-2018 Budget Period: 1

C. Equipment Description

List items and dollar amount for each item exceeding $5,000

Equipment Item Funds Requested ($)*

Total funds requested for all equipment listed in the attached file 0.00

Total Equipment 0.00

Additional Equipment: File Name:

Mime Type:

D. Travel Funds Requested ($)*

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions) 0.00

2. Foreign Travel Costs 0.00

Total Travel Cost 0.00

E. Participant/Trainee Support Costs Funds Requested ($)*

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other: 

 Number of Participants/Trainees Total Participant Trainee Support Costs

RESEARCH & RELATED Budget {C-E} (Funds Requested)

 Page 74
Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 1

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2017 End Date*: 03-31-2018 Budget Period: 1

F. Other Direct Costs Funds Requested ($)*

1. Materials and Supplies

2. Publication Costs 0.00

3. Consultant Services 0.00

4. ADP/Computer Services 0.00

5. Subawards/Consortium/Contractual Costs 0.00

6. Equipment or Facility Rental/User Fees 0.00

7. Alterations and Renovations 0.00

Total Other Direct Costs

G. Direct Costs Funds Requested ($)*

Total Direct Costs (A thru F)

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)*

1 . Federal (MTDC) 8

Total Indirect Costs

Cognizant Federal Agency

(Agency Name, POC Name, and POC Phone Number)

Department of Health and Human Services, Arif Karim,

214-767-3261

I. Total Direct and Indirect Costs Funds Requested ($)*

Total Direct and Indirect Institutional Costs (G + H)

J. Fee Funds Requested ($)*

0.00

K. Budget Justification* File Name:

BUDGET_JUSTIFICATION_AmbroggioK01_2016_07_08.pdf

Mime Type: application/pdf

(Only attach one file.)

RESEARCH & RELATED Budget {F-K} (Funds Requested)

Contact PD/PI: Ambroggio, Lilliam

 Page 75
OMB Number: 4040-0001

Expiration Date: 06/30/2016

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date: 2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  2

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2018 End Date*: 03-31-2019 Budget Period: 2

A. Senior/Key Person

# Prefix First Name* Middle

Name

Last Name* Suffix Project Role* Base

Salary ($)

Calendar

Months

Academic

Months

Summer

Months

Requested

Salary ($)*

Fringe

Benefits ($)*

Funds Requested ($)*

1 . Lilliam Ambroggio PD/PI 9 0 0

Total Funds Requested for all Senior Key Persons in the attached file 0.00

Additional Senior Key Persons: File Name: Total Senior/Key Person

Mime Type:

B. Other Personnel

Number of

Personnel*

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)*

Post Doctoral Associates

Graduate Students

Undergraduate Students

Secretarial/Clerical

0 Total Number Other Personnel Total Other Personnel 0.00

Total Salary, Wages and Fringe Benefits (A+B)

RESEARCH & RELATED Budget {A-B} (Funds Requested)

Contact PD/PI: Ambroggio, Lilliam

 Page 76
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 2

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2018 End Date*: 03-31-2019 Budget Period: 2

C. Equipment Description

List items and dollar amount for each item exceeding $5,000

Equipment Item Funds Requested ($)*

Total funds requested for all equipment listed in the attached file 0.00

Total Equipment 0.00

Additional Equipment: File Name:

Mime Type:

D. Travel Funds Requested ($)*

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions) 0.00

2. Foreign Travel Costs 0.00

Total Travel Cost 0.00

E. Participant/Trainee Support Costs Funds Requested ($)*

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other: 

 Number of Participants/Trainees Total Participant Trainee Support Costs

RESEARCH & RELATED Budget {C-E} (Funds Requested)

 Page 77
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 2

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2018 End Date*: 03-31-2019 Budget Period: 2

F. Other Direct Costs Funds Requested ($)*

1. Materials and Supplies

2. Publication Costs 0.00

3. Consultant Services 0.00

4. ADP/Computer Services 0.00

5. Subawards/Consortium/Contractual Costs 0.00

6. Equipment or Facility Rental/User Fees 0.00

7. Alterations and Renovations 0.00

Total Other Direct Costs

G. Direct Costs Funds Requested ($)*

Total Direct Costs (A thru F)

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)*

1 . Federal (MTDC) 8 118,750.00

Total Indirect Costs

Cognizant Federal Agency

(Agency Name, POC Name, and POC Phone Number)

Department of Health and Human Services, Arif Karim,

214-767-3261

I. Total Direct and Indirect Costs Funds Requested ($)*

Total Direct and Indirect Institutional Costs (G + H)

J. Fee Funds Requested ($)*

0.00

K. Budget Justification* File Name:

BUDGET_JUSTIFICATION_AmbroggioK01_2016_07_08.pdf

Mime Type: application/pdf

(Only attach one file.)

RESEARCH & RELATED Budget {F-K} (Funds Requested)

 Page 78
OMB Number: 4040-0001

Expiration Date: 06/30/2016

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date: 2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  3

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2019 End Date*: 03-31-2020 Budget Period: 3

A. Senior/Key Person

# Prefix First Name* Middle

Name

Last Name* Suffix Project Role* Base

Salary ($)

Calendar

Months

Academic

Months

Summer

Months

Requested

Salary ($)*

Fringe

Benefits ($)*

Funds Requested ($)*

1 . Lilliam Ambroggio PD/PI 9 0 0

Total Funds Requested for all Senior Key Persons in the attached file 0.00

Additional Senior Key Persons: File Name: Total Senior/Key Person

Mime Type:

B. Other Personnel

Number of

Personnel*

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)*

Post Doctoral Associates

Graduate Students

Undergraduate Students

Secretarial/Clerical

0 Total Number Other Personnel Total Other Personnel 0.00

Total Salary, Wages and Fringe Benefits (A+B)

RESEARCH & RELATED Budget {A-B} (Funds Requested)

Contact PD/PI: Ambroggio, Lilliam

 Page 79
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 3

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2019 End Date*: 03-31-2020 Budget Period: 3

C. Equipment Description

List items and dollar amount for each item exceeding $5,000

Equipment Item Funds Requested ($)*

Total funds requested for all equipment listed in the attached file 0.00

Total Equipment 0.00

Additional Equipment: File Name:

Mime Type:

D. Travel Funds Requested ($)*

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions) 0.00

2. Foreign Travel Costs 0.00

Total Travel Cost 0.00

E. Participant/Trainee Support Costs Funds Requested ($)*

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other: 

 Number of Participants/Trainees Total Participant Trainee Support Costs

RESEARCH & RELATED Budget {C-E} (Funds Requested)

 Page 80
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 3

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2019 End Date*: 03-31-2020 Budget Period: 3

F. Other Direct Costs Funds Requested ($)*

1. Materials and Supplies

2. Publication Costs 0.00

3. Consultant Services 0.00

4. ADP/Computer Services 0.00

5. Subawards/Consortium/Contractual Costs 0.00

6. Equipment or Facility Rental/User Fees 0.00

7. Alterations and Renovations 0.00

Total Other Direct Costs

G. Direct Costs Funds Requested ($)*

Total Direct Costs (A thru F)

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)*

1 . Federal (MTDC) 8

Total Indirect Costs

Cognizant Federal Agency

(Agency Name, POC Name, and POC Phone Number)

Department of Health and Human Services, Arif Karim,

214-767-3261

I. Total Direct and Indirect Costs Funds Requested ($)*

Total Direct and Indirect Institutional Costs (G + H)

J. Fee Funds Requested ($)*

0.00

K. Budget Justification* File Name:

BUDGET_JUSTIFICATION_AmbroggioK01_2016_07_08.pdf

Mime Type: application/pdf

(Only attach one file.)

RESEARCH & RELATED Budget {F-K} (Funds Requested)

 Page 81
OMB Number: 4040-0001

Expiration Date: 06/30/2016

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date: 2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  4

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2020 End Date*: 03-31-2021 Budget Period: 4

A. Senior/Key Person

# Prefix First Name* Middle

Name

Last Name* Suffix Project Role* Base

Salary ($)

Calendar

Months

Academic

Months

Summer

Months

Requested

Salary ($)*

Fringe

Benefits ($)*

Funds Requested ($)*

1 . Lilliam Ambroggio PD/PI 9 0 0

Total Funds Requested for all Senior Key Persons in the attached file 0.00

Additional Senior Key Persons: File Name: Total Senior/Key Person

Mime Type:

B. Other Personnel

Number of

Personnel*

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)*

Post Doctoral Associates

Graduate Students

Undergraduate Students

Secretarial/Clerical

0 Total Number Other Personnel Total Other Personnel 0.00

Total Salary, Wages and Fringe Benefits (A+B)

RESEARCH & RELATED Budget {A-B} (Funds Requested)

Contact PD/PI: Ambroggio, Lilliam

 Page 82
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 4

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2020 End Date*: 03-31-2021 Budget Period: 4

C. Equipment Description

List items and dollar amount for each item exceeding $5,000

Equipment Item Funds Requested ($)*

Total funds requested for all equipment listed in the attached file 0.00

Total Equipment 0.00

Additional Equipment: File Name:

Mime Type:

D. Travel Funds Requested ($)*

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions) 0.00

2. Foreign Travel Costs 0.00

Total Travel Cost 0.00

E. Participant/Trainee Support Costs Funds Requested ($)*

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other: 

 Number of Participants/Trainees Total Participant Trainee Support Costs

RESEARCH & RELATED Budget {C-E} (Funds Requested)

 Page 83
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 4

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2020 End Date*: 03-31-2021 Budget Period: 4

F. Other Direct Costs Funds Requested ($)*

1. Materials and Supplies

2. Publication Costs 0.00

3. Consultant Services 0.00

4. ADP/Computer Services 0.00

5. Subawards/Consortium/Contractual Costs 0.00

6. Equipment or Facility Rental/User Fees 0.00

7. Alterations and Renovations 0.00

Total Other Direct Costs

G. Direct Costs Funds Requested ($)*

Total Direct Costs (A thru F)

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)*

1 . Federal (MTDC) 8 118,750.00

Total Indirect Costs

Cognizant Federal Agency

(Agency Name, POC Name, and POC Phone Number)

Department of Health and Human Services, Arif Karim,

214-767-3261

I. Total Direct and Indirect Costs Funds Requested ($)*

Total Direct and Indirect Institutional Costs (G + H)

J. Fee Funds Requested ($)*

0.00

K. Budget Justification* File Name:

BUDGET_JUSTIFICATION_AmbroggioK01_2016_07_08.pdf

Mime Type: application/pdf

(Only attach one file.)

RESEARCH & RELATED Budget {F-K} (Funds Requested)

 Page 84
OMB Number: 4040-0001

Expiration Date: 06/30/2016

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date: 2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION A & B, Budget Period  5

ORGANIZATIONAL DUNS*:   

Budget Type*: ● Project ❍ Subaward/Consortium

Enter name of Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2021 End Date*: 03-31-2022 Budget Period: 5

A. Senior/Key Person

# Prefix First Name* Middle

Name

Last Name* Suffix Project Role* Base

Salary ($)

Calendar

Months

Academic

Months

Summer

Months

Requested

Salary ($)*

Fringe

Benefits ($)*

Funds Requested ($)*

1 . Lilliam Ambroggio PD/PI 9 0 0

Total Funds Requested for all Senior Key Persons in the attached file 0.00

Additional Senior Key Persons: File Name: Total Senior/Key Person

Mime Type:

B. Other Personnel

Number of

Personnel*

Project Role* Calendar Months Academic Months Summer Months Requested Salary ($)* Fringe Benefits* Funds Requested ($)*

Post Doctoral Associates

Graduate Students

Undergraduate Students

Secretarial/Clerical

0 Total Number Other Personnel Total Other Personnel 0.00

Total Salary, Wages and Fringe Benefits (A+B)

RESEARCH & RELATED Budget {A-B} (Funds Requested)

Contact PD/PI: Ambroggio, Lilliam

 Page 85
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTION C, D, & E, Budget Period 5

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2021 End Date*: 03-31-2022 Budget Period: 5

C. Equipment Description

List items and dollar amount for each item exceeding $5,000

Equipment Item Funds Requested ($)*

Total funds requested for all equipment listed in the attached file 0.00

Total Equipment 0.00

Additional Equipment: File Name:

Mime Type:

D. Travel Funds Requested ($)*

1. Domestic Travel Costs ( Incl. Canada, Mexico, and U.S. Possessions) 0.00

2. Foreign Travel Costs 0.00

Total Travel Cost 0.00

E. Participant/Trainee Support Costs Funds Requested ($)*

1. Tuition/Fees/Health Insurance

2. Stipends

3. Travel

4. Subsistence

5. Other: 

 Number of Participants/Trainees Total Participant Trainee Support Costs

RESEARCH & RELATED Budget {C-E} (Funds Requested)

 Page 86
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - SECTIONS F-K, Budget Period 5

ORGANIZATIONAL DUNS*: 

Budget Type*: ● Project ❍ Subaward/Consortium

Organization: Cincinnati Childrens Hospital Medical Center

Start Date*: 04-01-2021 End Date*: 03-31-2022 Budget Period: 5

F. Other Direct Costs Funds Requested ($)*

1. Materials and Supplies

2. Publication Costs 0.00

3. Consultant Services 0.00

4. ADP/Computer Services 0.00

5. Subawards/Consortium/Contractual Costs 0.00

6. Equipment or Facility Rental/User Fees 0.00

7. Alterations and Renovations 0.00

Total Other Direct Costs

G. Direct Costs Funds Requested ($)*

Total Direct Costs (A thru F)

H. Indirect Costs

Indirect Cost Type Indirect Cost Rate (%) Indirect Cost Base ($) Funds Requested ($)*

1 . Federal (MTDC) 8 118,750.00

Total Indirect Costs

Cognizant Federal Agency

(Agency Name, POC Name, and POC Phone Number)

Department of Health and Human Services, Arif Karim,

214-767-3261

I. Total Direct and Indirect Costs Funds Requested ($)*

Total Direct and Indirect Institutional Costs (G + H)

J. Fee Funds Requested ($)*

0.00

K. Budget Justification* File Name:

BUDGET_JUSTIFICATION_AmbroggioK01_2016_07_08.pdf

Mime Type: application/pdf

(Only attach one file.)

RESEARCH & RELATED Budget {F-K} (Funds Requested)

 Page 87
BUDGET JUSTIFICATION

The proposed budget includes expenses specific to the proposed research and training plan. Patient 

enrollment, data, and molecular and microbiological testing are collected as part of a parent study, “Catalyzing 

Ambulatory Research in Pneumonia Etiology and Diagnostic Innovations in Emergency Medicine” (CARPE 

DIEM). CARPE DIEM is led by Dr. Todd Florin as the principal investigator (see Collaborator Letter), Dr. 

Ambroggio as the co-principal investigator, and Drs. Ruddy and Shah (see Mentor Letters) as the two senior 

mentors. Dr. Ambroggio in addition to the other members of the team have received extramural funding

through FY17 for the infrastructure involved in recruiting participants, sample collection, molecular and 

microbiological testing of nasopharyngeal swabs and blood specimens and storage for CARPE DIEM. In order 

to ensure the success of the proposed K01 the budget described below will cover additional NMR spectral 

acquisition and analysis, urine collection kits for time points in Aim 1 and Aim 3, enrollment and specimen 

collection for healthy controls and personnel time distinct from CARPE DIEM. In addition the Division of 

Hospital Medicine devotes “professional” funds for each of its faculty members each year including Dr. 

Ambroggio to cover additional expenses regardless of grant funding. These professional funds will be used to 

cover travel to University of Michigan and travel to two national conferences per year. 

Personnel Salary Support

Lilliam Ambroggio, PhD, MPH, Principal Investigator (9.0 calendar months in years 1-5): Dr. Ambroggio is 

an Assistant Professor of Pediatrics in the Divisions of Hospital Medicine and Biostatistics and Epidemiology at 

Cincinnati Children’s Hospital Medical Center (CCHMC). She will devote 75% of her effort to her research and 

training for the 5 years of this award. She will be directly involved in every aspect of the study including study 

design, NMR sample preparation and assay, statistical data analysis, direct supervision of project personnel 

when applicable and manuscript preparation. She will also be responsible for the fiscal oversight of the 

proposed work. Benefits are calculated at 25%.

Research Support

Other

Cory Pfefferman, Clinical Research Coordinator (2.4 calendar months in years 2, 4 and 5). Ms. Pfefferman

works full-time in the Division of Hospital Medicine. She has worked with Dr. Ambroggio as the CRC for the 

pilot data for this proposal. She will assist with day-to-day activities of the work proposed here including: IRB 

processes, recruitment and consent of participants on the inpatient service and in the outpatient clinics for the 

control group, collection of biological specimens, and general organization of documents and protocols, 

entering electronic medical record data into REDCap and coordinate CRCs in the Emergency Department on 

project activities. Her effort in years 1 and 3 are covered by external grants that cover the infrastructure of 

CARPE DIEM, years 2, 4 and 5 will be covered by the K01. Benefits are calculated at 25%. Total salary and 

benefits are $9,961 in year 2, $10,568 in year 4 and $10,885 in year 5.

Jessi Poteet and Judd Jacobs, Data Management Team. Ms. Poteet and Mr. Jacobs are part of the Data 

Management Core and manage the master study database, which contains data from the REDCap database, 

the electronic medical record, the laboratory computer system, the biobanking tracking system, in addition to 

results from external laboratories not recorded in the patient’s EMR (i.e. laboratory tests not ordered for clinical 

reasons). They manage all data integrity through regular data checks and are responsible for data cleaning of 

the clinical data extracted from the EMR. In years 1 and 2 of the proposed K01, their initial support is funded 

through CARPE DIEM, however the last three years during the analysis phase of this proposal their 

involvement will be important in producing analytic datasets for the PI to use. Total salary and benefits charged 

to the Data Management Core for Poteet are $4,907 in year 3, $8,087 in year 4 and $8,330 in year 5. Total 

salary and benefits charged to the Data Management Core for Jacobs are $5,170 in year 3, $5,325 in year 4 

and $5,485 in year 5.

Equipment

No additional equipment will be purchased for this proposal. The study includes the use of NMR spectrometers 

available through the University of Michigan (see Dr. Stringer’s Letter) and CCHMC (see Dr. RomickRosendale’s Letter). In year 1, Dr. Ambroggio will receive ample training in all facets of NMR metabolomics 

by preparing, assaying and quantifying 50 samples from the study under the overall supervision of Dr. Stringer. 

In addition, Dr. Yeomans (NMR spectromist) and Ms. McHugh at the University of Michigan will be providing 

Dr. Ambroggio with the hands on training for the preparation and assaying of the samples. The personnel effort 

Contact PD/PI: Ambroggio, Lilliam

Budget Justification Attachment Page 88
for Dr. Yeomans and Ms. McHugh is included into the cost of the time on the NMR spectrometer for a total per 

sample cost of $317 in year 1. At CCHMC, as Dr. Ambroggio is preparing, assaying and quantifying all of the 

samples required for the study, the only charge is for time on the NMR spectrometer which will be $30 per 

sample in years 1-3. At CCHMC, 150 samples will be assayed in year 1, 350 in year 2 and 175 in year 3. 

Supplies 

The laboratory test and supplies needed to support this research are budgeted as follows:

Supply Samples Cost Total 

Cost

Y1 Y2 Y3 Y4/Y5

Home Urine Collection Kits for 2nd and 

3rd time point in Aim 1, and 3rd time 

point in Aim 3.

150 $20 $3,000 $1,000 $2,000 0 0

16S rRNA to aid in identifying 

unknown pathogens in Aim 1

50 $35 $1,750 0 0 $1,750 0

Viral and bacterial PCR for NP swabs 

from control samples 

145 $100 $14,500 $5,000 $2,500 $6,000 $1,000

Software

The following statistical software will be necessary to perform the proposed analysis. 

1. SAS software version 9.3 from SAS Institute Inc., Cary NC, USA is an advanced statistical software

package which will be used to accomplish Aims 1-3 of this proposal. However, SAS software is 

already provided to Dr. Ambroggio and therefore is not included in the K01 budget.

2. Mplus Base Program and Combination Add-On software (includes Mixture and Multilevel analysis

packages) is a statistical software package which will enable Dr. Ambroggio to perform structural

equation modeling and latent class analysis. This type of modeling procedures have not been well

developed in SAS 9.3 software hence the requirement for additional statistical software. The cost for an

academic license for this Mplus software is $895 and has been budgeted into year 3 of this award in

preparation for the analysis of Aim 2.

3. MetScape 2 is a plugin for Cytoscape, publicly available bioimformatics software used to visualize and

interpret data from metabolomics and expression profiling in the context of human metabolism.

Pathways are built using an international database stored on NCIBI that integrates data from Kyoto

Encyclopedia of Genes and Genomes (KEGG) and Edinburgh Human Metabolic Network (EHMN). As

this software is publicly available, no additional costs have been included in the K01 budget.

4. Chenomx NMR suite is commercially available software that allows for identification and quantification

of metabolites in NMR spectra. In addition it accounts for specifications of different NMR equipment. As

this software is available to Dr. Ambroggio with the permissions of Dr. Stringer and Dr. RosendaleRomick at University of Michigan and CCHMC respectively, no additional costs have been included in

the K01 budget.

Travel and Education

Education: As a member of the faculty at CCHMC and University of Cincinnati (UC), Dr. Ambroggio has tuition 

remission at UC. Therefore there is no cost for UC courses listed in the training plan. 

Meetings with Dr. Stringer (metabolomics mentor from University of Michigan): A key component of Dr. 

Ambroggio’s career development and mentorship plans involve her working with Dr. Stringer and learning how 

to run and process samples on the NMR and produce a quantified metabolite database that can be used for 

the proposed analysis. Travel will be from divisional professional funds to help cover the costs of mileage, 

meals and accommodations when Dr. Ambroggio visits the University of Michigan (see Dr. Shah letter of 

support). 

National Professional Meetings: Dr. Ambroggio will attend two scientific meetings per year for peer 

networking and presentation of findings. Additionally these national meetings will be a time for her to meet-inperson with Dr. Stringer in years 1-5. Meetings she will consider attending are: Pediatric Academic Societies, 

Infectious Disease Week, European Society for Pediatric Infectious Diseases, and International Conference of 

Contact PD/PI: Ambroggio, Lilliam

Budget Justification Attachment Page 89
the Metabolomics Society. She has budgeted between $300 and $1,000 in years 1-5 of the award to attend 

these conference with additional cost of attendance funded through divisional “professional” funding which are 

distributed each year to faculty. 

Indirect Costs

CCHMC has agreed to waive its usual indirect cost and has included indirect charges at 8% as specified in the 

RFA.

Contact PD/PI: Ambroggio, Lilliam

Budget Justification Attachment Page 90
Contact PD/PI: Ambroggio, Lilliam

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

RESEARCH & RELATED BUDGET - Cumulative Budget

Totals ($)

Section A, Senior/Key Person

Section B, Other Personnel 0.00

Total Number Other Personnel 0

Total Salary, Wages and Fringe Benefits

(A+B)

Section C, Equipment 0.00

Section D, Travel 0.00

1. Domestic 0.00

2. Foreign 0.00

Section E, Participant/Trainee Support

Costs

0.00

1. Tuition/Fees/Health Insurance 0.00

2. Stipends 0.00

3. Travel 0.00

4. Subsistence 0.00

5. Other 0.00

6. Number of Participants/Trainees 0

Section F, Other Direct Costs

1. Materials and Supplies

2. Publication Costs 0.00

3. Consultant Services 0.00

4. ADP/Computer Services 0.00

5. Subawards/Consortium/Contractual

Costs

0.00

6. Equipment or Facility Rental/User

Fees

0.00

7. Alterations and Renovations 0.00

8. Other 1 0.00

9. Other 2 0.00

10. Other 3 0.00

Section G, Direct Costs

(A thru F)

Section H, Indirect Costs

Section I, Total Direct and Indirect Costs

(G + H)

Section J, Fee 0.00

 Page 91
PHS 398 Cover Page Supplement

OMB Number: 0925-0001

Expiration Date: 10/31/2018

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

1. Human Subjects Section

Clinical Trial? ❍ Yes ● No

*Agency-Defined Phase III Clinical Trial? ❍ Yes ❍ No

2. Vertebrate Animals Section

Are vertebrate animals euthanized? ❍ Yes ❍ No

If "Yes" to euthanasia

Is the method consistent with American Veterinary Medical Association (AVMA) guidelines?

❍ Yes ❍ No

If "No" to AVMA guidelines, describe method and proved scientific justification

3. *Program Income Section

*Is program income anticipated during the periods for which the grant support is requested?

❍ Yes ● No

If you checked "yes" above (indicating that program income is anticipated), then use the format below to reflect the amount and

source(s). Otherwise, leave this section blank.

*Budget Period *Anticipated Amount ($) *Source(s)

Contact PD/PI: Ambroggio, Lilliam

 Page 92
PHS 398 Cover Page Supplement

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190 . Received Date:

2016-07-08T13:23:03.000-04:00

4. Human Embryonic Stem Cells Section

*Does the proposed project involve human embryonic stem cells? ❍ Yes ● No

If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the

following list: http://grants.nih.gov/stem_cells/registry/current.htm. Or, if a specific stem cell line cannot be referenced at this time,

please check the box indicating that one from the registry will be used:

Specific stem cell line cannot be referenced at this time. One from the registry will be used.

Cell Line(s) (Example: 0004):

5. Inventions and Patents Section (RENEWAL)

*Inventions and Patents: ❍ Yes ❍ No

If the answer is "Yes" then please answer the following:

*Previously Reported: ❍ Yes ❍ No

6. Change of Investigator / Change of Institution Section

❏ Change of Project Director / Principal Investigator

Name of former Project Director / Principal Investigator

Prefix:

*First Name:

Middle Name:

*Last Name:

Suffix:

❏ Change of Grantee Institution

*Name of former institution:

Contact PD/PI: Ambroggio, Lilliam

 Page 93
PHS 398 Career Development Award Supplemental Form

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190. Received Date:

2016-07-08T13:23:03.000-04:00

OMB Number: 0925-0001

Expiration Date: 10/31/2018

Introduction

1. Introduction to Application

(RESUBMISSION)

1_Introduction.pdf

Candidate Section

2. Candidate Information and Goals for Career

Development

2_Candidate_Information_2016_07_08.pdf

Research Plan Section

3. Specific Aims 3_Specific_Aims.pdf

4. Research Strategy* 4_Research_Strategy_2016_07_08.pdf

5. Progress Report Publication List

(for RENEWAL applications only)

6. Training in the Responsible Conduct of Research 6_TRAINING_IN_THE_RESPONSIBLE_CONDUCT_OF_RESEA.pdf

Other Candidate Information Section

7. Candidate's Plan to Provide Mentoring

Mentor, Co-Mentor, Consultant, Collaborators Section

8. Plans and Statements of Mentor and

Co-Mentor(s)

8_Mentor_Letters_of_Support_2016_07_08.pdf

9. Letters of Support from Collaborators,

Contributors, and Consultants

Combined_Letters_of_Support.pdf

Environment and Institutional Commitment to Candidate Section

10. Description of Institutional Environment 10_Description_of_the_Institutional_Environmen.pdf

11. Institutional Commitment to Candidate's

Research Career Development

11_Institutional_Commitment_Letter_2016.pdf

Human Subject Section

12. Protection of Human Subjects 12__Human_Subjects_Research.pdf

13. Data Safety Monitoring Plan

14. Inclusion of Women and Minorities 14_Inclusion_of_Women_and_Minorities_Ambroggio.pdf

15. Inclusion of Children 15_Inclusion_of_Children_Ambroggio_K01.pdf

Other Research Plan Section

16. Vertebrate Animals 16_Vertebrate_Animals.pdf

17. Select Agent Research 17__Select_Agent_Research.pdf

19. Consortium/Contractual Arrangements

19. Resource Sharing

20. Authentication of Key Biological and/or

Chemical Resources

Appendix

21. Appendix 21_Appendix_A_Inclusion_and_Exclusion_Criteria.pdf

21_Appendix_B_home_urine_collection_instructio.pdf

Contact PD/PI: Ambroggio, Lilliam

 Page 94
PHS 398 Career Development Award Supplemental Form

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190. Received Date:

2016-07-08T13:23:03.000-04:00

Citizenship*:

U.S. Citizen or Non-Citizen National?* ❏✔ Yes ❏ No

If no, select most appropriate Non-U.S. Citizen option

❏  With a Permanent U.S. Resident Visa

❏  With a Temporary U.S. Visa

❏  Not Residing in the U.S.

If with a temporary U.S. visa who has applied for permanent resident status and expect to hold a permanent resident

visa by the earliest possible start date of the award, also check here: ❏

Contact PD/PI: Ambroggio, Lilliam

 Page 95
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

1. Introduction: I appreciate the reviewers’ comments and the opportunity to resubmit this proposal. I am 

pleased that the reviewers found my proposal to be “outstanding” and that notable strengths were “the 

candidate’s extensive experience, independence, and productivity in epidemiology” and that the “project is of 

great importance to children’s health.” Although all weaknesses noted by reviewers were addressed in this 

resubmission, specific overarching concerns are mentioned below. 

Career Development/Career Goals & Objectives: 

“Ambitious schedule for training with 3 courses each in Y1-2” Response: I have taken 2 of these courses since 

the original submission. In this resubmission, I have decreased the course load to 3 courses over 3 years 

(Table 1); I will focus on molecular epidemiology through experiential learning rather than formal coursework. 

“it is not clear how she will achieve her goal of learning how to conduct multi-center studies” Response: I am 

now a site co-I of the Children’s Hospital Initiative for Research in Pneumonia, details in Section 2, Goal 4. 

Research Plan: 

“The panel was quite enthusiastic about the candidate’s potential and project itself and encouraged a 

resubmission with a restructuring of the research plan. Would be wise if stability across days in normal children 

were an “aim 1” and the current aim 1 change to “aim 2”.” Response: The proposal now includes 3 aims as 

suggested by the reviewers. Aim 1 examines diurnal variations in the metabolome of healthy children. Aim 2 

(previously Aim 1) differentiates bacterial and viral pneumonia from healthy children. Aim 3 (previously Aim 2) 

compares longitudinal changes in the metabolome of patients with pneumonia with healthy children to assess 

the patient’s response to therapy. 

“The data from the CARPE DIEM study should be presented” Response: Please see Section 4, Table 3 & 5. 

“Prelim data ...are compelling, but it would be helpful to know if the different metabolites ... had overlapping 

profiles across all pathogens” Response: Please see Section 4, Figure 5 for fold-change differences as 

suggested by pathogen group compared with healthy controls. 

“Aim 1 [Sample Size] It would have been better to keep the initial [viral, bacterial, healthy] groupings”

Response: The intent of this aim was to distinguish 3 groups: virus, bacteria, and normal, therefore the 

preliminary data is now better aligned with the original sample size calculation. 

 “...what type of clinical variables will be collected and what is likely to be missing” Response: According to the 

clinical variables collected for the 169 patients with pneumonia already enrolled in the study, no clinical data is 

missing. Data on clinical variables (variables listed in Section 4, Table 3) are collected either prospectively or 

through the EMR. For missing clinical variables, I will conduct a complete case analysis. It is possible that 

individual metabolites may not be identified in all samples therefore the metabolites that are reported in at least 

90% of the samples will be included in the analyses, Section 4.C.2e. 

“[the question of] pneumococcal colonization vs. disease and given the estimated 60-70% viral etiology, there 

is likely insufficient numbers to assess this important question. Suggest this be dropped from a resubmission 

application.” Response: Section 4.C.3a. has been revised to better illustrate the intent which was to decrease 

the potential of misclassifying a patient as being infected with Streptococcus pneumoniae, but not to directly 

test the research question of colonization versus infection. 

“...should specify that these samples represent pre-antibiotic samples given the hypothesis of Aim 2. This is 

important because many children have been seen first in clinic within a few days of presenting to an ED and 

may already be on antibiotics.” Response: Of the patients currently enrolled in CARPE DIEM, 23% are 

receiving antibiotics prior to the ED (Table 3). Prior antibiotic use will be taken into account in the multivariable 

model discussed in Aims 2 and 3. Importantly none of the patients included in the preliminary data in Aim 3 

received antibiotics prior to their first urine sample collection (Figure 6). 

Mentor. Co-Mentor, Consultants “There is an abundance of mentors in this application. However, the 

concern is offset by the long history that nearly all of them have in formally mentoring the candidate.”

Response: Each of the five mentors has been specifically chosen to complement the proposal according to 

their expertise therefore it was felt that a multidisciplinary and dedicated group of mentors was the best option 

to ensure the success of the candidate and the proposal (Table 1).

Contact PD/PI: Ambroggio, Lilliam

Introduction to Application Page 96
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

2. Candidate’s Background

My research program focuses on the development and application of novel diagnostic tools to determine the 

etiology of community-acquired pneumonia (CAP) in children. My overarching goal is to improve outcomes for 

children with serious infections by developing methods to facilitate accurate diagnosis and implementing these 

methods into clinical practice. As such I am pursuing a career combining epidemiological methodology with 

metabolomics, “epi-metabolomics”, an emerging field that quantifies small molecules produced from the 

complex biological interaction between the host and the pathogen.1 The application of metabolomics to 

pediatric CAP represents an enormous opportunity to advance knowledge in the field and holds promise for 

identifying diagnostic and prognostic biomarkers. I am uniquely qualified to conduct this research because I 

have a strong foundation in molecular and cellular biology with clinical epidemiology expertise and training in 

improvement science. This award will enable me to advance my knowledge and skills in metabolomics so that I 

can conduct epi-metabolomics studies that are needed to drive precision medicine in pediatric CAP. 

I have 7 years of experience in a laboratory-setting conducting molecular biology research. I previously 

investigated mechanisms of cell cycle dysregulation that lead to tumorigenesis using both animal and cell 

culture models. From this I gained a desire to translate knowledge from the bench to the bedside and pursued 

advanced degrees in Epidemiology. My master’s thesis investigated the potential factors that lead to poor 

outcomes in infants diagnosed with herpes simplex virus.2 I focused my PhD dissertation first on comparing the 

effectiveness of β-lactam monotherapy and β-lactam and macrolide combination therapy on clinical outcomes 

in the treatment of children hospitalized with CAP. The findings suggested that older children hospitalized with 

CAP may benefit from use of macrolide antibiotics, likely due to the effect of macrolides on atypical bacteria.

3

Secondly, using multi-level analysis, I also investigated the influence of hospital-level penicillin non-susceptible 

Streptococcus pneumoniae patterns on individual-level antibiotic prescription.4 Hospitals reporting higher levels 

of penicillin-resistance among pneumococcal bacteria disproportionately prescribed broad-spectrum 

antibiotics.2-4

During my post-doctoral fellowship, I led a multidisciplinary clinical team to implement national evidence-based 

recommendations for managing CAP in children. This effort provided me greater insight into clinical decision 

making regarding CAP in the ED and the inpatient service. Using quality improvement science, we were able 

to increase guideline recommended prescribing to 100% from a median baseline of <40%.5 In parallel, I 

received funding from the Thrasher Research Fund and, in collaboration with pediatric radiologists, evaluated 

the diagnostic accuracy of lung ultrasonography (LUS) compared with chest radiography (CXR) in detecting 

pneumonia using chest computed tomography (CT) as the gold standard for detection. Our findings suggest 

that LUS is as accurate as CXR when compared with chest CT for detecting consolidation and pleural effusion 

in children.6 Although imagining is useful in the management of CAP, the biggest limitation of any imaging 

modality is the inability to reliably identify the causative pathogen of CAP. 

My exploration of the scientific literature for innovative methods to differentiate bacterial and viral CAP led to 

recent applications of metabolomics in the field of infectious diseases.

7-9 To gain a better understanding of this 

new field, I participated in a metabolomics workshop in 2013 at the University of Alabama. It was clear that 

metabolomics with an epidemiological population health perspective could support the development of a 

diagnostic test to differentiate viral and bacterial pathogens in CAP. As an Assistant Professor of Pediatrics in 

the Divisions of Hospital Medicine and Biostatistics and Epidemiology I was awarded two Cincinnati Children’s 

Hospital Medical Center (CCHMC) awards and was a co-investigator on a Gerber Foundation grant. These 

grants have enabled me to establish and sustain the study infrastructure used in the proposed research and 

to obtain the preliminary data presented for all aims. These experiences have also uncovered critical areas in 

training and knowledge that are necessary to enable my independence as an investigator who conducts epimetabolomics studies for common childhood infectious diseases such as CAP.10

 

Career Goals and Objectives 

As a field, epidemiology is moving toward systems biology to better identify etiology and underlying disease 

risk factors.10 Because there is no fast and reliable diagnostic tool to detect etiology for CAP, new diagnostic 

tests derived from epi-metabolomics studies may lead to a better predictive model for prescribing effective 

pharmacotherapy, the goal of precision medicine.11 My short-term goal is to identify candidate metabolites that 

will ultimately be translated to point-of-care tests for rapid pathogen identification. In direct support of this goal, 

the overall objective of this application is to combine robust clinical data with metabolomics data using 

Contact PD/PI: Ambroggio, Lilliam

Candidate Information and Goals for Career Development Page 97
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

advanced statistical methodologies to inform pathogen-detection in childhood pneumonia (Figure 1). This 

award will provide me with the time, mentorship, hands-on laboratory-based research experience to conduct 

1H-NMR and liquid chromatography-mass spectrometry (LC/MS) quantitative metabolomics experiments and 

gain expertise in cluster analysis and interpretation.

Plan to Generate R01 Support I propose to submit my first R01 by year 4 of this award (Figure 1) and gain 

independence from my mentorship team. The first 3 years of this award I will work with my mentors to obtain 

training and practical research experience to give me the skills needed to be an independent investigator in 

epi-metabolomics research. In year 4, I will design a R01, multi-site study to validate the profiles established in 

this proposal through established networks within pediatric emergency medicine and pediatric hospital 

medicine. The R01 will be needed for the direct development of point-of care tests.

Career Development and Training 

Mentoring Team and Collaborators: My mentorship team includes prominent researchers in their respective 

fields. Each has strong records of publication, funding and mentoring (Table 1 and Mentor Statements). The 

mentoring committee has been meeting with me on a quarterly basis since 2013 to evaluate career progress 

and will continue to meet to assess my progress toward the training goals and adherence to the timeline in

Table 2. I meet with Dr. Shah weekly and I have had monthly meetings with Drs. Shah, Ruddy and Florin 

(since 2012) to discuss the execution of the prospective pneumonia cohort that Dr. Florin and I developed and 

that will be leveraged for this K01 proposal. Dr. Stringer and I have met in person 2-3 times per year since 

2013 and have had more frequent communication via email and phone throughout the development of this 

proposal. Dr. Macaluso and I have met monthly since my fellowship in 2011; he continues to guide my career 

as a molecular-based epidemiologist. Dr. Sucharew and I have met biweekly throughout the proposal 

development. These established relationships will ensure the success of the proposed work and my 

development into an independent investigator.

Table 1. Mentoring Committee 

Name 

(Institution) 

Associated 

Aims/Goals* 

Meeting Frequency and 

Format 

Area of Expertise and Role 

Samir Shah, MD, 

MSCE (CCHMC, 

UC) [Primary 

Mentor] 

Research: 

1,2,3 

Training:1, 3, 4 

Weekly meetings (and 

informally as needed, in 

person) 

Expertise: Pediatric community-acquired pneumonia, infectious 

diseases, hospital medicine, clinical epidemiology, multicenter inpatient 

studies (Vice Chair of the PRIS Network), leadership skills 

Role: Primary mentor for pneumonia, career guidance, study design 

and execution, multicenter research 

Maurizio 

Macaluso, MD, 

DrPH (CCHMC, 

UC) [Co-Mentor] 

Research:1,2,3 

Training:3,4

Monthly (in person) Expertise: Advanced epidemiological methods, causal inference, 

molecular epidemiology 

Role: Career mentor, primary mentor for molecular epidemiology

Kathleen 

Stringer, 

Research: 

1,2,3 

Training:1, 3, 4

Every other week (by 

phone/Skype), in person 

at 3x/year 

Expertise: quantitative NMR metabolomics, metabolomics study design 

and execution using biofluids including urine, statistical and 

Research: 

Molecular and Cellular 

Biology: 7 years of hands-on 

laboratory experience 

Epidemiology: Healthcare 

utilization in infectious diseases 

in children 

Quality Improvement: 

Antibiotic therapy 

implementation & intervention 

development

Training: 

MPH/PhD: epidemiology, 

biostatistics

Fellowship: propensity scores, 

quality improvement courses

Prior Research and Training NIH K01 Career Development Award Independent Investigator 

Research: 

Aim 1: To characterize the 

sources of variability in the 

urine metabolite profiles of 

healthy children. 

Aim 2: To determine and 

compare the urine 

metabolite profiles of 

children with viral or 

bacterial CAP with those of 

healthy children. 

Aim 3: To evaluate 

longitudinal changes in the 

urine metabolite profile of 

children with CAP compared 

with healthy children.

Training: 

Goal 1: Gain experiential learning in study 

design and execution of quantitative 1

H-NMR 

metabolomics. 

-Training: Sample collection, hands-on NMR 

experiential learning 

Goal 2: Apply advanced statistical analytics 

to large metabolomics datasets. 

-Training: Multivariate analysis and cluster 

analysis, Bioinformatics courses 

Goal 3: Interpret metabolomics data and its 

biological context. 

-Training: Molecular Epidemiology course, 

LC/MS 

Goal 4: Develop leadership and professional 

skills to execute multicenter studies. 

-Training: K-Club, CHIRP Clinical Shadowing 

Next Step-R01: 

Conduct a multi-site 

study validating 

metabolite profiles and 

investigate the 

pathobiology of 

treatment response in 

children with CAP. 

Future Research: 

Develop a diagnostic 

test using the validated 

metabolite profiles for 

children with CAP. 

Determine metabolite 

profiles of other 

common infectious 

diseases in children. 

Figure 1: Career Trajectory 

Contact PD/PI: Ambroggio, Lilliam

Candidate Information and Goals for Career Development Page 98
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

Training Goals: 

laboratories in the use of the software, Chenomx (www.chenomx.com), 

to identify and quantify metabolites from NMR spectra.12

GOAL 2: Acquire and apply advanced statistical analytics to large 

metabolomics datasets. (Key Individual: Sucharew). Through my prior 

training I have built a strong foundation in statistics that includes 

regression analysis and longitudinal data analysis. However, to 

accomplish Steps 5 and 6 (Figure 2) I will gain hands on experience 

performing the analysis for this proposal under the guidance of 

Dr.Sucharew and using SAS 9.3 (SAS Institute, Cary NC) and MPlus 7.3 

(www.statmodel.com). I will take Structural Equation Modeling (BE8094) 

that provides the foundation for pathway analysis, latent variable 

analysis, mixture models and multi-level models. 

GOAL 3: Interpret metabolomics data and its biological context.

(Key Individuals: Shah, Stringer, Ziady, Macaluso). To achieve Step 7

(Figure 2), under the guidance of Drs. Shah and Stringer, I will use current scientific literature to interpret the 

PharmD 

(UMichigan) 

bioinformatics analysis aimed at identifying metabolites of biological 

relevance, inflammatory lung diseases 

Role: Primary mentor for metabolomics, onsite externship at University 

of Michigan (3 2-week visits in year 1) 

Richard Ruddy, 

MD (CCHMC, 

UC) 

Research: 

1,2,3 

Training: 1, 4

Monthly (in person) Expertise: Multicenter pediatric emergency medicine research (nodal PI 

for PECARN), respiratory diseases in ED, leadership skills, 

Role: Content expertise for pediatric emergency medicine research, 

career guidance

Heidi Sucharew, 

PhD 

(CCHMC, UC) 

Research: 

1,2,3 

Training: 2 

Monthly (year 1 and 5, in 

person) 

Every other week (years 

2-4, in person) 

Expertise: Cluster analysis, functional data analysis with extension to 

large scale data such as metabolomics, latent class models 

Role: Statistical mentor on analysis of metabolomics dataset

Additional Collaborators (not on Mentoring Committee)

Lindsey RomickRosendale, PhD Research:1,2,3 

Training:1 

Every other week (Years 

1-3, in person); Monthly 

with Dr. Stringer (Year 1-

3); Monthly (Year 4-5) 

Expertise: 6 years of NMR metabolomics experience, complex 

metabolic pathways involved in diseases/infections 

Role: CCHMC onsite metabolomics expert, guidance in study design, 

execution and interpretation of NMR metabolomics portion of the 

proposal 

Assem Ziady, 

PhD 

Research:1,2,3 

Training:3 

Monthly (Year 4-5, in 

person) 

Expertise: Proteomic and metabolomics study studies using Liquid 

Chromatography Mass Spectrometry (LC/MS), inflammatory signaling in 

children with cystic fibrosis

Role: LC/MS metabolomics externship in his laboratory in year 4 

*Numbers correspond to specific aims (for research) and training goals (below)

Step 7: Interpretation of

Results and Dissemination

Step 6: Pathway Analysis

Step 5: Multivariate

Analysis

Step 4: Metabolite 

Identification & 

Quantification

GOAL 1: Gain experiential and didactic learning in study design and execution of quantitative 1H-NMR 

metabolomics. (Key Individuals: Stringer, Romick-Rosendale, Shah, Ruddy). My PhD training provided me a 

strong foundation in epidemiological study design and execution. However, only recently have I had 

experience designing a prospective cohort (Catalyzing Ambulatory Research in Pneumonia Etiology and 

Diagnostic Innovations in Emergency Medicine (CARPE DIEM)). Specimen collection is the first step in 

learning the metabolomics work flow (Figure 2). Drs. Shah, Ruddy, Florin and I use a team science approach 

to execute CARPE DIEM (see letters of support). To accomplish the next steps in the metabolomics work flow 

(Steps 2-4, Figure 2), collected urine samples will be shipped (50 samples total) to the University of Michigan 

NMR Metabolomics Laboratory, where, 3 times a year, I will travel to Michigan to prepare and assay samples 

(steps 2 &3), process spectra (step 4), conduct initial statistical analysis (step 5) and gain experience with 

pathway analysis (step 6) under the supervision of Dr. Stringer (see 

letter of support). I will further my expertise by running technical Figure 2: Metabolomics Work Flow

replicates of the same samples in the newly established metabolomics Step 1: Specimen

core laboratory at CCHMC under the supervision of Dr. Romick- Collection

Rosendale (see letter of support). This strategy will ensure reproducibility 

of my technique and enable me to independently assay the remaining Step 2: Sample Preparation

generated samples. In addition, I will gain a better understanding of 

cross-center NMR validation studies, which is important for future 

multicenter studies. My hands-on training will also include training in both Step 3: NMR Spectra

Acquisition

Contact PD/PI: Ambroggio, Lilliam

Candidate Information and Goals for Career Development Page 99
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

identified metabolites from my K01 project and begin planning the logical subsequent aims for the R01 

application. In addition, I will gain experience using the bioinformatics tool, Metscape, 

(http://metscape.ncibi.org/),for metabolomics data interpretation. I will spend 3 months in year 4 in Dr. Ziady’s 

laboratory validating the identity of low abundant metabolites found by NMR using LC/MS.10 In addition I will 

learn about designing targeted metabolomics studies using LC/MS in preparation for the R01 application (see 

letter of support). In parallel, I will also complete the following: Medical Microbiology (26MG7003) which 

discusses host-pathogen interactions; and experiential learning with Dr. Macaluso to discuss criteria for 

evaluating the medical importance of an identified biomarker in human populations and to address ethical 

concerns regarding biomarker research. 

GOAL 4: Develop leadership and professional skills to execute multicenter studies. (Key Individuals: 

Shah, Ruddy,Macaluso) To continue to develop and strengthen my professional skills I will attend regular 

monthly meetings of UC’s “K Club,” which is designed to support K-funded researchers in the transition to 

independent investigators. I will present findings from this project at national and international meetings. In the 

fourth year of this award I will take part in an institutional yearly intensive grant-writing workshop to prepare me 

for writing and submitting an R01. Finally, beginning fall 2015, I have participated as a site co-Investigator in a 

2 year, state-wide multicenter study, Children’s Hospital’s Initiative for Research in Pneumonia (CHIRP). This 

study collects biological specimens from six children’s hospitals within Ohio to develop a genomic “molecular 

distance to health” score for children with pneumonia.13 I, in collaboration with Dr. Shah, the site PI, coordinate 

the enrollment procedures within our institution. This study will give me direct hands-on experience in the 

organization needed to recruit and collect samples from multiple sites. I will use this experience in developing a 

multicenter R01 proposal collaborating with inpatient settings and emergency department sites, to validate 

metabolite profiles identified from this K01 award. 

Table 2: Timeline of future training, research and clinical work Goal Pre-K01 Year 1 Year 2 Year 3 Year 4-5 

Training (in calendar months) 4.8 4.8 3.6 2.4 

Courses 

Introduction to Functional Genomics (26GNTD881) 1 X 

Advanced Statistical Methods in Biomedical Research (BE8064C) 2 X

Structural Equation Modeling (BE8094) 2 X 

Medical Microbiology (26MG7003) 3 X 

Ethics in Research (26GNTD7003) 4 X 

Experiential learning 

NMR hands-on learning with Stringer and Romick-Rosendale 1 X X X 

Multivariate Analysis and Latent Class Modeling with Sucharew 2 X X X 

Advanced Molecular Epidemiological Methods with Macaluso 3 X X 

LC/MS2 hands-on learning with Ziady 3 X 

AAMC Early Career Women Faculty Professional Development Seminar 4 X 

Research 6 6 7.2 8.4 

1-4 Aim 1 Aim 1- 2 Aim 2- 3 Aim 2-3 

IRB Submission and Approval 1-4 X 

Teaching* 1.2 1.2 1.2 1.2 

*I spend 1.2 calendar months total teaching two courses per year: Comparative Effectiveness Research, Advanced Methods in Epidemiology) 

Seminars 

Weekly Hospital Medicine Research in Progress Meeting, Pediatric Grand Rounds 

Monthly Division of Biostatistics and Epidemiology Journal Club, Metabolomics Seminar, K-Club 

Conferences (2 annually) 

Infectious Disease Week (Annual Conference of the Infectious Diseases Society of America), Pediatric Academic Societies, Metabolomics 

Society, European Society for Infectious Diseases Annual Conference, Society for Epidemiologic Research Annual Conference 

 

Contact PD/PI: Ambroggio, Lilliam

Candidate Information and Goals for Career Development Page 100
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

3. SPECIFIC AIMS AND HYPOTHESES Community-acquired pneumonia causes substantial morbidity and 

mortality worldwide.14 In the U.S., CAP is among the most common and costly causes of hospitalization in 

young children.15 Clinical examination and chest radiography do not differentiate between viral and bacterial 

CAP.16,17 Conventional diagnostic tests (e.g., sputum cultures) used in adults are not feasible in young children 

and high yield tests (e.g., lung tap)18 are too invasive to be routine. Other bacterial diagnostics infrequently 

identify the causative pathogen (e.g., <7% for blood cultures) limiting their diagnostic utility. Viral tests, while 

often positive, do not exclude the possibility of bacterial co-infection.19,20 Therefore, patients with CAP receive 

empiric antibiotic therapy, which confers no benefit for children with non-bacterial infections, but places 

children at risk for adverse drug reactions, treatment-related complications (e.g., Clostridium difficile colitis) and 

antibiotic resistance.21 There is a pressing and unmet need for non-invasive diagnostic tests that permit 

accurate and timely clinical decision-making in children with CAP.22 

The interaction between pathogen and host results in a unique metabolic profile that is detectable in the host’s 

urine.7 Quantitative metabolomics can simultaneously detect and quantify metabolites (small molecules, < 1 

kDa) in a biological sample using 1H- NMR.23,24 Quantitative metabolomics testing of the urine is simple, 

noninvasive and rapid (< 1 hour, as opposed to >24 hours for conventional blood culture techniques).25 We 

developed a prospective cohort study in our Emergency Department to examine approaches to investigate the 

etiology of pediatric CAP. Using this cohort, I began investigating the potential for metabolomics to distinguish 

pathogens in CAP. Over the past 3 years, we enrolled 169 children between 3 months and 11 years of age 

with CAP. Our preliminary data suggest that distinct urine metabolite profiles cluster by class of pathogen. 

Evaluating the change in these metabolite profiles in response to antimicrobial therapy also offers a 

tremendous opportunity to non-invasively gauge appropriateness of initial antibiotic choice. Urine metabolite 

profiles may provide a fast, accurate and non-invasive approach for pathogen identification of CAP in children 

representing a critical innovation in the severely limited current practice. 

My long-term goal is to become an independent investigator in infectious diseases epidemiology with a focus 

on translating bench science research to bedside application. The overall objective of this application is to 

combine robust clinical data (e.g. smoking exposure, antibiotic receipt) with metabolomics data using 

advanced statistical and metabolomics methodologies to inform pathogen-detection in childhood CAP. I will 

use a clinical database and specimen biorepository from an established, funded, and fully-operational 

prospective cohort study of children with CAP. I will acquire knowledge and skills in systems biology sciences 

and their application to clinically challenging infections such as CAP. To accomplish this objective, I will pursue 

the following specific aims: 

1. To characterize the sources of variability in the urine metabolite profiles of healthy children. The 

primary hypothesis is that between subject variability will be larger than within subject variability in the 

metabolites in the urine of healthy children and the highest proportion of variance will be attributable to age 

and sex. 

2. To determine and compare the urine metabolite profiles of children with viral or bacterial CAP with 

those of healthy children. The primary hypothesis is that urine metabolite profiles of children who have 

viral pneumonia will be uniquely different from those of healthy children. In addition, urine metabolite profiles 

of children who have Streptococcus pneumoniae (the most common bacterial pathogen) or Mycoplasma 

pneumoniae (the most common atypical bacterial pathogen) will be distinct from those of healthy children. 

3. To evaluate longitudinal changes in the urine metabolite profile of children with CAP compared with 

healthy children. The primary hypothesis is the magnitude of change in the metabolome of a child with viral 

or bacterial CAP will be greater than the diurnal fluctuation of the metabolome in a healthy child. A 

secondary hypothesis is that longitudinal changes in metabolite patterns of children with CAP will 

differentiate response from non-response to antibiotics. 

Successful completion of these aims will generate preliminary data on distinct metabolite profiles associated 

with bacterial and viral pneumonia. These findings will inform an R01 application for a large scale, multi-center, 

validation study that includes more diverse microbial causes of CAP to advance the development of point-ofcare diagnostic tests. This study will further the field of CAP by introducing a method to differentiate bacterial 

and viral pathogens thereby increasing targeted antibiotic therapy for children. 

 

Contact PD/PI: Ambroggio, Lilliam

Specific Aims Page 101
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

4. RESEARCH STRATEGY 

4.A. Significance and Scientific Premise In the U.S., most cases of CAP are caused solely by viruses (73-

85%) with the remaining 18% caused by bacteria or bacteria-virus co-infections.26,27 However, CAP is the most 

common bacterial infection in children, with over 3 million cases each year.28 In young children, the annual total 

estimated direct medical costs exceed $1 billion for pneumonia-related hospitalizations.15,28 Although there are 

many factors that contribute to this high cost, the major driver is the use of extensive diagnostic testing.15 

Practice variation in the use of diagnostic tests highlights the absence of a gold standard,29,30 there is no 

currently available single test that can distinguish viral from bacterial CAP. Therefore biomarkers, such as 

white blood counts and serum procalcitonin levels are ordered to aid in the decision whether to initiate 

antibiotic therapy.20,31 These biomarkers are not sensitive for bacterial CAP (sensitivity <50%).20,32 The 

numerous bacterial and viral pathogens that can cause CAP, the lack of a true gold standard diagnostic test 

and the limited evidence to support a particular diagnostic approach for managing children with CAP contribute 

to the variation in care. The national pneumonia guideline highlights the need for better diagnostics in CAP by 

encouraging research on developing “diagnostic tests that are noninvasive yet sensitive and specific in 

documenting clinical disease caused by single pathogens or combinations of pathogens.”33

Currently, children with CAP are treated empirically with antibiotics based on age, signs and symptoms, and 

radiographic imaging, all of which have poor specificity for etiology.34 This approach leads to overtreatment of 

children who may have viral CAP, for which antibiotics have no benefit, and under treatment of children with 

more virulent pathogens such as Staphylococcus aureus, for whom conventional antibiotics such as ampicillin 

are ineffective.

33 The individual consequences of untargeted therapy include overuse of antibiotics, which place 

children needlessly at risk for common antibiotic side effects (e.g., allergic reactions, diarrhea) to severe 

complications (e.g., colitis caused by Clostridium difficile) and bacterial resistance. Children with C. difficile

infection experience a 6-fold higher risk of mortality than uninfected children, even when controlling for 

underlying medical diagnosis.35 These consequences of unnecessary antibiotic use underscore the need for 

more efficient and effective diagnostic tools. Identifying a group of metabolites that are by-products of a 

specific pathogen/host disease process provides a novel and timely aid in the diagnosis, treatment and overall 

management of CAP in children. 

4.B. Innovation: The proposed research is innovative because it uses an unbiased approach, the potential to 

identify all pathogens with one approach, that integrates robust clinical phenotype data with quantitative NMR 

metabolomics using novel statistical methods to address the clinically challenging problem of pediatric CAP 

diagnostics. The advantages of NMR for pathogen identification in children with pneumonia include: 1) rapid 

results- it takes < 1 hour to process and run a specimen by NMR; 2) non-invasive testing- it can be performed 

on urine; and 3) simple processing- NMR analysis of urine does not require extraction as required in other 

biological samples.36 Only recently has NMR been applied as an analytical platform for metabolomics.37

Establishing a metabolite profile for a given disease such as CAP can be used to direct targeted metabolomics 

studies and ultimately the development of point-of-care tests. Currently used microbiologic techniques, ones 

developed 150 years ago, often take >48 hours to produce results, long past when the patient was initially 

cared for in the ED. For many acute infections such as CAP, it is impractical and possibly harmful to delay 

treatment while awaiting a test result. The data from this proposal are expected to drive the development of a 

quick and reliable diagnostic tool for detecting etiology of CAP in children that will permit targeted management 

of the most common serious bacterial infection in children. 

4.C. Approach 

4.C.1. Overall Research Design 

CARPE DIEM Cohort: The proposed study, Metabolomics Evaluation of the Etiology of Pneumonia (MEEP), is 

part of a fully-funded and operational, prospective cohort study of CAP severity and etiology that I codeveloped entitled Catalyzing Ambulatory Research in Pneumonia Etiology and Diagnostic Innovations in 

Emergency Medicine (CARPE DIEM). The external funding for CARPE DIEM supports patient recruitment and 

specimen banking through 2017. We have enrolled 360 children with CAP since initiation of patient 

recruitment in July 2013 with a majority (n=169) able to provide a urine sample (Table 3). A funded K01 award 

will enable me to assay and analyze the urine specimens, aid in establishing me in the fields of metabolomics 

and infectious diseases epidemiology, and provide pilot data for an R01 to validate metabolomics profiles. 

Contact PD/PI: Ambroggio, Lilliam

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Patient Recruitment and Specimen Collection for 

CARPE DIEM: Trained clinical research coordinators

(CRC) staff the ED 12-16 hours/day 7 days/week to 

identify potential patients. Enrolled patients provide 

blood, urine, and nasopharyngeal (NP) swab samples. 

A strength of this study is that all covariates used in the 

analysis for all aims are collected prospectively and are 

available in the medical record. For patients enrolled to 

date there is no missing data (Appendix A). Specimen 

processing and storage is facilitated by the Cincinnati 

BioBank Core Facility (CBCF). For hospitalized 

patients, blood specimens and urine samples are also 

collected prior to discharge as a second time point and 

14 days after discharge for a third time point (Time 

points discussed in Aim 1 and 3). 

MEEP Healthy Control Cohort: Children, 3 months to 

11 years, visiting the Fairfield Primary Care Clinic, a 

CCHMC-affiliated clinic, for annual check-ups will be 

eligible as part of the control group (see letter of 

support from Dr. Morehous). Patients will be excluded if they have had a lower respiratory tract infection 

<7 days before the visit or have any additional exclusion criteria as described for CARPE DIEM. NP swabs 

and urine will be collected. Data on the control cohort will include applicable variables as in CARPE DIEM 

(Table 3). 

Sample Collection and Storage: The CBCF will receive and store all specimens for this proposal. At the 

time of collection, NP swabs are placed in viral transport medium and skim milk-tryptone-glucose-glycerin 

(STGG) for pneumococcal PCR testing38, and frozen at -80°C. Urine samples are collected in urine 

collection cups coated with 10% sodium azide (NaN3) solution; NaN3 is added to inhibit bacterial growth in 

the sample.39 Urine samples are centrifuged for 10 minutes and the supernatant is then aliquoted into 1 mL 

cryovials and stored at the CBCF (-80°C) until assayed. Use of urine samples are discussed in Sections 

4.C.2c, 4.C.3c, and 4.C.4c. 

Urine Sample Processing and Acquisition of 1

H- NMR Data: De-identified samples (n=50) will be shipped 

frozen on dry ice to UM using a next-day express service in year 1. Case and control samples will be randomly 

batched and processed to minimize artificial effects arising from day-to-day variation in NMR runs. However, 

unlike LC-MS, NMR is not prone to high day-to-day variability.23,24 All samples are frozen and will be thawed at 

room temperature on the day of NMR assay only. Urine metabolites are negligibly influenced by long term 

freezer storage or shipment on dry ice.12 The pH of each sample will be measured and if necessary, NaOH or 

HCl will be added to achieve a pH of 7.0± 0.25.12 A volume equivalent to 10% of the total sample volume of 

4,4-dimethyl-4-silapentane-1-sulfonic acid (DSS) will be added as an internal standard. We will acquire onedimensional 1H-NMR spectra of urine samples using the first increment of the standard NOESY pulse 

sequence on a four-channel Varian (Varian Inc., Palo Alto, CA) Inova-500 MHz NMR (UM) or on a Bruker 600 

MHz spectrometer (NMR-Based Core at CCHMC). 12,40,41 We will specify parameters such as pulse 

sequencing to acquire accurate spectra from both NMR spectrometers.12 Sample preparation by the PI will 

occur under the supervision of Drs. Stringer and Romick-Rosendale (see letters of support). 12 All spectra will 

be recorded at 25°C. For this proposal, the original raw 1H-NMR spectra will be processed using Chenomx 

software (NMR Suite 8.0; Chenomx Inc., Edmonton, Alberta, Canada), 12,40 which includes chemical shift 

referencing, shimming, phasing, and baseline correction followed by identification and quantification of 

metabolites.42,43 NMR is a unique platform in that every metabolite has its own distinct NMR spectrum, so 

metabolite identification and quantification for abundant metabolites can be done reliably across platforms 

without a secondary analytic platform needed to validate the metabolite. However, the identity of any 

statistically significant metabolites will be confirmed by 2D NMR. For these compounds as well as any that are 

of low abundance (< 5μM), I will also conduct analytical confirmation using LC/MS with Dr. Zaidy (Section 2, 

training goal 3). Before statistical analyses, quantified NMR metabolite data will be normalized to account for 

the influence of metabolites present in either high or low concentrations. 12 

Table 3: Description of CARPE DIEM Cohort (n=169) 

Age* N (%) 

3 months--1 year 25 (14.8) 

1-5 years 93 (55) 

6-11 years 51 (30.2) 

Male 99 (58.6) 

Race 

White 110 (65.1) 

Black 52 (30.8) 

Other 7 (4.2) 

Ethnicity 

Hispanic 6 (3.6) 

Season of ED visit 

Winter 53 (31.4) 

Spring 33 (19.5) 

Summer 32 (18.9) 

Fall 51 (30.2) 

Exposed to smoke** 64 (37.9) 

Antibiotics prior to ED presentation 39 (23) 

* Age groups based on the child’s immunological and general 

physiological stage in development.8 

**Smoking exposure is defined as 1 or more person living at 

the same residence as the patient who smokes. 

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Data Management Clinical data will be extracted from the same Epic electronic medical record for both the 

case and control groups and imported into a REDCap database.44 Metabolomics data will be expressed as one 

record per study ID per identified metabolite. 

4.C.2.Specific Aim 1: To characterize the sources of variability in the urine metabolite profiles of 

healthy children. 

4.C.2a. Rationale The human metabolome can be affected by external factors (e.g. diet and medications) as 

well as biological factors (e.g. age and sex). In adults metabolites 

that differentiated gender were mostly the result of changes in 

energy metabolism (e.g. creatinine) as males have more muscle 

mass than women.40,45 In pre-pubescent children the difference in 

muscle mass is much less pronounced than adults making it 

unclear the impact of gender on child’s metabolome. Diet in 

adults have demonstrated that there is greater variability in the 

metabolome between subjects than within subjects.46,47 However 

this variability was deemed insignificant in comparison to the 

variability that exists when evaluating disease progression.47 In 

addition, age may be an important predictor in changes of 

metabolites over time in adults.40,46 Likewise in children annual 

variation in the metabolome as the child aged was found.48 Due 

to the sparse pediatric literature on healthy children it is unclear 

which factors have the greatest effect on a child’s metabolome 

day to day. 

4.C.2b.Preliminary data A convenience sample of five healthy 

children provided two morning urine specimens 24 hours apart. 

Three subjects were female, and the age ranged from 5-7years 

old. Similar to a previous study we found large changes in creatine, 

citrate, trimethylamine N-oxide, and betaine over time (Figure 3). 

However, the magnitude of the changes in metabolite 

concentrations from our data is less than that of the previous study. This may be due to the tight age range or 

short time frame in which samples were collected. Additional healthy controls will allow us to determine the 

extent to which external and biological factors influence a child’s metabolome over time. 

4.C.2c. Methods 

Biological Specimens: Urine samples, from healthy children who provide urine samples at 3 time points will be 

eligible for inclusion in the analysis. The three time points are: 1) at the time of enrollment (T0); 2) 24 hours 

post enrollment collected at home by the patient (T1); and 3) 14 days’ post enrollment collected at home by the 

patient (T2). The time points were chosen to demonstrate acute changes in the metabolome. Patients will 

receive a home urine collection kit during enrollment and will be given three options to return the sample: 1) 

Mail the sample back with the provided box and shipping label; 2) Drop off the sample at their primary care 

office, which has a daily courier service to CCHMC; or 3) Drop off the sample at CCHMC (Appendix B). From 

previous studies at CCHMC, a return rate of >90% of samples was demonstrated.49 Therefore using an 

established protocol from the Centers for Disease Control and Prevention for home urine collection and our 

local experience we believe it will be feasible to collect three time points.50

Statistical Analysis: First, descriptive statistics (e.g. paired t-tests) and graphics (i.e. stick plots) will be used to 

evaluate metabolite concentration at each time point. Metabolite concentrations will be transformed if 

necessary to achieve a normal distribution. Only metabolites that are reported in at least 90% of the samples 

will be included in the analysis. For each metabolite, we will estimate the between-subject and within-subject 

variability by using linear mixed models. Metabolite concentration will be the dependent variable and a random 

effect will be included for subject and time nested within subject.51,52 Using these variance components, we will 

estimate the intraclass correlation (ICC), the ratio of between-subject variance and total variance. We will also 

include fixed effects for age and sex, and examine the proportion of the variance attributable to each of these 

covariates. To account for multiple testing which arises due to metabolites from the same child we will use 

false discovery rate procedures, such as Benjamini-Hochberg procedure. We will illustrate the distribution of 

the variance components and ICCs among all metabolites and describe the proportion of metabolites that are 

associated with age and sex by the false discovery rate procedure. 

Figure 3: Changes in metabolite concentrations over 

time. The y-axis is the concentration of the metabolite 

(uM); the x-axis is the time point, “0” is baseline, “1” is 

24 hours after the first time point. Each line 

represents a unique child. 

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Sample Size: We performed a log-normal power analysis to estimate the differences in metabolite 

concentrations between gender. The difference is defined as the linear t-contrast between logs of the 

geometric means derived from the mean concentrations of the metabolite. We examined power to detect the 

geometric mean ratio with p<0.01 for a coefficient of variation (CV) of 0.5 within each group. With a planned 

enrollment of 125 healthy controls, we estimate 110 (~90%) will provide at least 3 samples and be eligible for 

inclusion in Aim 1 analysis. We anticipate 65 (59%) will be male and 45 females and allow us to have 80% 

power to detect a geometric mean ratio of 1.38. 

4.C.2d. Expected Outcomes The main outcome is the change in metabolite concentration over three time 

points (i.e. T2-T0; T2-T1; T1-T0). 

4.C.2e. Potential Problems and Alternative Strategies Although NMR is highly reliable in identifying 

metabolites it is possible that certain metabolites are unable to be quantified accurately. From our preliminary 

data, 7 metabolites out of the initial 50 metabolites identified had random missing patterns for 3 of the samples. 

Therefore, as a subanalysis we will impute the missing concentration of the metabolite if it has between 10-

30% missing in the dataset.53,54 

4.C.3.Specific Aim 2: To determine and compare the urine metabolite profiles of children with viral or 

bacterial CAP with those of healthy children. 

4.C.3a. Rationale Viruses, particularly respiratory syncytial virus and influenza, are thought to account for 

most (73-85%) cases of CAP in children.26,27

However, antibiotic treatment is more common 

than the prevalence of bacterial pneumonia 

suggests due to clinicians’ inability to distinguish 

viral from bacterial etiologies.4 Conventional 

microbiological techniques such as blood, sputum 

or pleural fluid cultures demonstrate high specificity 

but are positive in very few children.55,56,57

Therefore, I will use multiple molecular and 

microbiological tests to increase the accuracy of 

identifying bacterial infection (see section 4.C.3c).

Metabolomics studies have distinguished different 

etiologies of CAP; however, those studies are 

limited by small sample sizes.25,58 Slupsky et al 

identified unique metabolite patterns excreted in urine of adults 

with pneumococcal infection (n=8) and Mycoplasma 

pneumoniae (n=9); these metabolites were significantly 

different from those in healthy adult control samples (n=115).25 

In other studies, distinct metabolites appeared in the urine of 

children with severe pneumonia (n=11) but not in controls.7,58

These initial studies are limited by the inclusion of only 

hospitalized patients, the lack of any viral testing, and the lack 

of clinical data. 4.C.3b. Preliminary Data In my preliminary 

data from CARPE DIEM, urine samples from children with 

CAP (n=39) were frequency matched by age and sex with 

samples from healthy children (n=14) and yielded 50 named 

and quantified metabolites by NMR. I compared healthy 

controls with viral (n=29) (Figure 4A) and bacterial CAP 

(n=10) (Figure 4B) by partial least squares-discriminant 

analysis (PLS-DA). This resulted in distinct groups with 

potentially important metabolites identified through the variable 

importance in projection (VIP) score and large fold differences 

in the concentrations of metabolites (Figure 5). Potential 

metabolites that may differentiate bacterial and healthy 

Figure 4: PLS-DA score plots of quantitative 1H-NMR 

metabolomics of urine from pediatric healthy controls (n=14) (red) 

compared with patients with pneumonia either due to virus (n=29) 

(green, 4A) or bacteria (n=10) (green, 4B). 

Figure 5: A radar plot of quantitative 1H-NMR 

metabolomics of urine from pediatric patients with 

pneumonia due to bacteria or virus and healthy 

controls. Each circle represents a 2-fold difference 

from the class of pathogen and healthy control. The 

smallest circle is the reference circle indicating no 

difference between healthy control and class of 

pathogen. The viral class is indicated by the orange 

line and the bacterial class is the blue line. 

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Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

samples included methylnicotinamide, taurine, acetone, choline, citrate, and methylgultarate. Alternatively, 

potential metabolites important in differentiating viral and healthy samples included hypoxanthine, 

methylgultarate, acetone, betaine, and phenylalanine. It is possible that metabolites that are identified in both 

analyses (e.g. methylgultarate and acetone) are indicators of infection 

regardless of pathogen, and that non-overlapping metabolites such 

as taurine and betaine are indicators of bacterial versus viral 

pathogens, respectively. Collectively, these data, although 

preliminary, provide additional support for the utility and feasibility of 

NMR metabolomics to differentiate CAP etiology. Here, I propose a 

more definitive study to corroborate and extend these findings using a 

substantially larger sample size, overcoming the limitations of prior 

studies. 

4.C.3c. Methods Pathogen Classification: Specimens from the 

CARPE DIEM study or from the control cohort will be included in the 

analysis. Final viral and bacterial classifications will be determined as 

defined in Table 4.

26,33,55,59 We will define bacterial pneumonia as a 

nasal swab positive for bacteria and a procalcitonin (PCT) of >1.5 

ug/mL which has moderate sensitivity and specificity to diagnose 

bacterial infection.59 PCR to detect pneumococcal autolysin A (lytA) 

and pneumococcal surface adhesion (psaA), pneumococcal surface 

antigens, will be performed on all NP swabs 60-66 and will be 

considered as either present or absent in the sample and of course 

cases with blood or pleural culture positive for pneumococcus will be 

classified as positive (Table 4). Currently of the 169 urine samples 

collected the majority of patients (60.4%) had only a virus detected 

(Table 5). A subset of samples will be classified as “unknown” and be 

further analyzed using 16S rRNA on blood samples to identify 

bacteria at the genus level.67-69 

Statistical Analysis of Metabolomics Data: Descriptive statistics will be 

conducted and continuous variables will be transformed if necessary 

to achieve a normal distribution. Case samples will be analyzed with 

age- and sex-matched controls. 

The first stage of analysis will include a crude examination of the 

metabolite data. Principal component analysis (PCA) and PLS-DA, 

multivariate statistical methods, will be perfomed which transform a 

large set of correlated data (e.g. individual metabolites) into a smaller 

number of uncorrelated principal components while maintaining 

variability 

within the 

data. PCA 

and PLS-DA 

allow for a visual display of the clusters that are 

inherent in the dataset by creating a scores plot 

(Figure 4), and a loading plot, which shows which 

metabolites are the most important in deciding the 

clusters.70 We will use the results of the PCA to guide 

the number of latent variables or PLS components of 

the PLS-DA classification procedure. The second 

stage is to use PLS-DA is to optimize separation of the 

metabolomics data between the three groups with an 

analytic advantage of being able to handle highly 

collinear and noisy data common in metabolomics. 

Through this approach, we will obtain VIP score and 

Table 4: Etiology Definitions 

Viral Etiology 

Anticipated Prevalence: 60-75% 

NP Swab Positive for Virus* 

AND 

NP Swab Negative for bacteria** 

AND 

Negative cultures from collected sources 

Bacterial Etiology 

Anticipated Prevalence: 5-10% 

NP Swab Negative for Virus* 

AND 

Blood/Pleural Fluid Culture Positive for 

Bacteria*** 

OR 

NP Swab Positive for Bacteria** 

AND 

Procalcitonin (PCT) indicative of bacterial 

infection (≥ 1.5ng/mL) 

Viral/Bacterial Co-Infection Etiology 

Anticipated Prevalence: 5-10% 

Viral Classification AND Bacterial Classification 

Criteria Met 

Unknown Etiology 

Anticipated Prevalence: 15-20% 

NP Swab Negative for Virus and Bacteria 

AND 

Culture Negative from collected sources 

Footnote 

*Includes: Influenza A/B, Parainfluenza 1/2/3, 

Respiratory Syncytial Virus (RSV) A/B, Human 

Metapneumovirus, Enterovirus/Rhinovirus, 

Adenovirus, Coronavirus, Human Bocavirus 

**Includes: Streptococcus pneumoniae, 

Mycoplasma pneumoniae, Chlamydophila 

pneumoniae, Legionella pneumoniae

***Includes: Streptococcus pneumoniae, 

Haemophilius influenza, Staphylococcus aureus, 

Streptococcus pyogenes, Klebsiella pneumoniae

Table 5: Etiology from CARPE DIEM Cohort (n=169) *

Overall Pathogen Classification N (%) 

Virus Only 102 (60.4) 

Bacteria Only 21 (12.4) 

Viral and Bacterial Co-infection 12 (7) 

Unknown Etiology 34 (20) 

Specific pathogens identified** N (%) 

Influenza A/B 12 (7.1) 

Parainfluenza 1/2/3 6 (3.6) 

Respiratory Syncytial Virus A/B 32 (18.9) 

Human Metapneumovirus 11 (6.5) 

Enterovirus/Rhinovirus 57 (33.7) 

Streptococcus pneumoniae 17 (51.5) 

Mycoplasma pneumoniae 14 (42.4) 

Staphylococcus aureus 2 (6.1) 

*Etiology determined as defined in Table 4. 

**Note one patient may have multiple pathogens identified 

therefore percentages were calculated based on number of 

specimens with the identified pathogen divided by total number of 

pathogens identified in that class (Virus or Bacteria) of pathogen. 

Contact PD/PI: Ambroggio, Lilliam

Research Strategy Page 106
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

regression coefficients to identify the most important variables in separating groups. 

 The third stage of analysis will use analysis of covariance (ANCOVA) to compare groups with respect to 

individual metabolite concentrations with clinical and demographic characteristics included as covariates. 

Covariates with a p-value <.10 in 1-to1 regressions will be considered statistically significant and examined in 

the final model. The final model will indicate whether or not the means of the metabolite concentrations 

between each group are significantly different by examining t-contrasts from the model. The t-statistic from 

each contrast will be used to compare groups. To account for multiple testing I will use false discovery rate 

procedures, (i.e. Benjamini-Hoceberg procedure).71 As an exploratory analysis, I will conduct pathway analysis 

via Metscape to construct metabolic networks using the differentiating metabolites to aid in the interpretation of 

the data.70 

Sample Size: We performed a log-normal power analysis where the difference was defined as the linear tcontrast between logs of the geometric means derived from the mean concentrations of the metabolites 

identified from our preliminary study. We examined power to detect the geometric mean ratio with p<0.01 

for a coefficient of variation (CV) of 0.5 within each group. An enrollment of 250 cases with 175 (70%) 

estimated to be viral and 125 healthy controls would allow us to have 80% power to detect a geometric 

mean ratio of 1.21. 

 4.C.3d. Expected Outcomes We expect to identify and quantify the concentrations of approximately 50-60 

metabolites in each urine sample.12,72

4.C.3e. Potential Problems and Alternative Strategies It is possible that results from lytA and psaA will be 

discordant for detecting S. pneumoniae. In that situation I will use a Latent Class Modeling (LCM) approach 

which estimates a probability of pneumococcal infection in cases when a true gold standard is not available for 

all cases (e.g. limited blood or pleural fluid cultures for each case).62,73 Cases with positive blood or pleural 

culture for pneumococcus will be included in the model as known disease cases. The LCM will be implemented 

using Mplus 7.1. 

4.C.4. Specific Aim 3: To determine longitudinal changes in the urine metabolite profile in children with 

CAP compared with healthy controls.

4.C.4a Rationale and Preliminary Data Assessing the physiological response to antibiotic therapy is 

challenging because the etiology of pneumonia is usually not known and antibiotics are prescribed empirically. 

In addition, traditional culture 

techniques are substantially less 

sensitive and less specific in 

detecting bacterial pathogens 

when the samples are collected 

after the patient receives antibiotic 

therapy.74 Therefore, measuring 

longitudinal changes in metabolite 

patterns will aid in differentiating 

response from non-response to 

antibiotics; and determining the 

effect of different antibiotics on 

the identified metabolomics 

profile. Samples will be collected 

at 3 time points from children with CAP: 1) at the time of presentation in the ED; 2) 24 hours post exposure to 

antibiotics to allow for response to the infection if bacterial which will be collected on the inpatient service; and 

3) 14 days post discharge to determine a non-infected state of the metabolome collected at home by the 

patient. Samples from controls are described in 4.C.2c. 4.C.4b. Preliminary Data In my preliminary data, I 

compared changes (delta) in metabolite concentrations for urine samples taken at the first 2 time points on 

each of 7 hospitalized patients from CARPE DIEM and from 5 healthy controls (from Aim 1). Patients with CAP 

had larger changes in their metabolite profiles over 24 hours compared with healthy controls (Figure 6). All 

patients with CAP received ampicillin within the 24 hours of their first urine sample. Choline is a known 

metabolite of aminopenicillins, however had one of the smallest changes among all the metabolites.75 In 

addition other metabolites (e.g. betaine and citrate) that were identified in the preliminary analysis in Aim 2 

have consistently greater changes in patients with CAP than healthy controls. 

Figure 6: Changes in metabolite concentrations over time. The y-axis is the change 

in concentration of the metabolite (uM); the x-axis is the individual metabolites. 

Orange bars indicate pneumonia subjects and blue bars indicate healthy subjects. 

Black bars indicate standard errors. 

Contact PD/PI: Ambroggio, Lilliam

Research Strategy Page 107
Metabolomics Evaluation of the Etiology of Pneumonia Lilliam Ambroggio, PhD, MPH 

4.C.4c Methods

Biological Specimens: Urine samples, from cases and controls, who provide samples at 3 time points will be 

eligible for inclusion in the analysis. 

Statistical Analysis: First, descriptive statistics and graphics will be used to evaluate metabolite concentration 

at each time point by group (i.e. viral, bacterial, healthy). Metabolite concentrations will be transformed if 

necessary to achieve a normal distribution. For each metabolite, we will utilize a linear mixed model with 

normalized metabolite concentration as the dependent variable. The models will include a between- subject 

variable (group) with 3 levels (group: viral, bacterial, and healthy control) and one within-individual variable 

(time) with 3 levels (baseline, 24 hours, and 14 days) along with covariates. Our primary goal will be to assess 

overall group effects and group by time interactions. Group differences in changes over time, will be tested 

using least square means contrasts.52

Sample Size: We calculated power to detect differences in longitudinal changes between 2 groups, cases and 

controls. Assuming a log-normal distribution, we examined the smallest geometric mean ratios between the 2 

groups that would be detectable and assumed a CV of 0.50 and t-contrasts corresponding to the geometric 

mean ratios for power calculations. We have sufficient power (80%), with an alpha of 0.01, to detect a 

geometric mean ratio of 1.61 for our anticipated sample of 50 cases and 50 sex and age matched healthy 

controls, having data at all 3 time points. 

 4.C.4d. Expected Outcomes The outcome of interest is the change in the metabolite concentrations at each 

time point across groups. 

 4.C.4e. Potential Problems and Alternative Strategies As multiple therapies (e.g. bronchodilators) can be 

administered within the time frame of sample collection for patients in CARPE DIEM, we will include timevarying covariates for each therapy to better evaluate the influence of these therapies on the temporal changes 

in the metabolite profiles. In addition, it is possible that we only receive two time points from cases or controls 

therefore a subanalysis will be conducted including these samples with the cohort of children with all 3 time 

points. 

4.C.5. Timeline and Future Directions The 

timeline for the research and training goals are 

outlined in Table 6. The metabolites identified 

in Aim 2 will be the foundation for a targeted 

approach using LC/MS to validate the 

metabolite profiles in a multicenter study. Data 

generated from Aim 1 and 3 will be used as 

preliminary data to further investigate the 

response to therapy over time compared with 

normal changes. The strength of this study is 

the identification of candidate metabolites that 

will ultimately be translated to point-of-care 

tests for rapid pathogen identification for 

children with CAP. 

Table 6: Timeline of Proposed Research Activities 

PreGrant Y1 Y2 Y3 Y4 Y5 

IRB Approval X 

Case Patient Recruitment (n) 175 75 

Control Patient Recruitment (n) 75 50 

NMR Work Flow (n of samples)* 81 100 350 175 

16S rRNA X 

Statistical Analysis X X X 

Dissemination of Results X X X 

R01 Application X 

Training Goal 1 2, 3 2,4 3,4 3,4 

*N’s include 3 time points for Aim 1 and 3. In Year 1, technical replicates 

(n=50) will be assayed at two sites. 

Contact PD/PI: Ambroggio, Lilliam

Research Strategy Page 108
TRAINING IN THE RESPONSIBLE CONDUCT OF RESEARCH

The responsible conduct of research was a significant part of my graduate school training. I completed two ten

week courses on public health ethics and epidemiological research methods that were taught by a historian 

and ethicist in the School of Public Health at Drexel University. The course topics included understanding

bioethics, legal basis of public health, ethical considerations in health disparities, ethical failures in the past and

present human subjects’ research and new challenges to ethical research. In addition doctoral seminars were 

held on conflict of interests, data sharing and roles and responsibilities of individuals versus institutions during

the scientific process. During my post-doctoral fellowship, I participated in multiple group discussions on topics

related to ethical research in the clinical pediatric setting. I have also completed the on-line Collaborative IRB

Training Initiative (CITI) Program during graduate school and fellowship and I will continue to keep my CITI

training current during this award and my scientific career. The CITI program includes training in all facets of

human subject’s research, including IRB regulations, informed consent, and research with protected 

populations, and research involving children. The CITI training is the industry standard human subjects

training, with funding from DHHS and over 1.3 users from over 1,130 institutions worldwide. This training

maintains our institutional compliance with NIH’s RCR Notice #NOT-OD-10-1019.

Preparation of IRB Proposals and Protocol Management (~12-15 hours over two years)

CCHMC’s research community structure supports the responsible conduct of research, as evidenced by

having received full accreditation from the Association of the Accreditation of Human Research Protection

Programs in 2008.The institutional review board assigns “research compliance specialists” to each division.

This allows for close relationships between each division and the IRB, as well as facilitating the development of

research protocols through open dialogue between researchers and the IRB. Additionally the IRB at CCHMC

has Standard Operating Procedures (SOPs) which will be applied as is relevant to my research. These include 

the SOPs on obtaining informed consent, documentation procedures, and participant recruitment and 

protection. The SOPs were designed to optimize protection of research subjects and promote ethical conduct

of research. Throughout the course of this award, I will review these SOPs with my mentors and utilize them

when appropriate. Finally, all research will be reviewed by co-mentors as well as by our division scientific

review process and the IRB to confirm both the scientific validity and the responsible conduct of all proposals.

Seminar on Ethics in Research and Scientific Integrity (24 hours over 5 years)

Additional training will be gained through my attendance at the University of Cincinnati’s (UC) Center for

Clinical and Translational Science seminars which routinely offers forums and workshops on trending topics 

including ClinicalTrials.gov in regards to intellectual property ownership, biorepositories and research ethics. 

Human Subjects Protection Symposium (8 hours every two years) 

UC and CCHMC also offer a yearly, one-day “Human Subjects Protection” symposium that addresses topics 

relevant to pediatric research which I attended in 2012 and will attend again in 2017. 

Formal coursework (10+ hours over 5 years)

I will complete a course offered by the UC entitled “Ethics in Research / Scientific Integrity” (26 GNTD 730

001). Lectures and group discussions will focus on topics including mentoring, record keeping, Institutional

Review Boards (IRBs), authorship, and scientific misconduct. In addition, annual metabolomic workshops such 

as those at the University of Alabama and at the University of Michigan include sessions specifically regarding 

ethics in “-omics”. These sessions include discussions on what constitutes scientific misconduct, data storage

of -omic data, appropriate data retention as required by the NIH and NSF, data sharing and reporting both with 

the scientific community and with the study participants. These sessions are also incredibly useful in 

presenting the most recent regulations surrounding -omics data as the field and the regulations surrounding

this type of subject data is ever changing. As discussed in my training plan I will attend these –omics

workshops throughout the award period.

Division of Hospital Medicine Faculty Educational Conference (~24 hours over 2 years). Clinical and

research faculty and staff in the Division of Hospital Medicine meet approximately once per month (as part of

our weekly faculty meetings) to discuss research topics relevant to the responsible conduct of research 

including study design, IRB relationships, presentation formats, and data management. Dr. Armand 

Antommaria, an Associate Professor in the Division of Hospital Medicine and Director of the Ethics Center at

CCHMC leads quarterly sessions focused on ethics in research and clinical care. Dr. Antommaria begins each 

session with a broad topic and then refines his approach after a needs assessment of the faculty and fellows.

Attendance at these training-pertinent conferences is required and tracked.

Contact PD/PI: Ambroggio, Lilliam

Training in the Responsible Conduct of Research Page 109
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Re: Mentorship Plan and Statement from Primary Mentor: Samir Shah, MD, MSCE

Dear Study Section Members:

It is with great pleasure and enthusiasm that I write this letter in support of Dr. Ambroggio’s K01 proposal, 

“Metabolomic Evaluation of the Etiology of Pneumonia” (MEEP). I am Professor of Pediatrics at the University 

of Cincinnati College of Medicine. I also serve as the Director of the Division of Hospital Medicine and hold the 

James M. Ewell endowed chair at Cincinnati Children’s Hospital Medical Center (CCHMC). I have known Dr. 

Ambroggio for over 7 years during her time as a graduate student at Drexel University. I currently serve as Dr. 

Ambroggio’s primary mentor and division director. During this time we have developed a rich relationship, 

collaborating on multiple publications focused on the management of pneumonia in children. I have always 

been impressed with her insight and understanding of the clinical decision making process. She has spent time 

rounding with pediatric hospitalists and infectious diseases specialists both at Children’s Hospital of 

Philadelphia and at CCHMC. I believe that her experience shadowing pediatricians, collaborating with 

pediatricians within multiple specialties through different research studies, attending weekly pediatric grand 

round lectures and her exposure to many facets of clinical medicine have provided her with a deep 

understanding of the intricacies of diagnosing and managing pneumonia from an individual patient level as well 

as from a health care systems level. It is this combination of her clinical understanding and her research 

acumen that makes her an exceptional candidate for this K01 award.

As an infectious diseases pediatrician, my own research has focused on factors associated with severe 

disease in children diagnosed with community-acquired pneumonia in the hospital settings. I served as 

Associate Chair of the writing committee and co-first author on the recently published national pediatric 

pneumonia guidelines, jointly sponsored by the Pediatric Infectious Diseases Society and the Infectious 

Diseases Society of America. I have a strong track record of extramural funding, (~$10 million as PI or coinvestigator) and a productive record of publishing (>200 peer-reviewed manuscripts). 

Mentoring talented junior faculty is a priority in my career and as a result I had the privilege of receiving the 

prestigious national Miller-Sarkin Mentorship Award from the Academic Pediatric Association in April 2015. I 

have served as the primary research mentor for over 45 trainees, ranging from medical students and residents 

to doctoral students, fellows, and junior faculty. Virtually all of my former mentees have been successful at 

securing academic positions with many receiving extra-mural research funding. It is in this context that I can 

confidently say that Dr. Ambroggio is clearly one of the best and most talented young researchers with whom I 

have worked. My own research, combined with my mentorship experience, provides me with the expertise 

necessary to guide and monitor Dr. Ambroggio’s progress toward accomplishing her proposed research 

agenda, and becoming an independent investigator.

Dr. Ambroggio has been extremely successful in her academic career thus far. During her graduate training, 

she clearly stood out from her peers at Drexel University and the University of Pennsylvania where I was 

faculty at that time, in terms of initiative, inquisitiveness and an affinity for epidemiological and statistical 

methodology. As such she was awarded the Outstanding Promise Doctoral Award in Physical and Life 

Sciences from Drexel University upon receiving her PhD. PhD candidates from fields such as biochemistry, 

engineering, and nursing are eligible, however only one award is given per year and, prior to Dr. Ambroggio, 

had never been given to a PhD candidate in Epidemiology. I recruited her as a post-doctoral fellow to CCHMC

in 2011 and very quickly Dr. Ambroggio developed strong collaborations with faculty in the Department of 

Radiology to investigate ultrasonography as alternate imaging modality compared with chest radiography to 

detect pneumonia in children. As a first year fellow, she received a highly competitive grant from the Thrasher 

Research Foundation for early investigators and led a team of seven faculty members, including four 

radiologists, to perform chest ultrasounds, chest radiographs and chest computed tomography scans on 

children with diagnosed pneumonia. 

During her first month as faculty Dr. Ambroggio received an internal Trustee Award to fund and co-lead the 

development of the infrastructure needed to collect biological samples, including urine, blood and nasal swabs, 

from children with radiographically-confirmed pneumonia in the emergency department. The study, called 

Catalyzing Ambulatory Research in Pneumonia Etiology and Diagnostic Innovations in Emergency Medicine

(CARPE DIEM), will be leveraged in this K01 proposal. Dr. Ambroggio and I meet monthly with Dr. Todd Florin 

and Dr. Rich Ruddy from the Division of Emergency Medicine to discuss study progress and provide senior 

and peer research mentorship formally and informally. All four investigators have distinct interests and career 

Contact PD/PI: Ambroggio, Lilliam

Plans and Statements of Mentor and Co-Mentor(s) Page 110
2

paths, but a unified focus on improving CAP outcomes, which allows for complementary expertise in 

approaching our research questions. The CARPE DIEM infrastructure is funded to enroll through end of fiscal 

year 2017 using funds from the Gerber Foundation grant and the Ohio Governor’s Research Fund. These 

funds ensure that the cost of study enrollment infrastructure, general study management, and sample 

collection is covered during the recruitment periods in the K01. The K01 award funds will be critical to support 

the NMR spectral acquisition of the urine specimens collected as part of CARPE DIEM and for the collection of

control samples from healthy patients. The team science approach for CARPE DIEM has resulted in Dr. 

Ambroggio (as the lead author) over the past couple of years in collaboration with Drs. Florin, Ruddy, Stringer 

and myself to submit abstracts to national and international conferences where she has been able to present

preliminary results.

In addition, Dr. Ambroggio has had the opportunity to become a site co-investigator in a multicenter study 

entitled “Children’s Hospital’s Initiative for Research in Pneumonia (CHIRP)”. The goal of CHIRP is to develop 

a genomic “molecular distance to health” score for children with pneumonia. This 6 hospital study is exposing 

Dr. Ambroggio to the processes needed to collect biological samples from multiple sites. This opportunity will 

enable Dr. Ambroggio to construct an effective multicenter study collaborating with the PRIS and PECARN 

network as part of a R01 application at the end of her K01 award.

As the primary mentor on this K01, I am extremely invested in Dr. Ambroggio’s success and thus will provide

her with clinical content expertise in pediatric pneumonia as well as the appropriate environment, resources, 

and mentorship necessary for her to success. Dr. Ambroggio’s long term research program focuses on 

improving diagnostic capabilities for common childhood infections using a combination of epidemiologic and 

metabolomics methodologies that are clearly distinct from my own program, which focuses on improving 

resource utilization for CAP and determining the comparative effectiveness of different treatments. Dr. 

Ambroggio will lead all aspects of the proposed studies including the preparation and assay of the urine 

samples in Dr. Stringer’s and Dr. Romick-Rosendale’s laboratory, the identification, quantification and analysis 

of the metabolomics data she generates. I will personally supervise her development throughout the period of 

the award as I have great confidence that she will develop into a successful independent investigator. The two 

of us meet regularly with weekly formal meetings and additional informal meetings to discuss her research 

progress and career development. Formal meetings will continue at least weekly during the initial years of this 

grant and then transition to bi-weekly meetings in years 3-5 as Dr. Ambroggio develops greater independence. 

Additionally, we have adjacent offices and I am available to her on an “open door” basis. Our one-on-one 

mentoring sessions will continue to focus on progress towards completing the proposed research, manuscript 

writing, abstract submission to national meetings, career development and grant identification and writing. In 

addition we have been and will continue to meet with Drs. Ruddy, Macaluso, Sucharew and Stringer (by 

phone) on a quarterly basis to discuss Dr. Ambroggio’s overall career and research trajectory. By years 4-5, 

Dr. Ambroggio will have developed the required skillsets to pursue an independent research career, including 

her own R01 application, and independence on manuscript publications without me as a senior author.

CCHMC has a formal process for annual faculty evaluation that includes a review of progress towards meeting

the previous year’s goals, as well as the establishment of new goals for the coming year. I will provide the 

primary guidance to Dr. Ambroggio in this process, and the goals and progress towards goals will be shared 

with the entire advisory committee. Dr. Ambroggio and I have created specific goals including 2-4 publications 

per year for the duration of the award. Committee meetings occur every 4 months with her scholarly oversight 

committee to guide Dr. Ambroggio in achieving both her research and career development aspirations as well 

as to discuss her strategies in achieving her goals. As her primary mentor, I will also complete the required 

evaluation for her annual NIH progress report. In addition as the Director of the Division of Hospital Medicine, 

where Dr. Ambroggio holds a primary appointment, I will continue to ensure that she has at least 75% of her 

time protected for research and research training specific to this award, with an additional 10% effort 

devoted to teaching two epidemiology courses per year at the University of Cincinnati. While I have great 

confidence in Dr. Ambroggio, her ongoing dedicated research time is not contingent on the success of this 

application. I will also support her by providing professional fees that can be used for the K award in excess 

of allowable costs such as for travel and registration to scientific conferences. 

In conclusion, it is a true pleasure to serve as a primary mentor for Dr. Ambroggio for this award. Dr. 

Ambroggio has shown herself to excel in everything she has done to date including 19 publications (10 as 

Contact PD/PI: Ambroggio, Lilliam

Plans and Statements of Mentor and Co-Mentor(s) Page 111
Contact PD/PI: Ambroggio, Lilliam

3

first author, 15 in relation to pneumonia) and 10 grants (5 as PI), and I am absolutely confident that she will 

continue to do so. In summary, Dr. Ambroggio has enormous potential to succeed as an independent 

investigator and to be a national leader in the field of infectious disease epidemiology. I offer my most 

enthusiastic and unreserved support for Dr. Ambroggio. 

Sincerely,

Samir S. Shah, M.D., M.S.C.E.

James Ewell Professor, Department of Pediatrics, University of Cincinnati College of Medicine 

Director, Division of Hospital Medicine, Cincinnati Children’s Hospital Medical Center

Re: Mentor Statement from Co-Mentor: Maurizio Macaluso, MD, DrPH

Dear Study Section Members:

I am writing to convey my strong commitment to serve as the co-mentor for Dr. Ambroggio’s K01 and to work 

closely with her primary mentor, Dr. Samir Shah, to ensure Dr. Ambroggio’s success in completing the 

proposed research and career development plan. I believe that her plan will help her establish herself as an 

independent investigator in infectious diseases epidemiology and metabolomics. I am Professor of Pediatrics 

and Environmental Health at the University of Cincinnati and Director of the Division of Biostatistics and 

Epidemiology of Cincinnati Children’s Hospital Medical Center. I am also the director of the Biostatistics, 

Epidemiology, and Research Design core of the UC Center for Clinical and Translational Science and Training 

(CCTST). In my thirty-year career in public health research, including my experience as a Professor of 

Epidemiology at the University of Alabama, my leadership position as Distinguished Consultant and Branch 

Chief at the Centers for Disease Control and Prevention in Atlanta, and in my present position, I have led large 

and diverse research groups. I have mentored many master level students, 15 doctoral students in 

epidemiology and related disciplines, Epidemiologic Intelligence Service Officers, Public Health Fellows and 

Preventive Effectiveness Research Fellows resulting in over 60 joint publications out of 200 publications (Hindex: 39). I believe that my background enables me to provide depth and breadth of mentorship, and 

complements well the expertise of the primary mentor and other aspects of her training plan.

I have known Dr. Ambroggio for four years, since she joined the Division of Hospital Medicine at Cincinnati 

Children’s as a post-doctoral research fellow. I served as the epidemiologist co-mentor with Dr. Shah, her 

primary clinical research mentor. During the interview process that led to her selection as a post-doctoral fellow 

I was impressed by her strong foundations in epidemiologic research methods and in her biological foundation 

in regards to infectious diseases. She joined the program with a clear research focus on advancing the 

diagnosis and treatment of community-acquired pneumonia, but also with the desire to expand her horizons 

into novel diagnostic methods. Soon after joining CCHMC she developed a coherent research program 

including a study of the comparative effectiveness of alternative antibiotic regimens in the treatment of 

community-acquired pneumonia and a comparison of the diagnostic accuracy of chest ultrasound and x-ray 

receiving funding from an Early Career Award by the Thrasher Fund in her first year as a post-doctoral fellow. 

Her determination, early success as a post-doctoral fellow and potential as an independent investigator led to a 

joint faculty recruitment by my own Division and the Division of Hospital Medicine. 

Dr. Ambroggio’s proposal to use metabolomics methods to identify pathogens in children diagnosed with 

community acquired pneumonia is reflective of a transition in the field of epidemiology to focus on translating 

bench science to bedside application. She is well positioned to succeed in this proposal as she has a strong 

foundation in study design, statistical analysis, and molecular and cellular biology. However, -omics 

epidemiology and specifically metabolomics, is a subset of epidemiology that is not taught in the majority of 

graduate programs. As her co-mentor I will ensure that Dr. Ambroggio receives timely and appropriate 

assistance with methodological aspects of her work. Overall, I believe, Dr. Ambroggio has assembled an 

outstanding group of mentors and advisors who whose expertise is complementary to ensure her success in 

accomplishing the proposed research and in her overall career as an independent investigator and future 

leader in the fields of epidemiology and metabolomics. Dr. Ambroggio’s proposal has the potential to 

significantly and positively impact diagnostic tools for detecting pathogens in community-acquired pneumonia 

in children.

Plans and Statements of Mentor and Co-Mentor(s) Page 112
Contact PD/PI: Ambroggio, Lilliam

4

I am committed to fostering Dr. Ambroggio’s career development, by supporting her while she strengthens her 

already well developed research skills, develops leadership and management skills and transitions from a 

mentored investigator position, to an externally-funded, independent investigator role. As she outlined in her 

career development plan, I will meet with her monthly during the period of performance of the award and more 

frequently as needed. I will be an active participant in the progress toward the goals outlined in this proposal

and I look forward to learning from our collaborative effort into the adaptation of epidemiologic methods to the 

area of metabolomics. I strongly believe that Dr. Ambroggio is a talented junior scientist who can become a 

leader and that the proposed K01 plan will ensure her success. Thus, I highly recommend her for your 

consideration and hope that you will support her application for this award.

Sincerely,

Maurizio Macaluso, MD, DrPh, FACE; Professor of Pediatrics and Environmental Health, University of 

Cincinnati College of Medicine; Director, Division of Biostatistics and Epidemiology, Cincinnati Children’s 

Hospital Medical Center

Re: Mentor Statement from: Kathleen Stringer, PharmD 

Dear Members of the Review Committee, 

It is my great pleasure to write a letter in strong support of Dr. Ambroggio’s K01 application entitled 

“Metabolomics Evaluation of the Etiology of Pneumonia”. Dr. Ambroggio is an exceptional candidate and I am 

enthusiastic to provide this recommendation on her behalf. I have known Dr. Ambroggio for two years. We first 

met in the summer of 2013 at the University of Alabama’s (UAB) NIH-funded 1st Metabolomics Workshop 

where I was serving as an invited speaker and Dr. Ambroggio was an attendee. Dr. Ambroggio’s keen interest 

in metabolomics and its application to her research in pediatrics was readily apparent. We had a number of 

one-on-one discussions about metabolomics at the meeting. These fruitful conversations naturally extended 

beyond the workshop and have continued on a regular, monthly basis as we have worked together to construct 

her K01 application. Together we have developed the application’s study design and a standard operating 

procedure for the study’s sample collection so that reliable, high quality metabolomics data will be generated. 

Dr. Ambroggio has spent time over the past two summers in my laboratory understanding the different aspects

of metabolomics study design. During this time we jointly generated the preliminary metabolomics data 

included in this application. Throughout our interactions in and outside of the laboratory it is evident that Dr. 

Ambroggio has a steep learning curve for this field and will be successful in her endeavors in this field of 

research. 

I am uniquely qualified to serve as Dr. Ambroggio’s metabolomics mentor on her K01 application. I am a 

Professor of Clinical and Translational Pharmacy at the University of Michigan’s College of Pharmacy. My 

research is focused in fibrin-inflammatory lung diseases, which includes the study of the rare, most often, 

pediatric illness, plastic bronchitis. I have also conducted a number of metabolomics studies using a range of 

biofluids, including urine. Most often I utilize quantitative NMR metabolomics with statistical and bioinformatics 

analyses aimed at identifying and quantifying metabolites of biological relevance. My research program is 

supported by grants from NIGMS and metabolomics supplements from NIGMS and NIMH. I have over 60 

peer-reviewed publications. I have mentored numerous students and post-doctoral fellows and was recently 

named a Distinguished Mentor by the University of Michigan’s CTSA. Based on my mentoring experience, I 

can confidently say that Dr. Ambroggio is clearly one of the best trainees I have encountered. Dr. Ambroggio 

is insightful, smart, highly organized, efficient, and very motivated. As an example we recently were invited to 

write a metabolomics review of sepsis. 

Dr. Ambroggio has designed a robust study, collecting relevant clinical data that are essential during the 

analysis phase of the study. As outlined in the training plan, Dr. Ambroggio will undergo intensive training in 

my laboratory during three 2-week visits in the first year. During this time Dr. Ambroggio will gain hands-on 

experience in processing and running her samples by NMR under my guidance and with the aid of the NMR 

spectromist, Dr. Larisa Yeomans and our laboratory technician, Cora McHugh. Dr. Ambroggio will gain 

experience with Chenomx (chenomx.com) software as well as Metscape 2 (www.metscape.ncibi.org), a plugin 

for Cytoscape (www.cytoscape.org), and other publicly available netware tools. 

Plans and Statements of Mentor and Co-Mentor(s) Page 113
Contact PD/PI: Ambroggio, Lilliam

5

We will also work closely with Dr. Sucharew, the biostatistician on the project, on statistical analysis and 

interpretation of the data. My knowledge and training in clinical pharmacy will be extremely helpful in the 

interpretation of the results from this proposal as many children with community-acquired pneumonia will have 

received antibiotics. Deciphering the influence of pharmacotherapy on the metabolome is of critical 

importance in furthering knowledge of community-acquired pneumonia. In addition to this time, I will continue 

having scheduled bi-weekly phone calls with Dr. Ambroggio throughout the period of the award, with a joint 

monthly phone call with Dr. Ambroggio and Dr. Romick-Rosendale to discuss study progress, Dr. 

Ambroggio’s ability to reproduce the data generated in my lab and other facets of cross-center NMR validation 

studies. 

I have also participated in Dr. Ambroggio’s quarterly mentorship team meetings over the past three years and 

have been able to interact with her outstanding group of mentors and advisors, including Dr. Shah. I believe 

that our collective expertise will afford Dr. Ambroggio an intensive career development experience that I am 

confident will lead to her research independence in the fields of metabolomics and epidemiology. I look forward 

to my continued involvement in the research and career development of this talented individual. 

Sincerely, 

Kathleen A. Stringer, PharmD 

Professor of Clinical and Translational Pharmacy 

College of Pharmacy, University of Michigan 

Re: Mentor Statement from: Richard Ruddy, MD

It is with great enthusiasm that I write in support of the K01 application of Lilliam Ambroggio, PhD, MPH as one 

of her co-mentors. I have known Dr. Ambroggio for three years, since her second year of fellowship at 

Cincinnati Children’s Hospital Medical Center. Her zealousness and passion to improve clinical outcomes for 

children with pneumonia through implementing evidence based guidelines to investigating emerging diagnostic 

tools has been evident from the beginning. During her first year as faculty, she secured a highly competitive 

internal Trustee award, and together with Dr. Todd Florin, developed a prospective research study of children 

with community-acquired pneumonia who present to the emergency department including an associated 

biorepository. Dr. Ambroggio and Dr. Florin, under the supervision of Dr. Shah and I, have enrolled 248 

children since enrollment began in July 2013. The feasibility of this study has been clearly demonstrated.

Enrollment will continue through July 2017 with funding by the Gerber Foundation and the Ohio Governor’s 

Research Fund, both of which Dr. Ambroggio is a co-Investigator. This well established and funded 

prospective study entitled Catalyzing Ambulatory Research in Pneumonia Etiology and Diagnostic Innovations 

in Emergency Medicine (CARPE DIEM) will provide Dr. Ambroggio with the biological samples and robust 

clinical data she needs to complete the research and training aims outlined in her K01. 

Academically, I am a Professor of Pediatrics in the College of Medicine at the University of Cincinnati and was 

the Division Director of Emergency Medicine in the Department of Pediatrics until June of 2015. My research 

focuses on defining the role of diagnostic testing on management decisions in the emergency department. My 

current research investigates respiratory illness and febrile young infants who are at low risk of serious 

bacterial infection. I am the principal investigator of one of six research nodes of pediatric emergency 

departments in the Pediatric Emergency Care Applied Research Network (PECARN), the first federally-funded 

multi-institutional network for research in pediatric emergency medicine. We are funded through 2019 I will 

continue to advise Dr. Ambroggio in respiratory illness content, in enrollment and quality metrics for her study 

patients as well as her aspirations for this work to be multicenter through PECARN. That includes nodal and 

network wide studies which may help expand Dr. Ambroggio’s metabolomics investigation to a larger 

population of children in a future R01 award. I am excited to continue to play the role as mentor and advisor to 

her work the next 5 years. 

Dr. Ambroggio has developed a strong mentorship team that has been meeting quarterly as part of her 

scholarly oversight committee since she became faculty in 2013. In this time I have had many opportunities to 

communicate with Drs. Shah, Macaluso, Sucharew and Stringer in the development of this award as well as 

Plans and Statements of Mentor and Co-Mentor(s) Page 114
Contact PD/PI: Ambroggio, Lilliam

6

the pathway for Dr. Ambroggio to establish herself as an independent investigator studying pediatric infectious 

diseases.

In conclusion, I believe that Dr. Ambroggio’s leadership, analytical skills, and ability to form strong relationships 

across disciplines combined with her scholarly accomplishments in the past and in the future will make her one 

of the leaders in the field of infectious diseases epidemiology. This K01 will move her forward as an 

independent investigator in this field. I am fully committed in providing Dr. Ambroggio the support that is 

needed for her to successfully accomplish her research aims as outlined in her application as one of her 

mentors.

Sincerely,

Richard M. Ruddy, MD

Professor of Pediatrics, University of Cincinnati College of Medicine

Medical Director, Cincinnati Children’s Hospital Medical Center - Liberty

Re: Mentor Statement from: Heidi Sucharew, PhD

Dear Members of the Review Committee, 

It is with the utmost support that I write this letter for Dr. Ambroggio’s K01 proposal “Metabolomics Evaluation 

of the Etiology of Pneumonia”, as her statistical mentor. Dr. Ambroggio developed a strong foundation in 

statistical methods during her PhD and I believe that she is extremely capable of learning and applying the 

statistical methods outlined in her proposal for her current research aims. In our interactions over the past four 

years since her arrival at CCHMC, she has been impressive in her attention to detail, calm, and thoughtfulness 

in solving design and methodological problems. She has been successful as a junior faculty member and the 

formation of a well-rounded mentoring team that has been meeting quarterly over the past three years 

demonstrates her initiative and leadership abilities. 

I am an Assistant Professor of Pediatrics in the Division of Biostatistics and Epidemiology at CCHMC with a 

methodological expertise in structural equation modeling, latent class variable analysis (e.g. statistical methods 

applied to imperfect gold standards) and cluster analysis. My recent areas of interest include latent profile 

analysis of infant neruobehavior and of individual NIH stroke scale scores for mortality prediction. I have 

collaborated and mentored many clinical fellows and faculty since beginning at CCHMC. I will advise Dr. 

Ambroggio in advanced statistical techniques such as cluster analysis and when an imperfect gold standard is 

available to estimate the sensitivity and specificity of a multiple diagnostic tests. Dr. Ambroggio’s proposed 

career development and training plan builds on her existing expertise and complements the proposed 

research. Additionally, her training plan will prepare her to transition to become an extramurally-funded, 

independent investigator focused on diagnostics using metabolomics methodology and advanced statistical 

analysis for pediatric infectious diseases. I will continue to meet with her monthly for the first year of the grant 

and then bi-weekly in years 2-4, however I am always available for informal meetings as needed. 

The rapidity with which Dr. Ambroggio developed collaborative relationships and garnered recognition for her 

work at CCHMC is just the beginning of a trajectory that promises to lead her to become an independent 

investigator. The proposed research constitutes a deliberate and thoughtful set of studies that follows naturally 

from her prior work. This work will provide Dr. Ambroggio with the necessary data and research skills to submit 

and successfully complete a future R01-funded application. I look forward to my continued involvement in the 

research and career development of this talented individual.

Sincerely,

Heidi Sucharew, PhD

Biostatistician, Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center

Assistant Professor of Pediatrics, University of Cincinnati College of Medicine

Plans and Statements of Mentor and Co-Mentor(s) Page 115
Division of Pathology 

and Laboratory 

Medicine

David P. Witte, M.D.

Division Director

Paul E. Steele, M.D.

Medical Director

Michael L. Baker, MD

Staff Pathologist

Kevin E. Bove, M.D.

Staff Pathologist

Margaret H. Collins, M.D.

Staff Pathologist

Anita Gupta, M.D.

Staff Pathologist

Robert Lorsbach, M.D., Ph.D.

Staff Pathologist

Richard McMasters, M.D. 

Staff Pathologist

Lili Miles, M.D.

Staff Pathologist

Lindsey Romick-Rosendale, Ph.D.

Mass Spectrometry

Kenneth Setchell, Ph.D.

Mass Spectrometry

Shiva Shanmukhappa, Ph.D.

Research Pathologist

Amy Sheil, M.D.

Staff Pathologist

Rachel Sheridan, M.D.

Staff Pathologist

Jerzy W. Stanek, MD, Ph.D. 

Staff Pathologist

Keith F. Stringer, M.D.

Medical Education

Dehua Wang, M.D.

Staff Pathologist

Mika Warren, M.D.

Staff Pathologist

Kathryn Wikenheiser-Brokamp, 

M.D., Ph.D.

Staff Pathologist

(513) 636-4261 Anatomic

(513) 636-3924 Fax

(513) 636-4686 Mass Spec

(513) 636-7853 Fax

Dear Members of the Review Committee:

It is with great pleasure that I support Dr. Ambroggio’s K01 training goals related to 1H-NMR 

quantitative metabolomics experimentation. As the Director of the newly established NMR-based 

Metabolomics Core Facility at Cincinnati Children’s Hospital Medical Center, I can ensure the 

committee that Dr. Ambroggio will have the necessary resources at her disposal to accomplish the 

specific aims proposed in her study titled “Metabolomic Evaluation of the Etiology of Pneumonia”, 

in addition I will gladly provide intensive laboratory training in collaboration with the training she 

receives from Dr. Stringer as outlined in her K01 training plan. The Metabolomics Core Facility is 

supported by the Cincinnati Children’s Research Foundation (CCRF), therefore, Dr. Ambroggio 

will only be charged $30 per sample for time on the NMR; however, all other reagents needed for 

urine preparation and assay will be provided free of charge as well as access to Chenomx NMR 

Suite software for the identification and quantification of metabolites. I will meet with Dr. 

Ambroggio every other week for the first three years of the award and then monthly in years 4-5. In 

addition I will be on monthly phone calls with Drs. Stringer and Ambroggio during the period of 

award to discuss progress of Dr. Ambroggio’s training and any potential barriers that may arise in 

regards to sample preparation, spectral analysis, or data interpretation. 

The NMR-Based Metabolomics Core Facility is conveniently housed in the basement of the R

building on the CCHMC main campus. The facility includes a wet lab, freezer space and has 3 

full-time employees, including myself. The CCRF at CCHMC has purchased a new Bruker 

600MHz NMR spectrometer, which is fully automated and optimal for metabolomics analysis of 

biological fluids. The instrument is equipped with a 96-well SampleJet autosampler and is ideal 

for high-throughput NMR data acquisition of patient samples. The spectrometer uses the same 

techniques as the NMR spectrometer in Dr. Stringer’s laboratory. Thus, Dr. Ambroggio should 

easily be able to transfer techniques learned at one facility to the other. I and my staff have the 

necessary expertise and analytical capabilities to assist Dr. Ambroggio in carrying out this 

important research endeavor. Although Dr. Ambroggio will be performing all aspects of the 

Metabolomic Work Flow as described in her training plan, my staff and I will be available for 

supervision and guidance as she performs each step. I am also available for informal meetings 

with Dr. Ambroggio to discuss day to day questions while she is running her own samples for this 

award. 

In closing, I offer my utmost support to Dr. Ambroggio in her K01 research and training goals. I 

am completely committed to the success of her proposal and training experience in the 

Metabolomics Core. Dr. Ambroggio is an exceptional investigator and this K01 will provide the 

necessary skills and experience to allow her to transition to an independent investigator.

Sincerely, 

Lindsey Romick-Rosendale, PhD 

Assistant Professor of Pathology

Director, NMR-Based Metabolomics Core Facility

Contact PD/PI: Ambroggio, Lilliam

Letters of Support from Collaborators,Contributors, and Consultants Page 116
Contact PD/PI: Ambroggio, Lilliam

Letters of Support from Collaborators,Contributors, and Consultants Page 117
Contact PD/PI: Ambroggio, Lilliam

Letters of Support from Collaborators,Contributors, and Consultants Page 118
Contact PD/PI: Ambroggio, Lilliam

Assem G. Ziady, Ph.D. 

 Associate Professor of Pediatrics 

Department of Pediatrics, 

Division of Pulmonary Medicine 

Cincinnati Children’s Hospital Medical Center

3333 Burnet Avenue 

MLC 2021

Cincinnati, OH 45229

Office R6391

T: 513-803-9094; F:513-803-4820

email: assem.ziady@cchmc.org

Dear Members of the Review Committee,

I am writing this letter in strong support of Dr. Lilliam Ambroggio’s K01 award proposal, “Metabolomic 

Evaluation of the Etiology of Pneumonia”. Dr. Ambroggio has identified a major gap in the management of 

community-acquired pneumonia (CAP), specifically the ability to identify the etiology causing pneumonia 

in children. Her proposal is thoughtful in its investigation of using quantitative NMR to distinguish 

bacterial and viral pathogens in children with pneumonia. As she indicates in her K01 training plan the 

logical next step is a R01 application to validate these profiles using a targeted approach such as tandem 

Liquid Chromatography-Mass Spectrometry (LC/MS2

). I am happy to train Dr. Ambroggio in using 

LC/MS in my laboratory during the 4th year of her award. This will give her the practical expertise needed

to add mass spectrometry to a multi-faceted approach in preparation for her future R01 application. 

I recently joined faculty at Cincinnati Children’s Hospital Medical Center in the fall of 2014 as an 

Associate Professor in the Division of Pulmonary Medicine. Prior to arriving, I was an Associate Professor 

and Associate Director of Cystic Fibrosis Basic and Translational Research within the Department of 

Pharmacology at Emory University. I also serve as a member of the Cystic Fibrosis Foundation Biomarker 

Consortium. My research program focuses on investigating inflammation in chronic lung disease and 

interventions that can modulate this inflammation. A central approach in our studies is the use of mass 

spectrometry for proteomic and metabolomic analysis of inflammation and the laboratory houses a state of 

the art LCMS ion trap mass spectrometer for these analyses. I will train Dr. Ambroggio on the study 

design, development and execution of targeted metabolomics studies using mass spectrometry. 

As a PhD trained epidemiologist, Dr. Ambroggio brings a unique expertise that is lacking in the field of 

metabolomics. This field is moving toward clinical application for which population-based studies are 

invaluable. I believe that Dr. Ambroggio is an excellent candidate for this K01 award and look forward to 

providing her with the practical learning needed for her to accomplish this and future proposals. In 

addition I believe she will develop into a leader in the field with whom I hope to collaborate.

Sincerely,

Assem G. Ziady, Ph.D.

Associate Professor

 

Department of Pediatrics, Cincinnati 

Children’s Hospital Medical Center

Division of Pulmonary Medicine 

 

3333 Burnet Avenue 

MLC 2021

Cincinnati, OH 45229

Office R6391

T: 513-803-9094; F:513-803-4820

email: assem.ziady@cchmc.org

Letters of Support from Collaborators,Contributors, and Consultants Page 119
DESCRIPTION OF THE INSTITUTIONAL ENVIRONMENT 

Cincinnati Children’s Hospital Medical Center (CCHMC) is a free-standing children’s hospital with 629 beds 

and over 30,000 annual admissions that houses the Department of Pediatrics for the University of Cincinnati 

College of Medicine (UC). CCHMC is the primary provider of inpatient, subspecialty and emergency care in 

Greater Cincinnati and the surrounding counties serving over 2 million people. CCHMC is ranked second

nationally among US pediatric institutions receiving NIH funding, having received $129 million in overall 

sponsored program awards in fiscal year 2015. The Cincinnati Children’s Research Foundation (CCRF) was 

established in 1931 with an endowment that would exclusively support research. Currently this endowment 

exceeds $2 billion, and continues to support research today. CCHMC is the largest pediatric research 

institution in the nation, with nearly 1.5 million square feet of research space. The CCRF has a proven record 

of producing high-quality research and supporting the development of junior faculty through career 

development programs, and a commitment to collaboration. CCRF has 724 faculty members engaged in basic, 

clinical and translational research. In 2015, CCRF faculty authored >2,000 published manuscripts. In addition, 

junior faculty have access to all available academic programming at UC, including tuition remission and library 

resources. UC’s Center for Clinical and Translational Science and Training (CCTST) is located on the CCHMC 

campus. It provides data management, bioinformatics support, and research nurses to aid in specimen 

collection for patients and grant development, through a Clinical and Translational Science Award and other 

mechanisms. Additionally, the CCTST sponsors a “K club” designed to provide both senior and peer 

mentorship to assist K-award recipients in achieving their research and career goals, as well as promote 

successful transitioning to R01 funding. The Office for Faculty Development offers relevant seminars for 

faculty, including a monthly grantsmanship series addressing challenges in writing grants and managing funds. 

CCHMC has an active Women’s Faculty Association (WFA) that was developed in 1984. The overall goal of 

the WFA is to promote career development, advancement and recognition of women in the Department of 

Pediatrics. The WFA also provides an opportunity for women faculty to meet, network, and participate in

informal mentoring activities. A major goal is to advance the careers of women in science. Division of 

Hospital Medicine, directed by Samir S. Shah, MD, MSCE, includes 45 academic faculty members and 7

fellows. The division includes 3 clinical services and cares for > 25,000 encounters each year, which is onefourth of all patients hospitalized at CCHMC. Divisional faculty received ~$1 million in direct annual grant 

support in FY16 and collaborate regularly with faculty in 17 other CCHMC divisions on groundbreaking 

research initiatives. The Division is dedicated to providing travel support to all faculty members who have 

research abstracts accepted for presentations at national meetings. Division of Pediatric Emergency 

Medicine, directed by Dr. Stephen Porter is responsible for managing two large emergency departments (ED)

and four urgent care facilities with annual visits of over 163,000 pediatric patients. This research will take place 

in the primary emergency department, a Level 1 Trauma Center, which had over 92,000 visits in 2014 and 

>1100 visits for pneumonia. The Division has 42 full-time faculty members with a research agenda to improve 

healthcare delivery among the ED population and was awarded over $1.67 million in research funding in 2014. 

This Division has a sophisticated infrastructure of research personnel who assist investigators with all aspects 

of their research. Division of Biostatistics and Epidemiology, directed by Maurizio Macaluso, MD, DrPH, 

was established to advance the capacity of CCHMC for clinical, translational, and population-based research 

that contributes to improving child health. The Division includes 98 faculty and staff who have received over 

$11.69 million in grant funding through collaborative and individual grants. The Division provides collaborative 

support to 54 research divisions at CCHMC. Division faculty members are also independently funded from the 

National Institutes of Health and other sources. NMR-Based Metabolomics Core, directed by Lindsey 

Romick-Rosendale, PhD, has a fully equipped laboratory within the Division of Pathology and Laboratory 

Medicine at CCHMC. The lab is fully equipped to process urine samples and conduct the proposed 

metabolomics experiement. Dr. Romick-Rosendale has direct access to a Bruker IVDr 600MHz spectrometer 

and Chenomx NMR suite 8.0 software to aid in spectral analysis. Ziady Laboratory, located at CCHMC is 

directed by Assem Ziady, PhD and houses a Tandem Liquid Chromatography-Mass Spectrometer and a fully 

equipped laboratory (~800 sq. ft) to process biofluid samples such as urine and blood specimens. Stringer 

Laboratory, University of Michigan, directed by Kathleen Stringer, PharmD, has a fully equipped laboratory 

(~500 sq. ft) in the College of Pharmacy on the central University of Michigan campus. Her lab is fully equipped 

to process urine samples and conduct the proposed metabolomics experiments. Dr. Stringer’s laboratory 

shares the same building as the Biochemical NMR core laboratory allowing Dr. Stringer direct access to a 

state-of-the-art Varian 500 NMR spectrometer. It is a "research grade" instrument capable of performing all of 

the solution NMR techniques being proposed. The Stringer Laboratory processed and in collaboration with Dr. 

Ambroggio analyzed the samples used for preliminary data in this proposal.

Contact PD/PI: Ambroggio, Lilliam

Description of Institutional Environment Page 120
Contact PD/PI: Ambroggio, Lilliam

Institutional Commitment to Candidate's Research Career Development Page 121
12. PROTECTION OF HUMAN SUBJECTS

Multiple precautions, described below, have been put in place to protect participants in the studies proposed 

for this application. Except where a specific group is listed (i.e. case group or control group), 

precautions apply to all participants being enrolled as part of the entire proposal. This protocol has 

been approved under CCHMC IRB #2014-1290.

1. Risk to Human Subjects: Involvement, Characteristics, and Design.

a. Human Subjects Involvement and Characteristics

Inclusion Criteria

Patients will be eligible for enrollment in the control group if they:

• Are 3 months to 11 years of age;

• Are being seen at a CCHMC-affiliated primary care clinic for a well visit

• Have not had a documented LRTI in the past 7 days

Patients will be eligible for enrollment in the case group if they:

• Are 3 months to 11 years of age AND

• Have signs and symptoms of lower respiratory tract infection as defined by at least one of the following:

new or different cough, new or different sputum production, chest pain, dyspnea/shortness of breath,

documented tachypnea, abnormal findings consistent with LRTI on examination (e.g. crackles, rhonchi,

wheezing, dullness), or acute respiratory failure requiring mechanical ventilation; AND

• Have a new focal infiltrate on chest radiograph

Exclusion Criteria

Patients will be ineligible for enrollment in either control or case group if any of the following is present or 

anticipated:

• Lack of parental consent and/or child assent for children 11 years of age.

• Hospitalized ≤14 days before the study ED visit

• Immunodeficiency or immunosuppression, including malignancy, chronic corticosteroid use

• Chronic pulmonary disease, including cystic fibrosis, tracheostomy-dependent patients

• Congenital cardiac disease

• Sickle-cell disease

• Neuromuscular disorders

• History of aspiration or aspiration pneumonia at any time in the potential subject’s medical history

b. Sources of Materials

The study will be conducted within the ED and when applicable on the Hospital Medicine service at CCHMC or 

at a CCHMC-affiliated primary care clinic. Trained clinical research coordinators (CRC) who staff the ED 16 

hours per day for 4 days per week and 8-12 hours per day for 3 days per week will initially identify patients with 

respiratory-related chief complaints, such as “cough,” “difficulty breathing,” “shortness of breath,” “respiratory 

distress,” “fever,” “pneumonia,” or “wheezing.” These subjects will then be screened using the protocol 

inclusion and exclusion criteria. Eligible subjects will be approached to obtain informed consent in the ED.

Trained CRC from Hospital Medicine (HM) will screen subjects using the protocol inclusion and exclusion 

criteria for the control group at the CCHMC-affiliated primary care clinic. HM CRCs will be available 8 hours per 

day for 5 days a week for recruitment. 

Emergency Department OR Primary Care Clinic Phase

After consent is obtained, research staff will collect demographic and historical information from the patient

and/or parent. Attending physicians will complete a case report form assessing clinical symptoms, motivations

for disposition decisions and patient severity. All data will be recorded in a secure database in the REDCap 

system. Research staff will also provide nursing staff with the specimen collection tubes to obtain the 

necessary blood, urine, and/or nasopharyngeal samples as detailed by the research protocol. For easily 

obtained samples, such as urine in an older child, the CRC will provide the specimen containers directly to 

the patient for collection. Specimen collection will occur as part of routine care as much as possible (e.g. 

blood samples will be collected at the time of IV placement). Any collection procedures not part of routine 

care will occur only with consent of the parents and/or patients. 

Contact PD/PI: Ambroggio, Lilliam

Protection of Human Subjects Page 122
Specimen processing and storage will be facilitated by the CBCF. Clinical data, such as vital signs, history 

and physical exam findings, test results, will be extracted from the electronic medical record into the REDCap 

database. All patients will have the following tests performed as part of either their clinical care or the 

research protocol if not obtained as part of their clinical care: c-reactive protein (CRP), procalcitonin, blood 

culture, and respiratory viral panel. Clinicians caring for enrolled patients will be blinded to all study laboratory 

results, with the exception of positive blood culture results. 

Hospital Phase for Case Samples Only

For those patients admitted to the hospital from the ED, daily clinical data will be extracted from the EPIC, the 

electronic medical record, into the REDCap database. A Hospital Medicine CRC will review the REDCap 

database regularly to check for any enrolled patients that were admitted. A HM CRC will collect blood and 

urine samples prior to the patient being discharged from the hospital.

Follow-Up Phase

All patients enrolled in the study will receive a follow-up phone call approximately 7-10 days after

their ED visit to assess clinical symptoms and disease course.

c. Potential Risks

There is minimal risk associated with this protocol. This study does not involve any medications or therapies.

The primary risks associated with this protocol are those related to sample collection including blood and other 

biological specimen collection procedures, which are typical procedures in a hospital setting. Potential 

discomforts associated with a blood draw are bruising and possible infections. There is potential discomfort 

associated with a nasopharyngeal swab. Every effort will be made to minimize these risks. Additionally, this 

research also carries a minimal risk of loss of data confidentiality/security. Section 2.b., below, describes the 

ways in which we will mitigate exposures to risks. These risks will be presented to the patient and parent prior 

to enrollment, and if the subject is interested in study participation, informed consent will be obtained. 

Alternatively, a potential subject can receive standard care if they choose to not enroll in the study.

2. Adequacy of Human Subjects Protection

a. Recruitment and Informed Consent

During the research study, potential participants will be screened for possible eligibility, approached in the

CCHMC ED or primary clinic and presented the opportunity to participate in the study. After determining 

eligibility and interest in the study, research study staff will review the consent document with the parent or 

legally authorized representative (LAR), and the patient. The consent document is prepared to account for 

participant consent, parental permission, participant assent, and HIPAA Authorization. In cases where the 

patient is not able to consent for himself/herself, the parent or LAR will provide parental permission for their 

child to participate in the research study. When the parent or LAR provides written permission, the child (if 

appropriate) will be asked to provide written assent. Written assent will be documented for participants 11 

years of age and older. The consent is written in a way that agreeable participants have the opportunity to 

deny the collection of specimens which the participant and/or parent does not allow to be collected as part of 

their participation in the research study. This study was approved by the CCHMC IRB on April 24, 2013 (IRB # 

2012-4959). 

b. Protection against Risk

Blood and Biological Specimen Collection

When possible, blood draws and other sample collections from patients will coincide with sample collection for 

clinical care. Potential risks associated with obtaining nasopharyngeal samples include a brief period of 

discomfort when the swab is inserted into the nose to collect the sample. Urine collection is non-invasive and is 

collected in a bag or cup depending on developmental stage of the child.

Data Confidentiality

Data will be entered into a secure electronic database. Risks associated with loss of electronic data 

confidentiality/security will be mitigated through the utilization of standard CCHMC research network security 

process to ensure that only authorized CCHMC personnel have access to the research data.

Contact PD/PI: Ambroggio, Lilliam

Protection of Human Subjects Page 123
Consistent with CCHMC information security policies, no individually identifiable information will be transmitted 

outside CCHMC’s secure research network environment. Additionally, no identifiers will be used in 

publications.

3. Potential Benefits of the Proposed Research to the Participants and Others

There are no potential direct benefits for the participants, as the data derived from this study will not be 

used for clinical decision making for each individual patient. Overall, the potential benefits will be 

improvement in clinical care provided to patients with CAP, in that identification of CAP severity and etiology 

may result in less antibiotic therapy, more appropriate antibiotic therapy when required and improved 

clinical prediction of prognosis.

4. Importance of Knowledge to be Gained

There is currently no accurate method to predict CAP severity or etiology in children using either clinical 

scores or biomarkers. This can result in overtreatment with antibiotics, unnecessary hospitalization, or 

delays in appropriate treatment in patients who are at risk for CAP-related morbidity. There is an urgent 

need for accurate and reliable tools to predict which children with CAP will develop severe disease or 

complications requiring hospitalization and which children will require aggressive antibiotic therapy. 

Completion of the aims outlined in this proposal will identify pathogens within broad classes of disease, viral 

and bacterial, which cause CAP. We expect this to result in a key positive impact by facilitating 

observational and interventional studies in children with CAP, with the ultimate goal of targeting antibiotic 

therapies for children diagnosed with bacterial CAP while reducing use of unnecessary antibiotics in 

children diagnosed with viral CAP.

5. Data Safety and Monitoring Plan

A Data Safety Monitoring Board will not monitor this study because this is a minimal risk and non-therapeutic 

protocol. There is no research study intervention. The principal investigator and study team will review any 

unanticipated problems related to data safety or adverse events, and the principal investigator or study 

personnel will report unexpected adverse events according to CCHMC IRB policy. Any serious adverse event 

will lead to a cessation of enrollment until the relationship between the adverse event and the study conduct is 

determined. All serious adverse events will be reported to the IRB within 48 hours and other adverse events 

will be reported on an annual basis at time of continuing review by the IRB.

Contact PD/PI: Ambroggio, Lilliam

Protection of Human Subjects Page 124
14. INCLUSION OF WOMEN AND MINORITIES

No study subject will be excluded based on gender on race/ethnicity. Based upon the known demographics in 

the Emergency Department at CCHMC and the Fairfield Primary Care Clinic, we expect the study population 

for both aims to be approximately 48% female, 48% white, 45% black or African American and 96% identifying 

as non-Hispanic ethnicity. 

Contact PD/PI: Ambroggio, Lilliam

Inclusion of Women and Minorities Page 125
PHS Inclusion Enrollment Report

This report format should NOT be used for collecting data from study participants.

OMB Number:0925-0001 and 0925-0002

Expiration Date: 10/31/2018

 

Tracking Number: GRANT12210815 Funding Opportunity Number: PA-16-190. Received Date: 2016-07-08T13:23:03.000-04:00

*Study Title: Metabolomic Evaluation of the Etiology of Pneumonia

*Delayed Onset Study? ❏ Yes ❏✔ No

If study is not delayed onset, the following selections are required:

Enrollment Type ❏✔ Planned ❏ Cumulative (Actual)

Using an Existing Dataset

or Resource

❏ Yes ❏✔ No

Enrollment Location ❏✔ Domestic ❏ Foreign

Clinical Trial ❏ Yes ❏✔ No

NIH-Defined Phase III

Clinical Trial

❏ Yes ❏✔ No

Comments: 250 patients with pneumonia and 125 patients without any known infections will be recruited for this study.

Racial Categories

Ethnic Categories

Not Hispanic or Latino

Female Male Unknown/

Not Reported

Hispanic or Latino

Female Male Unknown/

Not Reported

Unknown/Not

Reported Ethnicity

Female Male Unknown/

Not Reported

Total

American Indian/Alaska Native 0 0 0 0 0

Asian 1 1 0 0 2

Native Hawaiian or

Other Pacific Islander 0 0 0 0 0

Black or African American 79 83 0 0 162

White 83 90 1 1 175

More than One Race 12 14 5 5 36

Unknown or Not Reported

Total 175 188 6 6 375

Report 1 of 1

Contact PD/PI: Ambroggio, Lilliam

 Page 126
15. INCLUSION OF CHILDREN

Children are the focus of this research. We plan to include children, 3 months to 11 years of age, in all the 

studies outlined in this research proposal. All participants will require parental consent, as well as child 

assent for children 11 years old. All studies are considered minimal risk. 

Contact PD/PI: Ambroggio, Lilliam

Inclusion of Children Page 127
16. Vertebrate Animals

Vertebrate animals will not be used to conduct this study. 

Contact PD/PI: Ambroggio, Lilliam

Vertebrate Animals Page 128
17. Select Agent Research

There will be no hazardous biological agents or toxins that are used as part of this study. 

Contact PD/PI: Ambroggio, Lilliam

Select Agent Research Page 129