Clinical Implementation of Metagenomic Next-Generation Sequencing for Precision Diagnosis of Acute Infectious Diseases; Neuroinflammatory Cohort
Phase: NA
Conditions: Encephalitis, Meningitis
Sponsor: University of California, San Francisco

 
 
 
 
 
 
 
 
 
Study Protocol for the PDAID trial 
 
Neuroinflammatory Cohort 
 
 
 
 

 
 
TABLE OF CONTENTS 
 
1. Protocol Synopsis  
 
 
 
 
 
 
  
4 
 
2. Original Study Protocol (IRB Study Application Version 1.4)  
 
 
 
6 
 
3. Final Study Protocol (IRB Study Application Version 1.16)  
 
 
              49 
 
4. Summary of Changes to the Original Study Protocol   
 
 
 
            108 
 
5. Regulatory Committee Approvals   
 
 
 
 
            111 
 
6.  Statistical Analysis Plan   
 
 
 
 
 
            112 
6.1 Original Statistical Analysis Plan  
 
 
 
 
            112 
6.2 Final Statistical Analysis Plan  
 
 
 
 
            112 
6.3 Summary of Changes to the Statistical Analysis Plan  
 
 
            113 
 
7. Appendix  
 
 
 
 
 
 
 
            114 
7.1. Enrollment Flow Chart  
 
 
 
 
 
            114 
 
 
 
 
 
 
 
 
 
 
 

 
 
Clinical metagenomic next-generation sequencing for diagnosis of meningitis and 
encephalitis – the PDAID trial 
 
 
 
Short title – Precision Diagnosis of Acute Infectious Diseases – PDAID 
 
 
 
 
 
Protocol Number NCT02910037 
 
 
 
Version 1.2 (Initial IRB Approval for Study Protocol) 
 
 03/01/2016 
 
Version 1.4 (Original Study Protocol at start of enrollment) 
 06/10/2016 
 
Version 1.16 (Final Study Protocol at completion of study) 
 08/17/2017 

 
 
 
CONFIDENTIAL This document is conﬁdential and the property University of California, San 
Francisco.  No part of it may be transmitted, reproduced, published, or used without prior written 
authorization from the institution. 
 
 
STATEMENT OF COMPLIANCE 
This document is a protocol for a clinical research study. The study was conducted in 
compliance with all stipulations of this protocol, the conditions of ethics committee approval, 
the NHMRC National Statement on Ethical Conduct in Human Research (2007) and the Note 
for Guidance on Good Clinical Practice (CPMP/ICH-135/95). 
 
 
1. PROTOCOL SYNOPSIS 
 
 
Title                 Clinical metagenomic next-generation sequencing for diagnosis of       
meningitis and encephalitis – the PDAID trial 
 
Short Title       Precision Diagnosis of Acute Infectious Diseases – PDAID 
 
 
Objectives       To compare the performance of a clinically validated metagenomic  next-
generation sequencing (mNGS) assay with conventional microbiological 
testing in diagnosis of infectious causes of meningitis and encephalitis in 
acutely ill hospitalized patients 
 
Design             Single-group, multisite, prospective clinical diagnostic trial. 
 
Outcomes       Primary 
1. Clinical mNGS assay performance (sensitivity, speciﬁcity, positive predictive 
value, negative predictive value)  
2. Number and proportion of infectious diagnoses made using the mNGS assay 
 
Secondary 
1. Impact of mNGS results (positive and negative) on clinical reasoning  
2. Impact of mNGS results (positive) on clinical management and outcomes 
3. Potential clinical utility of communicating results from supplementary mNGS 
analyses to physicians 
4. Feasibility of a clinical microbial sequencing board (CMSB) for discussing and 
interpreting mNGS results in clinical context 
 
Interventions   1.  Running an mNGS assay for pathogen detection from cerebrospinal ﬂuid (CSF) 
in a CLIA (Clinical Laboratory Improvement Amendments)-certiﬁed laboratory. 
2. Reporting mNGS results in the patient electronic medical record 
3. Discussing mNGS results with primary care providers and associated consulting 
physicians during weekly CMSB meetings 
Study Protocol Page 4 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

 
 
 
 
Sample Size    300 
Population      Pediatric and adult patients with meningitis, encephalitis, and/or myelitis 
 
Eligibility  
 
Criteria 
 
 
Abbreviations: CSF, cerebrospinal fluid; WBC, white blood cell. 
*Fever and CSF pleocytosis were not required for patients with an immunosuppressed state if the treating physician was suspicious for 
a neurologic infection. 
 
 
Study 
Duration       1 year: 06/01/2016 – 07/31/2017 
 
 
 
Inclusion Criteria
     Age: Any
     Hospital admission or transfer with clinical syndrome of meningitis, encephalitis or myelitis
     Symptom onset (or exacerbation) within 2 weeks of CSF sampling
     Lack of an etiologic diagnosis at time of enrollment
  Meningitis
    Fever ≥ 38°C* 
    AND:
     Abnormal neuroimaging or CSF WBC count ≥ 5/cubic mm*
     With or Without:
     stiff neck, headache or seizure
  Encephalitis
     Major Criterion:
       Altered mental status lasting ≥ 24 h with no alternative cause identified
     Minor Criteria (at least 2 required):
       Fever ≥ 38°C*
       Seizures not fully attributable to a preexisting seizure disorder 
       New onset of focal neurologic findings
       CSF WBC count ≥ 5/cubic mm*
       Abnormal brain imaging suggestive of encephalitis
       Abnormal electroencephalography consistent with encephalitis
  Myelitis
     Abnormal spinal cord imaging suggestive of myelitis
     AND
     CSF WBC count ≥ 5/cubic mm*
Exclusion Criteria
     Psychiatric hold
     Hospital or university employees or students, or close associates of key study personnel
Study Protocol Page 5 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 1 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
    Study Application (Version 1.4)
1.0
General Information
*Enter the full title of your study:
Precision Diagnosis of Acute Infectious Diseases
 
 
*Enter the study number or study alias
DAID
* This field allows you to enter an abbreviated version of the Study Title to quickly identify this
study.
 
 
2.0
Add Department(s)
2.1 List departments and/or research programs associated with this study:
Primary
Dept?
Department Name
UCSF - 115001 - M_Biochemistry and Biophysics
UCSF - 135118 - M_CTSI-SOS
UCSF - 144075 - M_Laboratory Medicine
UCSF - 138300 - M_MEDICINE
UCSF - 140020 - M_Neurology
 
3.0
Assign key study personnel(KSP) access to the study
3.1 *Please add a Principal Investigator for the study:
 
Chiu, Charles Y MD
Select if applicable
Department Chair
Resident
Fellow
If the Principal Investigator is a Fellow, the name of the Faculty Advisor must be supplied below.
 
3.2 If applicable, please select the Research Staff personnel:
 
A) Additional Investigators
Study Protocol Page 6 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 2 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Berger, Amy 
 Other Investigator
Chow, Eric D PhD, PhD 
 Other Investigator
Chow, Felicia 
 Other Investigator
Derisi, Joseph L. PhD 
 Co-Principal Investigator
Gelfand, Jeffrey M 
 Other Investigator
Geschwind, Michael D MD, MD, PhD 
 Other Investigator
Langelier, Charles R 
 Other Investigator
Miller, Steven A 
 Co-Principal Investigator
Naccache, Samia N 
 Other Investigator
Samayoa, Erik L 
 Other Investigator
Wilson, Michael R, MD 
 Co-Principal Investigator
B) Research Support Staff
Federman, Scot M 
 Biostatistician
Naccache, Samia N 
 Data Manager
Pham, Elizabeth 
 Technician
Samayoa, Erik L 
 Technician
Sample, Hannah 
 Study Coordinator
Stryke, Doug 
 Biostatistician
Yu, Guixia 
 Technician
3.3 *Please add a Study Contact:
 
Chiu, Charles Y MD 
Derisi, Joseph L. PhD 
Mccaleb, Kristen L 
Miller, Steven A 
Sample, Hannah 
Wilson, Michael R, MD 
Study Protocol Page 7 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 3 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
The Study Contact(s) will receive all important system notifications along with the Principal
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the Principal
Investigator themselves).
3.4 If applicable, please add a Faculty Advisor/Mentor:
 
3.5 If applicable, please select the Designated Department Approval(s):
 
Hauser, Stephen L M.D., M.D, 
Department Chair
Lowell, Clifford A MD 
Department Chair
Add the name of the individual authorized to approve and sign off on this protocol from your
Department (e.g. the Department Chair or Dean).
4.0
Initial Screening Questions
Updated June 2017
4.1  * PROJECT SUMMARY: (REQUIRED)
Give a brief overview of this project (250 words or less). Tell us what this study is about, who is
being studied, and what it aims to achieve. If you have an NIH Abstract, paste it here:
 
Click on the orange question mark to the right for more detailed instructions.
Currently, up to 50% of hospitalized patients with pneumonia, sepsis, and encephalitis / meningitis are
treated without a laboratory-confirmed cause of their disease, resulting in delayed and ineffective
therapy, increased mortality, and excess healthcare costs.   Here we aim to use metagenomic next-
generation sequencing (mNGS) to provide the first-ever demonstration of precision medicine
for the diagnosis of acute infectious diseases in hospitalized patients, with immediate impact
on clinical care and patient outcomes.  We are currently clinically validating the mNGS assay in a
licensed clinical diagnostic laboratory (the UCSF Clinical Microbiology Laboratory).  Clinical validation of
cerebrospinal fluid (CSF) for diagnosis of encephalitis / meningitis, plasma for sepsis, and bronchoalveolar
lavage (BAL) fluid for pneumonia is estimated to be complete by Mar 2016, July 2016, and Dec 2016,
respectively.  In Mar 2016, we will launch a prospective clinical study enrolling patients from 3 UC
hospitals (UCSF, UCLA, and UC Davis) to evaluate the performance of the clinically validated mNGS assay
relative to routine microbiological testing.  Patients will be consented for (1) review of their medical chart
and eventual publication, (2) blood draw for orthogonal laboratory testing and/or research, and (3)
collection and mNGS analysis of excess material from related sample types that have not been clinically
validated (e.g. brain biopsy). We will specifically evaluate how the mNGS results obtained from the
clinically validated test affect patient management and clinical outcomes.  Ultimately, we aim to deliver a
clinically reimbursable, self-sustaining genomic test for infectious diseases that will improve patient
outcomes long past the 1-year study time frame.  
4.2  * HUD DEVICE: (REQUIRED)
Does this application involve a Humanitarian Use Device (HUD):
No 
Yes, and it includes a research component 
Study Protocol Page 8 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 4 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Yes, and it involves clinical care ONLY 
4.3  * TYPE OF RESEARCH: (Click the Help link for definitions and guidance): (REQUIRED)
Biomedical research 
Social, behavioral, educational, and/or public policy research 
Hybrid - includes aspects of BOTH types of research (check this option if your research is mainly
social/behavioral but also involves specimen collection or blood draws to look at biological measures) 
4.4  * SUBJECT CONTACT: (REQUIRED)
Does this study involve ANY contact or interactions with participants:
Yes (including phone, email or web contact) 
No (limited to medical records review, biological specimen analysis, and/or data analysis) 
4.5  * RADIATION EXPOSURE: Does your protocol involve any radiation exposure to
patients/subjects EITHER from standard care OR for research purposes (e.g., x-rays, CT-scans,
DEXA, CT-guided biopsy, radiation therapy, or nuclear medicine including PET, MUGA or bone scans):
(REQUIRED)
  Yes   
  No
4.6  * RISK LEVEL: (REQUIRED)
What is your estimation of the risk level, including all screening procedures and
study activities (Help Text updated 9/13):
Minimal risk 
Greater than minimal risk 
4.7  * REVIEW LEVEL: (REQUIRED)
Requested review level (Click on the orange question mark to the right for definitions and
guidance):
Full Committee 
Expedited 
Exempt 
4.8  * EXPEDITED REVIEW CATEGORIES: (REQUIRED)
If you think this study qualifies for expedited review, select the regulatory categories that the
research falls under: (check all that apply)
Category 1: A very limited number of studies of approved drugs and devices
Category 2: Blood sampling
Category 3: Noninvasive specimen collection (e.g. buccal swabs, urine, hair and nail clippings, etc.)
Category 4: Noninvasive clinical procedures (e.g. physical sensors such as pulse oximeters, MRI,
EKG, EEG, ultrasound, moderate exercise testing, etc.)
Category 5: Research involving materials (data, documents, records, or specimens) that were
previously collected for either nonresearch or research purposes
Study Protocol Page 9 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 5 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Category 6: Use of recordings (voice, video, digital or image)
Category 7: Low risk behavioral research or research employing survey, interview, oral history, focus
group, program evaluation, human factors evaluation, or quality assurance methodologies
4.11  * CLINICAL TRIAL: (REQUIRED)
Is this a clinical trial? According to The World Health Organization (WHO) and the International
Committee of Medical Journal Editors (ICMJE) a clinical trial is:
Any research study that prospectively assigns human participants or groups of humans to
one or more health-related interventions to evaluate the effects on health outcomes.
ICMJE requires registration of a clinical trial in a public database (such as ClinicalTrials.gov) prior
to enrollment, for eventual publication of results in member biomedical journals.
Guidance: Public Law 110-85 requires that all investigators who perform an applicable clinical
trial must ensure that the trial is registered on a government web site called ClinicalTrials.gov.
 
The FDA requires registration for “applicable clinical trials,” defined as follows:
For any trials of drugs and biologics: controlled clinical investigations, other than Phase 1
investigations, of a product subject to FDA regulation.
For trials of biomedical devices: controlled trials with health outcomes of devices subject to
FDA regulation, other than small feasibility studies, and pediatric post-market surveillance.
For additional information on the ClinicalTrials.gov registration process at UCSF and the definition
of a clinical trial for purposes of registration, visit the ClinicalTrials.gov section of the UCSF Clinical
Research Resource HUB.
  Yes   
  No
Clinical Trial Registration
"NCT" number for this trial:
4.13  * INVESTIGATOR-INITIATED: (REQUIRED)
Is this an investigator-initiated study:
 Yes   
 No
4.14  SCIENTIFIC REVIEW:
If this study has undergone scientific or scholarly review, please indicate which entity performed
the review (check all that apply):
Cancer Center Protocol Review Committee (PRC) (Full approval is required prior to final CHR approval
for cancer-related protocols.)
CTSI Clinical Research Services (CRS) Advisory Committee
CTSI Consultation Services
Departmental scientific review
Other:
* Specify Other: (REQUIRED)
California Initiative to Advance Precision Medicine
4.15  * STEM CELLS: (REQUIRED)
Does this study involve human stem cells (including iPS cells and adult stem cells), gametes or
Study Protocol Page 10 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 6 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
embryos:
No 
Yes, and requires CHR and GESCR review 
Yes, and requires GESCR review, but NOT CHR review 
4.16  * FINANCIAL INTERESTS: (REQUIRED)
Do you or any other responsible personnel (or the spouse, registered domestic partner and/or
dependent children thereof) have financial interests related to this study:
  Yes   
  No
5.0
Funding
5.1  * FEDERAL FUNDING: (REQUIRED)
Is this study currently supported in whole or in part by Federal funding, even by a subcontract, OR
has it received ANY Federal funding in the past:
  Yes   
  No
5.2  * DoD INVOLVEMENT: Is this project linked in any way to the Department of Defense (DoD):
(REQUIRED)
  Yes   
  No
5.3  SPONSORS:
Identify all sponsors and provide the funding details. If funding comes from a Subcontract, please
list only the Prime Sponsor:
External Sponsors:
 
 
View
Details
Sponsor Name
Sponsor Type
Awardee
Institution
Contract
Type:
UCSF RAS
"P
number"
or
eProposal
number 
UCSF
RAS
System
Award
Number
("A" +
6
digits) 
CALIF Governors Ofc of
Planning & Resrch 
02 
UCSF 
Grant 
P0509948  
Sponsor Name:
CALIF Governors Ofc of Planning & Resrch 
Sponsor Type:
02 
Sponsor Role:
Funding
Grant/Contract Number:
P0509948 
Awardee Institution:
UCSF 
Study Protocol Page 11 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 7 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Is Institution the Primary Grant
Holder:
Yes 
Contract Type:
Grant 
UCSF RAS "P number" or
eProposal number:
P0509948 
UCSF RAS System Award Number
("A" + 6 digits):
 
Grant Number for Studies Not
Funded thru UCSF:
 
Grant Title:
Clinical Implementation of Metagenomic Next-Generation
Sequencing for Precision Diagnosis of Acute Infectious Diseases 
PI Name:
(If PI is not the same as identified
on the study.)
Charles Y Chiu 
Significant Discrepancy:
 
If the funding is coming through UCSF and you don't know the
A or P number,  you can search the eProposal side for the
contract or grant (this does NOT replace adding the sponsor by
name above AND entering the A or P number):
Project Status
Proposal Number
Project Title
Principal Investigator
Submitted to Sponsor
P0509948
CIAPM Full Proposal
Charles Y Chiu MD
Clinical implementation of metagenomic next-
generation sequencing for precision diagnosis of
acute infectious diseases
Submitted to Sponsor
P0522592
ChiuC New NSF
BIGDATA 22Mar201 ...
Charles Y Chiu MD
BIGDATA: IA: Collaborative Research: Patient
Data-Driven Machine 
Learning for Diagnosis of Infectious Diseases
Submitted to Sponsor
P0526430
Dr. Gu_new K08_due
10/12/2017_ ...
Wei Gu, MD/PhD
Noninvasive Risk Stratification of Prostate Cancer
Using Cell-Free Nucleic Acids
Other Funding Sources and Unfunded Research - Gift,
Program, or Internal Funding (check all that apply):
Funded by gift (specify source below)
Funded by UCSF or UC-wide program (specify source below)
Specific departmental funding (specify source below)
Unfunded (miscellaneous departmental funding)
Unfunded student project
* List the gift, program, or departmental funding source: (REQUIRED)
Study Protocol Page 12 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 8 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Sandler-Bowes Foundation Award, UCSF Clinical Laboratory
6.0
Sites, Programs, Resources, and External IRB Review
6.1  UCSF AND AFFILIATED SITES (check all that apply):
UCSF (including Laurel Heights and all the other sites outside the main hospitals)
Parnassus
Mission Bay
China Basin
Mount Zion
Helen Diller Family Comprehensive Cancer Center
Langley Porter Psychiatric Institute
San Francisco General Hospital (SFGH)
SF VA Medical Center (SF VAMC)
Blood Centers of the Pacific (BCP)
Blood Systems Research Institute (BSRI)
Fresno Community Medical Center
Gallo
Gladstone
Jewish Home
Institute on Aging (IOA)
SF Dept of Public Health (DPH)
Research involving SFGH: You are required to obtain additional approvals
from the SFGH Dean's Office. Download the SFGH Protocol Application
Form and submit the completed form to the SFGH Dean's Office.
6.2  LOCATIONS: At what locations will study visits and activities occur:
UCSF/Clinical Microbiology Laboratory
185 Berry Street, Suite #290
San Francisco, CA  94107
UCSF/Chiu Lab
185 Berry Street, China Basin 185
San Francisco, CA 94107
UCSF/DeRisi Lab
1700 4th Street
QB3 Room BH 401
San Francisco, CA 94158
UCSF/Pleasure Lab
Department of Neurology
675 Nelson Rising Lane, Room 260-270
San Francisco, CA 94158
UCSF/Oksenberg Lab
Department of Neurology
675 Nelson Rising Lane, Room 240-242
San Francisco, CA 94158
Study Protocol Page 13 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 9 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
UCSF/ Center for Advanced Technology
Genentech Hall, Second floor, room S252
600 16th St.
San Francisco, CA 94158
UCLA Medical Center
UCD Medical Center
6.3  OFF-SITE PROCEDURES: Will any study procedures or tests be conducted off-site by non-UCSF
personnel:
 Yes   
 No
Please identify which procedures may be done off-site:
UC Davis and UCLA Medical Centers will serve as a major patient recruitment sites for the DAID study
outside of UCSF. They will be identifying eligible patients and once consented, collecting patient clinical
data and biospecimens relevant to the study. All biospecimens will be shipped to UCSF and relevant
clinical data will be uploaded into a RedCap project maintained by the UCSF coordinating team and
relying sites for their respective research candidates.
6.4  RESEARCH PROGRAMS:
Check any UCSF research programs this study is associated with:
Cancer Center
Center for AIDS Prevention Sciences (CAPS)
Global Health Sciences
Immune Tolerance Network (ITN)
Neurosciences Clinical Research Unit (NCRU)
Osher Center
Positive Health Program
6.5  * CTSI CRS SERVICES: (REQUIRED)
Will this study be carried out at one of the UCSF Clinical Research Services (CRS) units or utilize CRS
services:
  Yes   
  No
6.6  * MULTI-CENTER TRIAL: (REQUIRED)
Is this a multicenter research trial? By multi-center trial, we mean a study where the protocol is
developed by an industry sponsor, consortium, a disease-group, etc., who then selects sites across
the nation or in different countries to participate in the trial. The local sites do not have any control
over the design of the protocol. 
 Yes   
 No
Is UCSF the coordinating center:
 Yes   
 No
6.7  OTHER SITE TYPES: Check all the other types of sites not affiliated with UCSF with which you are
Study Protocol Page 14 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 10 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
cooperating or collaborating on this project:
 
Do NOT check any boxes below if this is a multi-center clinical trial, UCSF is
just one of the sites, and neither UCSF nor its affiliates are the coordinating
center.
Other UC Campus
Other institution
Other community-based site
Foreign Country
Sovereign Native American nation (e.g. Navajo Nation, Oglala Sioux Tribe, Havasupai, etc.)
6.8  OTHER UC COLLABORATORS: Check any other UC campuses with which you are collaborating on this
research study:
UC Berkeley
UC Davis
Lawrence Berkeley National Laboratory (LBNL)
UC Irvine
UC Los Angeles
UC Merced
UC Riverside
UC San Diego
UC Santa Barbara
UC Santa Cruz
6.10  * RELYING ON AN EXTERNAL IRB: Does this application include a request to rely on an a
central IRB (other than the NCI CIRB) or an external IRB (UC, commercial, or institutional):
(REQUIRED)
  Yes   
  No
6.11  UC RELIANCES: Are any of the above UC campuses requesting to rely on UCSF's IRB:
Yes
No
7.0
Outside Site Information
7.1  Outside Site Information
Click "Add a new row" to enter information for a site. Click it again to add a second site again to add a
Study Protocol Page 15 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 11 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
third site, a fourth site, etc.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
University of California, Los Angeles
Contact name:
Dr. Jeffrey Klausner
Email:
JDKlausner@mednet.ucla.edu
Phone:
415 876 8901
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
 Yes   
 No
Study Protocol Page 16 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 12 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
If not, do NOT submit your application until after the other site has completed
this step.
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
UC Reliance Registry Application #1595
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Note: your application cannot be processed without the training
certificates.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
University of California, Davis
Contact name:
Dr. Christopher Polage
Email:
crpolage@ucdavis.edu
Phone:
(916) 734-3655
For Federally-funded studies only, corresponding FWA#:
Study Protocol Page 17 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 13 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
 Yes   
 No
If not, do NOT submit your application until after the other site has completed
this step.
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
UC Reliance Registry #1595
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Note: your application cannot be processed without the training
certificates.
Click here to view this form.
 
Study Protocol Page 18 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 14 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Syapse
Contact name:
Adam Jonas
Email:
adamj@syapse.com
Phone:
608.320.1042
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
 Yes   
 No
If not, do NOT submit your application until after the other site has completed
this step.
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
Study Protocol Page 19 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 15 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Andi Barsan
Andrew Fisher
Maylee Wu
Preeti Bhat
Taylor Horwood
Tom Lemberg
Adam Jonas
Sonny Van
Stephen Mitchell
Syapse team is responsible for 1) facilitating the reporting of
metagenomic NGS data, 2) correlating clinical data extracted from the
Electronic Medical Record, alongside mNGS data from research samples
in a easily searchable database. In addition, Syapse provides the
software platform to enable the Precision Medicine Consult service; where
subject matter experts can offer clinical guidance to providers, in the
context of mNGS and other clinical information.
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Note: your application cannot be processed without the training
certificates.
8.0
Research Plan and Procedures
8.1  This new consolidated section requests information about:
Hypothesis
Aims
Study Design
Background and Significance
Preliminary Studies
Procedures
Statistical Methods
References
Later sections include:
Drugs and Devices
Sample Size, Eligibility, and Subjects
Recruitment and Consent
Risks and Benefits
Study Protocol Page 20 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 16 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Data and Safety Monitoring Plan
Confidentiality, Privacy and Security
Financial Considerations
Qualifications of Personnel
Other Approval and Registrations
8.2  HYPOTHESIS: Describe the hypothesis or what the study hopes to prove (Help Text updated 9/13):
We hypothesize that many clinical illnesses in the hospital (meningitis, encephalitis, sepsis, and
pneumonia) are caused by infectious agents but remain undiagnosed because current laboratory testing
lacks sensitivity and scope.  Clinical implementation of an mNGS assay in a licensed diagnostic laboratory
(the UCSF Clinical Microbiology Laboratory) will result in more rapid and accurate diagnoses, decreased
costs, and improved clinical outcomes.
8.3  AIMS: List the specific aims:
This study is a prospective, multi-institutional study with the following specific aims:
1. Compare the diagnostic yield of a newly clinically validated metagenomic next-generation
sequencing (mNGS) assay to standard microbiologic testing in 300 consented and enrolled
patients presenting with (1) acute meningitis and/or encephalitis, (2) sepsis, or (3) pneumonia at
3 hospitals in California
2. To collect clinical specimens for mNGS testing in a licensed diagnostic laboratory and excess
specimens or blood for orthogonal laboratory testing and/or research from patients with the
aforementioned illnesses.
3. To interpret clinical mNGS results in the context of a precision medicine board and clinical
interface
4. To evaluate impact of the mNGS assay on costs and clinical outcomes
8.4  DESIGN: Briefly describe the study design (e.g., observational, interventional, randomized, placebo-
controlled, blinded, cross-over, cross-sectional, longitudinal, pharmacokinetic, etc.):
 
This is a 1-year prospective cohort study which will enroll 300 patients at UCSF, UCLA, and UC Davis with
encephalitis, meningitis, sepsis, or pneumonia.  Patients will be enrolled if the clinical mNGS assay
correpsonding to the appropriate sample type -- cerebrospinal fluid (CSF) for encephalitis / meningitis
(anticipated launch date 3/2016), plasma for sepsis (7/2016), and bronchoalveolar lavage (BAL) fluid for
pneumonia (12/2016 --- has been validated in the CLIA laboratory (the UCSF Clinical Microbiology
Laboratory). Accordingly, we anticipate that the majority of patients enrolled in the study will be
encephalitis and meningitis patients.  Patients will be consented for (1) clinical mNGS testing and review
of their electronic medical record (clinical, laboratory, and radiological data) and publication of their case
histories and (2) collection of blood and additional clinical samples that have not been validated for
clincial mNGS testing (e.g. brain biopsy) for the purpose of orthogonal clinical testing to confirm mNGS
results and biobanking to facilitate research on additional novel assay development (e.g. autoantibody
and host gene transcriptome profiling).  If additional clinical samples are to be used only for research
purposes and not for orthogonal clinical testing, then only available excess / surplus sample will be
collected.  As the research on transcriptome profiling will involve deposition of deidentified genetic data
into public databases, patients will be explicitly consented for release of their deidentified genetic
information.
After clinical mNGS testing is performed and results communicated to the patient and clinical provider, a
"precision medicine board" consisting of clinicians, laboratory directors, and research investigators will be
available to interpret mNGS results and recommend further diagnostic testing, management, and
treatment.  This board for infectious diseases is analogous to the tumor board in oncology. We will also
extract data from the electronic medical record and evaluate the impact of the mNGS assay on costs and
clinical outcomes as compared to a subset of historical controls obtained by retrospective chart review of
similar cases in the past for which the mNGS assay was not available.  
Study Protocol Page 21 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 17 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
8.5  BACKGROUND AND SIGNIFICANCE: Briefly provide the background and significance of this study
(e.g. why is this study needed) (space limit: one half page):
If this is a first in humans study, please summarize the safety data from the
animal studies. For pediatric drug or device studies, please identify if this is the
first study in pediatric populations.  
We aim to provide the first-ever demonstration of precision medicine for diagnosis of acute infectious
diseases in hospitalized patients, with the goal of directly impacting clinical care and improving patient
outcomes.  Existing methods fail to diagnose many life-threatening infections in a clinically relevant
timeframe, resulting in excessive health care costs and unnecessary morbidity and mortality.
Failure to obtain a laboratory-confirmed diagnosis for many acute infectious diseases directly contributes
to poor patient outcomes and a high cost burden to the health care system. Key areas of unmet clinical
need targeted by this proposal include neurological infections (encephalitis and meningitis), pneumonia,
and sepsis. The principal advantage of this approach is the ability to detect all viruses, bacteria, fungi,
and parasites in a single, standardized universal test, the clinically validated mNGS assay, directly from
diverse sample types such as cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL), and plasma. This
approach is comprehensive because all pathogens with the exception of prions are based on nucleic acid
(DNA/RNA).  Thus, a single shotgun sequencing test is able to simultaneously screen nearly all pathogens
directly from clinical samples, bypassing the "one bug, one test" traditional paradigm of infectious disease
diagnosis and maximizing the potential impact on patients with acute, life-threatening infections, where
time is of the essence.
Currently, up to 50% of hospitalized patients with pneumonia, sepsis, and encephalitis / meningitis are
treated empirically without a confirmed etiologic diagnosis, resulting in delayed or ineffective treatments,
increased mortality, and excess healthcare costs. For encephalitis, the annual disease burden in the U.S.
exceeds 20,000 hospitalizations with a high rate of long-term sequelae and mortality and $2.0 billion cost
to the healthcare system. Pneumonia and sepsis are associated with >43,000 avoidable deaths, 2.3
million excess patient days, and $8.1 billion in added costs each year. Metagenomic NGS, by providing a
more timely diagnosis in infected patients and the ability to "rule-out" infectious etiologies in patients
with non-infectious illness, has the potential to significantly reduce healthcare costs by decreasing
hospital lengths of stay and eliminating unnecessary treatments, procedures, and testing. Our NGS assay
also aligns perfectly with the Centers for Disease Control and Prevention (CDC) and President's Obama's
National Action Plan to Combat Antibiotic-Resistant Bacteria by enabling an early, specific diagnosis that
may obviate the need for empiric antibiotics and inform targeted, appropriate treatment, with the
potential to ultimately decrease antibiotic resistance in hospitals.
8.6  PRELIMINARY STUDIES: Briefly summarize any preliminary studies relevant to your proposed
research (space limit: one half page):
At UCSF, we have pioneered the use of unbiased metagenomic next-generation sequencing (mNGS) for
detection of all potential pathogens in a single assay, and have demonstrated its utility in saving the life
of a critically ill 14-year old boy with previously unrecognized neuroleptospirosis in a case report
published in the New England Journal of Medicine. We have further demonstrated the value of our mNGS
assay by identifying clinically significant pathogens in over 1,000 patients with severe, undiagnosed
pulmonary, blood and neurological infections.  We have also previously developed an automated sample-
to-answer pathogen identification pipeline named SURPI ("Sequence-based Ultra-Rapid Pathogen
Identification") to accelerate the speed of the bioinformatics analysis and ensure that NGS results will be
available in a fast enough time frame to impact patient care.
8.7  * TREATMENT PROTOCOL: Is this a treatment study, i.e. does this study intend to provide treatment
to individuals with a medical or psychological condition: (REQUIRED)
  Yes   
  No
8.8  * COMMON RESEARCH ACTIVITIES: Types of research activities that will be carried out. Check all
that apply and describe in more detail in the 'Procedures / Methods' section: (REQUIRED)
Study Protocol Page 22 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 18 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Interviews, questionnaires, surveys
Educational or cognitive tests
Focus groups
Observation
Non-invasive imaging or testing (MRI, EEG, pulse oximetry, etc.)
Administration of contrast agent
Imaging procedures or treatment procedures that involve radiation (x-rays, CT scans, CT-guided
biopsies, DEXA scans, MUGA or PET scan)
Biopsy conducted solely for research purposes
Use of placebo
Sham surgical procedure
Collection of data from wearable tech such as Fitbit, Apple Watch, Garmin, motion actigraphs, etc.)
Fitness tests or other exertion activities
Use of mobile health apps or other apps
Social media-based research activities
None of the above
8.9  * PROCEDURES / METHODS: (REQUIRED)
For clinical research, list all study procedures, tests and treatments
required for this study, including when and how often they will be
performed. If there are no clinical procedures, describe the research
activities.
 
If some of the activities would occur even if the person were not in the
study, as in the case of treatment or tests performed for diagnostic
purposes, clearly differentiate between those activities that will be
done solely for research purposes and those that are happening as part
of routine care.
 
Examples may include:
additional scans outside standard clinical diagnosis or monitoring
additional biopsies to collect tissue for research
extra clinic visits
extra lab tests not required for clinical care
If you have a procedure table, attach it to the submission with your other
study documents.
The investigators will seek to identify and enroll patients with a clinical syndrome that may have an acute
infectious etiology. Consent will follow procedures outlined under application section for recruitment and
consent.
The study investigators or site coordinator will review the medical record and abstract clinical, laboratory,
and radiographic data.
A RedCap survey will be used to collect basic demographic information, exposure/travel history, and
clinical information such as imaging results, labs, treatment history and clinical phenotype. The patient
may be asked directly by the study investigator or site coordinator to provide exposure/travel history,
Study Protocol Page 23 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 19 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
however, most data will be obtained by reviewing the medical record.
All patients will have had the validated mNGS assay ordered clinically by a provider and the appropriate
sample (CSF, plasma, or BAL fluid) collected for clinical testing at UCSF. Specimens will be shipped and
processed at UCSF.
An additional sample (e.g. biopsy sample) that has not been clinically validated for mNGS testing may
also be collected for orthogonal diagnostic testing to confirm mNGS results and/or for research purposes.
If this additional sample is to be used only for research purposes, only available excess / surplus sample
will be collected. Specimens will be shipped to UCSF.
A tissue bank will be established at UCSF for future research.
Research candidates will be asked to consent for collection of a venous blood sample of up to 30 ml or 1-
3 tubes. Blood collected will be processed to isolate peripheral blood mononuclear cells (PBMCs) and
serum for (1) orthogonal clinical validation of the mNGS assay, and/or (2) research analysis.
Blood draws will only be performed on patients who consent and who are 13 years and older. Blood
collections may be done on patients who are younger than 13, but only by adding 1-2 tubes to an already
scheduled blood draw, thus avoiding venipuncture solely for the research collection.
Subjects will also be consented to be re-contacted to provide short and longer-term follow-up to confirm
final diagnosis and outcome.
8.11  INSTRUMENTS: List all questionnaires, surveys, interview, or focus group guides that will be used
for this study:
Given that many patients will be severely ill, we will utilize the standardized form, Capacity Assessment
Record for Research Informed Consent, to insure that subject capacity is assessed in a systematic
manner.
Patients will be requested to participate in a short questionnaire. This questionnaire will be administered
verbally at the time of consent and completed by either the patient or surrogate. This is a RedCap
questionnaire entitled 'Clinical Case History'. The patient will only be requested to provide information for
the following sections: patient information, exposures 1 month before onset, and travel 1 year before
onset. The patient or surrogate will not see the remaining sections of the survey. The treating physician
will be requested to complete the remainder of the survey. The information to be completed by the
treating physician will have already been gathered as part of the patient's routine work-up.
Attach any unpublished instruments in the 'Other Study Documents'
section of the Initial Review Submission Packet form after completing the
study application. Published instruments should NOT be attached.
8.12  * BIOSPECIMEN COLLECTION: Are you drawing any blood or collecting other biosamples (e.g.
tissue, buccal swabs, urine, saliva, hair, etc.): (REQUIRED)
 Yes   
 No
* Could this study generate genetic data that may be broadly shared (e.g., submitted to
NIH in compliance with Genomic Data Sharing (GDS)/Genome-Wide Association
Studies (GWAS) requirements): (REQUIRED)
 Yes   
 No
Please make sure your consent form includes the recommended genomic
data sharing language. 
8.13  * TYPE OF SPECIMENS (check all that apply): (REQUIRED)
Blood
Tissue (describe below):
Study Protocol Page 24 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 20 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Existing/archival materials (name source below): ​
Other (describe below):
Describe and/or name source:
clinical mNGS testing at the UCSF Clinical Microbiology Laboratory: cerebrospinal fluid, plasma,
bronchoalveolar lavage fluid
blood draw: blood for PBMCs and serum/plasma
additional specimen types for orthogonal clinical validation or research (surplus): biopsy tissue, nasal
swabs, cyst / abscess fluid
8.14  * SPECIMENS ARE: (check all that apply): (REQUIRED)
Leftover specimens from a clinical diagnostic or therapeutic procedure
Specimens collected for research purposes only (including extra samples taken during a clinical
procedure)
Other
8.15  * DESTINATION: Specimens will ultimately be stored (check all that apply): (REQUIRED)
Outside Entity:
Cooperative group bank
NIH
Other university
Industry sponsor
Other
UCSF:
UCSF repository/bank being established under this protocol
Existing UCSF specimen repository/bank with CHR approval
Other location at UCSF (please describe)
Provide the name of the bank and iRIS approval number (if not being banked at
UCSF under this protocol). If you checked 'Other,' please provide the location or
lab:
Chiu Laboratory Biobank:
H9187-32565-02 Chiu, Charles Y MD 
Pathogen Detection and Discovery in Hospitalized Patients with Unexplained Acute or Chronic Illness
Clinical Microbiology Laboratory Biobank:
H52699-34941-01 Miller, Steven A 
Improved diagnosis of infectious meningitis / encephalitis using multiplex molecular methods
H52699-35006-01 Miller, Steven A 
Identification and characterization of infectious causes for respiratory infection
Study Protocol Page 25 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 21 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
8.16  UCSF-BANK PHYSICAL LOCATION: The repository/bank is physically located at (list the address and
room number for all locations):
1. UCSF Clinical Microbiology Laboratory (Directors: Steve Miller and Charles Chiu), 185 Berry Street,
Suite 290, San Francisco, CA 94107
1. Chiu Lab, 185 Berry Street, Room 185, San Francisco, CA 94107
2.DeRisi Lab, 1700 4th Street, QB3 Room BH 401, San Francisco, CA 94158
3. Pleasure Lab, 675 Nelson Rising Ln. Room 260, San Francisco, CA 94158
8.18  * FUTURE SPECIMEN USE: Will any specimens or portions of specimens be retained after the study
is over for possible use in future research studies: (REQUIRED)
 Yes   
 No
8.19  * SPECIMEN BANKING - CONSENT METHOD: Consent for retaining specimens for future research
studies will be obtained via (check all that apply): (REQUIRED)
Specimen section within a main research study consent form
Separate specimen consent form
UCSF surgical consent form with tissue donation brochure
8.20  * CLINICAL FOLLOW-UP DATA: Will clinical follow-up data be linked to specimens (i.e., will medical
record information continue to be abstracted after the specimen is collected): (REQUIRED)
 Yes   
 No
Provide duration of follow-up or 'indefinitely':
indefinitely
8.21  * UCSF-BANKED SPECIMENS - LINKING OF IDENTIFIERS: (REQUIRED)
Samples are completely de-identified before being added to the bank/repository. There is no way to
link the specimens back to the subjects.
Samples are coded and researchers are able to link the specimens to specific subjects.
Samples are stored with direct identifiers in the repository.
Explain under what circumstances identifiers may be released with specimens or
say none if identifiers will NEVER be released with specimens:
none. Only researchers directly involved in this study will have access to identifiers.
8.22  UCSF-BANKED SPECIMENS – IDENTIFIERS: List the identifiers that will be collected, stored, or
linked with the specimens:
Name
Date of birth
Social Security number
Medical record number
Study Protocol Page 26 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 22 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Address
Phone number
Email address
Other dates (dates of surgery, visit dates)
8.23  DISTRIBUTION: Specimens banked at UCSF may be made available to (check all that apply):
UCSF researchers
Non-UCSF researchers
Industry
None of the above - specimens will be retained and used within our own research program
8.24  UTILIZATION REVIEW: Is there a formal utilization review process for distribution of specimens:
  Yes   
  No
8.25  STATISTICAL METHODS: Briefly summarize the methods and types of analyses that will be
performed:
The UCSF Clinical Microbiology Laboratory will process the clinical sample under validated standardized
operating procedures.  Bioinformatics analysis will be performed using the SURPI pipeline (Naccache, et
al., 2014).  We will also occasionally need to perform orthogonal clinical testing (serological, PCR testing)
or research polymerase chain reaction (PCR) testing for confirmation of results. All data will be
deidentified prior to submission and submitted to dbGaP (database of Genotypes and Phenotypes), an
NIH database which archives deidentified data beyond a controlled-access firewall and makes such data
only accessible to a limited number of investigators (see http://www.ncbi.nlm.nih.gov/sites/entrez?
db=gap).
For the additional excess clinical samples used for research for the purposes of new assay development,
we will perform additional analyses including autoantibody profiling, human transcriptome profiling, and
probe-based sequencing enrichment.
8.26  REFERENCES: List only the 5-10 most relevant references (a separate bibliography can be attached
for reference purposes if this study involves novel approaches, agents, or an emerging technology
that the IRB may not be familiar with):
Goldberg B, Sichtig H, Geyer C, Ledeboer N, and Weinstock GM. (2015) Making the leap from
research laboratory to clinic: challenges and opportunities for next-generation sequencing in
infectious disease diagnostics. mBio 6(6):e01888-15.
Naccache SN, Federman S, Veeraraghavan N, Zaharia M, Lee D, Samayoa E, Bouquet J, Greninger
AL, Luk, KC, Enge B, Wadford DA, Messenger SL, Genrich GL, Pellegrino K, Grard G, Leroy E,
Schneider BS, Fair JN, Martinez MA, Isa P, Crump JA, DeRisi JL, Sittler T, Hackett, Jr. J, Miller S,
and Chiu CY. (2014) A cloud-compatible bioinformatics pipeline for ultra-rapid pathogen
identification from next-generation sequencing of clinical samples. Genome Research 24(7):1180-
9. (PMCID: PMC4079973).
Wilson MR, Naccache SN, Samayoa E, Biagtan M, Bashir H, Yu G, Salamat SM, Somasekar S,
Federman S, Miller S, Sokolic R, Garabedian E, CAndotti F, Buckley RH, Reed KD, Meyer TL,
Seroogy CM, Galloway R, Henderson SL, Gern JE, DeRisi JL, and Chiu CY. (2014) Actionable
diagnosis of neuroleptospirosis by next-generation sequencing. New England Journal of Medicine
370:2408-2017. (PMCID: PMC4134948).
Greninger AL, Naccache SN, Messacar K, Clayton A, Yu G, Somasekar S., Federman S, Stryke D,
Anderson C, Yagi S, Messenger S, Wadford D, Xia D, Watt JP, Van Haren K, Dominguez SR, Glaser
C, Aldrovandi G, and Chiu CY. (2015) A novel outbreak enterovirus D68 strain associated with
acute flaccid myelitis cases in the United States from 2012-2014: a retrospective cohort study.
Lancet Infectious Diseases S1473-3099(15)70093-93. E-pub ahead of print.
Study Protocol Page 27 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 23 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Naccache SN, Peggs KS, Mattes FM, Phadke R, Garson JA, Grant P, Samayoa E, Federman S, Miller
S, Lunn MP, Gant V, and Chiu CY. (2015) Diagnosis of neuroinvasive astrovirus infection in an
immunocompromised adult with encephalitis by unbiased next-generation sequencing. Clinical
Infectious Diseases 60(6):919-23. (PMCID: PMC4345816).
9.0
Drugs and Devices
9.1  * DRUGS AND/OR BIOLOGICS: Are you STUDYING any drugs and/or biologics that are either
approved or unapproved: (REQUIRED)
  Yes   
  No
Note: This question is frequently answered incorrectly. If any drugs or
biologics, approved or unapproved, are being administered under this
protocol, you should check 'Yes' unless you are absolutely sure that
NONE of the drugs are part of the research protocol. Tip: Ask the PI or
the sponsor if you are not sure how to answer this question.
9.3  * MEDICAL DEVICES: Are you STUDYING any medical devices, in vitro diagnostics, or assays that are
either approved or unapproved:(REQUIRED)
 Yes   
 No
9.4  * NSR: Are you requesting a Non-Significant Risk (NSR) determination for an investigational
device: (REQUIRED)
 
Note: an NSR determination is different from an Investigational Device Exemption (IDE). Check the
Help link for more guidance on what types of devices can qualify for an NSR determination.
  Yes   
  No
9.5  LIST THE DEVICES: List the medical devices or in vitro diagnostics to be studied or used. In the
device details screen you will be asked questions such as:
Whether the device is FDA approved or investigational
Medicare device category
If the device will be provided at no cost
If an IDE is necessary, the IDE number, and who holds the IDE
Risk category of the device
FDA status of the device
Please see the UCSF IRB website for more details about the use of devices in research, including the
Investigator Checklist for Significant Risk, Non-Significant Risk, and/or IDE Exempt Device Studies
 
Verification of IDE numbers: If the sponsor’s protocol does not list the IDE number, you must submit
documentation from the sponsor or FDA identifying the IDE number for this study. Attach this
documentation in the Other Study Documents section of the Initial Review Submission Packet.
 
If you have any correspondence from the FDA or sponsor regarding this device,
please attach it to the application.
 
Study Protocol Page 28 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 24 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
View
Details
Device Name
Is the Device FDA
Approved
Is this a new
device or a new
use of an already
approved device
IDE Number
mNGS IVD for diagnosis of
infectious diseases 
No 
Yes 
 
Manufacturer/Supplier of Device
University of California, San Francisco 
Medicare Category
A
B
Where will the Devices Be Stored
 
Will Devices be supplied at no
Cost
Yes 
Is this a HUD (HDE)
No 
HDE Number
 
Is the Device FDA Approved
No 
Is this a new device or a new use
of an already approved device
Yes  
Is an IDE necessary
No  
IDE Number
 
Who holds the IDE
N/A  
IDE Details
The in vitro diagnostic under study (mNGS for diagnosis of
infectious disease) will be performed as a laboratory-developed
test in the UCSF clinical laboratory. As a laboratory-developed
test, FDA approval or IDE registration are not required. The
primary purpose of the test is to diagnose patients enrolled in
the study.  
In the opinion of the sponsor,
select the level of risk associated
with this device
Significant Risk  
9.6  * Is this an expanded access or compassionate use protocol, meaning the primary purpose is to
diagnose, monitor or treat a patient's condition, rather than the collection of safety and efficacy data
of the experimental agent: (REQUIRED)
 Yes   
 No
10.0
Sample Size and Eligibility Criteria
10.1  ENROLLMENT TARGET: How many people will you enroll:
 If there are multiple participant groups, indicate how many people will be in each
group:
10.2  TOTAL PARTICIPANTS: For multicenter studies, how many people will be enrolled in total:
 
Study Protocol Page 29 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 25 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
300
10.3  SAMPLE SIZE JUSTIFICATION: Explain how and why the number of people was chosen. For multi-
site studies, this is referring to the number that will be enrolled across all sites:
10.4  * PARTICIPANT AGE RANGE: Eligible age ranges: (REQUIRED)
0-6 years
7-12 years
13-17 years
18-64 years
65+
10.5  * STUDY POPULATIONS: Data will be collected from or about the following types of people (check
all that apply): (REQUIRED)
Inpatients
Outpatients
Family members or caregivers
Providers
People who have a condition but who are not being seen as patients
Healthy volunteers
Students
Staff of UCSF or affiliated institutions
None of the above
10.6  * SPECIAL SUBJECT GROUPS: Check the populations that may be enrolled: (REQUIRED)
Children / Minors
Subjects unable to consent for themselves
Subjects unable to consent for themselves (emergency setting)
Subjects with diminished capacity to consent
Subjects unable to read, speak or understand English
Pregnant women
Fetuses
Neonates
Prisoners
Economically or educationally disadvantaged persons
None of the above
10.7  INCLUSION CRITERIA:  Briefly describe the population(s) that will be involved in this study.
Include anyone that data will be collected from or about (e.g. patients, healthy controls,
caregivers, providers, administrators, students, parents, family members, etc.):
Study Protocol Page 30 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 26 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
10.8  EXCLUSION CRITERIA: List any exclusion criteria (e.g. reasons why someone would not be included
in the study):
10.9  * RESEARCH CONDUCTED ON PATIENT CARE WARDS: Do any study activities take place on patient
care units at UCSF medical facilities: (REQUIRED)
  Yes   
  No
11.0
Recruitment and Consent
11.1  * RECRUITMENT METHODS: What kinds of methods will be used to identify potential participants
for recruitment (check all that apply): (REQUIRED)
Medical records review
Recruitment registry
Re-contact of participants from the investigators' previous studies
Referrals from colleagues (attach the 'Dear Colleague' letter or other recruitment materials you will
provide to colleagues)
Referrals from the community / word of mouth
Advertisements (flyers, brochures, radio or t.v. ads, posting on clinical research sites or social media,
presentation of the study at community events/media, etc.)
Online recruiting tool such as TrialSpark
CTSI Recruitment Services unit
Other method (describe below)
11.2  * SEARCHING OF MEDICAL RECORDS: (REQUIRED)
Whose patients are they:
Investigators' own patients or patients seen within the same practice
Patients not under the care of the investigators
How and by whom will records be accessed and searched (check all that apply):
Self-search in APeX or other medical records source
Self-search using UCSF's Research Cohort Selection Tool
CTSI Consultation Service Recruitment Services
UCSF Academic Research Services (ARS)
University of California Research Exchange (UC ReX)
Other method (describe below)
11.3  DETERMINATION OF ELIGIBILITY: How, when, and by whom will eligibility for recruitment be
determined:
Study Protocol Page 31 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 27 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Treating clinicians on the infectious disease, neurology, and critical care services will refer patients with
infectious disease syndromes. At that point, the Study Investigator, co-Investigators or Study Coordinator
will review the patient's clinical information to determine whether they are eligible for the study. The
Study Investigator, co-Investigator or Study Coordinator will then approach and consent the patient (or
his/her surrogate decision maker) for the study.
Similarly, the Study Investigator, co-Investigator, or Study Coordinator will screen patients in APeX for
eligiblility. If patients meet criteria, the primary treating team will be contacted for permission to
approach and discuss the study with the potential research candidate. The Study Investigator, co-
Investigator or Study Coordinator will approach for possible consent.
A RedCap Referral survey will be used to assist with determining patient eligibilty. This will be submitted
to either the CRC, PI, or co-PI to review and determine eligibility prior to approaching patients for
consent.
11.4  * INITIATION OF CONTACT: Who initiates contact (check all that apply): (REQUIRED)
Investigators/study team
UCSF recruitment unit (e.g. CTSI Consultation Services)
Potential participant
Other (explain below)
11.5  * HOW IS CONTACT INITIATED: (check all that apply): (REQUIRED)
In person
Phone
Letter / email
Website or app
Other (explain below)
Attach the telephone recruitment script in the Other Study Documents
section of the Initial Review Submission Packet Form. If potential
participants will initiate contact, attach the telephone screening script
that will be used to provide more information about the study and
determine if callers are eligible to participate.
11.6  RECRUITMENT PLAN: Based on the checkboxes you chose above, please provide a narrative
describing your recruitment plan. We want to know:
Who is conducting the search for potential participants, and how?
How are potential subjects being approached for recruitment? By whom, and when?
If there will be more than one participant group (e.g. patients, healthy controls, caregivers, family
members, providers, etc.), provide details about the recruitment plans for each group.
(Recommended length - 100-250 words)
Potential participants will be identified by treating clinicians who have ordered the clinical UCSF mNGS
and referred the patient to opt into research participation. Study team members will also review medical
records for potential subjects that meet criteria.
Subjects will be approached by their treating clinician(s) in the context of their ongoing clinical care (e.g.
at the treating medical center).
11.7  * CONSENT METHODS: How will permission to participate (i.e., informed consent) be obtained from
each potential participant. If there will be multiple groups and different plans for consenting each,
check all that apply. See the orange Help bubble to the right for more detailed guidance.
Study Protocol Page 32 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 28 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
 
Participants will (check all that apply): (REQUIRED)
Sign a consent form at the end of the consent discussion (signed consent)
Provide online 'eConsent' using DocuSign or another E-Signature system
Click through a link in a survey or email after reading about the study and then complete the study
online (electronic consent)
Be told about the study and be given a handout/information sheet and be asked if they agree to
participate (verbal consent)
Complete the study activities and turn in materials, as in the case of a completed survey that is
placed in a drop box or mailed to the study team (implied consent)
Not be able to provide consent and will have a family member consent for them, as in the case of a
critically ill or unconscious patient (surrogate consent)
Not be able to provide consent (emergency waiver of consent - allowed for minimal risk research or
greater than minimal risk research with an approved community consultation plan)
Not know about the study, as in the case of chart reviews or observations of public behavior (waiver
of consent)
Other method (describe below)
Attach your consent form, information sheet, or electronic consent text in
the Informed Consent Documents section of the Initial Review
Submission Packet Form.
11.8  * CONSENT PROCESS: Describe the process for obtaining informed consent, including details such
as who will have the consent discussion and when participants will be asked to sign the consent
form in relation to finding out about the study: (REQUIRED)
 
We encourage researchers to review our guidance on obtaining and documenting informed
consent.
If there are multiple groups being consented differently, provide details about the consent
process for each group.
If you are relying on verbal or implied consent, provide details about how that will happen.
For studies using online recruitment and consent or consent via mail, provide details here.
As this study coincides with the release of the new UCSF metagenomic Next-Generation
Sequencing (mNGS) test, candidates and/or surrogates will be approached for possible
consent to the study after the mNGS clinical test has been ordered by the treating team.
UCSF Research Candidate with Capacity to Consent
The PI or other study key personnel will approach the research candidate and invite them to learn more
about the study. The PI or study key personnel will describe the study and the research candidate will be
given ample time to ask questions and consider their choice. Written informed consent will only be
obtained when the candidate feels comfortable proceeding with the study. A photocopy of the signed
consent documents will be provided to the candidate after they have been signed.
Specimens may be sent to the Clinical Microbiology Lab at UCSF for mNGS prior to the patient being
approached for possible consent. However, ancillary specimens will not be obtained prior to candidate
consent.
UCSF Surrogate Consent
Some research candidates will not be able to provide informed consent due to altered mental status or
cognitive impairment caused by their illness. Surrogates who are local and able to meet the study
personnel at bedside will be consented in person. The study PI or other key personnel will approach the
surrogate at the hospital to explain the research study and invite them to give consent on behalf of the
research candidate. The surrogate will be given ample time to discuss and ask questions. They surrogate
will complete the “Self-Certification of Surrogate Decision Makers for Potential Subject's Participation in
University of California Research”. When ready to sign the documents, they will sign the consent
documents and be provided a photocopy of the signed forms.
Surrogates who are not local or unable to meet the study personnel at the hospital, may be contacted
Study Protocol Page 33 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 29 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
and invited to learn more about the study over the phone. Surrogate contact information will be gathered
from either the electronic medical record, the treating physician, or by contacting the nurse, case
manager or other hospital staff involved in caring for the research candidate. The PI or other study
personnel will reach out to the surrogate by phone to explain the research study and invite them to give
consent on behalf of the research candidate. If the surrogate provides verbal consent, ancillary
specimens may be collected after this initial contact with the surrogate, including a blood draw. At the
time of initial verbal consent either the study personnel will schedule a meeting with the surrogate at a
later date at the hospital to review and sign the consent documents or they will be sent a package with 2
copies (one to be returned and one for the participant to keep) of each of the following documents: the
study consent forms, bill of rights, HIPPA authorization form and self-certification of surrogate form. A
stamped envelope will also be provided to return the signed documents in. If requested, an electronic
copy will also be sent to the surrogate. The surrogate will be given ample time to consider and discuss
the study. No ancillary samples will be collected until verbal consent is received.
Ancillary specimens may be collected and processed after verbal consent. Signed consent will be obtained
after obtaining verbal consent. If signed consent is not received by the surrogate within 4 months of
receiving the specimen(s), the participant will be considered not enrolled and PHI will be removed from
records/ destroyed and banked specimens will be destroyed.
Specimens may be sent to the Clinical Microbiology Lab at UCSF for mNGS prior to the patient being
approached for possible consent.
Outside Relying Site Research Candidate with Capacity to Consent
Outside relying sites will similarly ordering the clinical mNGS test and subsequently or simultaneously be
approaching candidates for possible consent to the research study.
The relying outside site PI or other study key personnel will approach the research candidate and invite
them to learn more about the study. The PI or study key personnel will describe the study and the
research candidate will be given ample time to ask questions and consider their choice. Written informed
consent will only be obtained when the candidate feels comfortable proceeding with the study. A
photocopy of the signed consent documents will be provided to the candidate after they have been
signed.
Specimens may be sent to the Clinical Microbiology Lab at UCSF for mNGS prior to the patient being
approached for possible consent. However, ancillary specimens will not be obtained prior to candidate
consent.
Outside Relying Site Surrogate Consent
Some research candidates at outside sites will not be able to provide informed consent due to altered
mental status or cognitive impairment caused by their illness. Surrogates who are local to the relying
sites and able to meet the local study personnel at bedside will be consented in person. The local study PI
or other key personnel will approach the surrogate at the hospital to explain the research study and invite
them to give consent on behalf of the research candidate. The surrogate will be given ample time to
discuss and ask questions. They surrogate will complete the “Self-Certification of Surrogate Decision
Makers for Potential Subject's Participation in University of California Research”. When ready to sign the
documents, they will sign the consent documents and be provided a photocopy of the signed consent
form, HIPPA auth, and Bill Rights. One version of the consent document will be used at all sites.
Surrogates who are not local or unable to meet the local study personnel at the hospital, may be
contacted and invited to learn more about the study over the phone. Surrogate contact information will
be gathered from either the electronic medical record, the treating physician, or by contacting the nurse,
case manager or other hospital staff involved in caring for the research candidate. The local PI or other
study personnel will reach out to the surrogate by phone to explain the research study and invite them to
give consent on behalf of the research candidate. If the surrogate provides verbal consent, ancillary
specimens may be collected after this initial contact with the surrogate, including a blood draw. At the
time of initial verbal consent either the study personnel will schedule a meeting with the surrogate at a
later date at the hospital to review and sign the consent documents or they will be sent a package with 2
copies (one to be returned and one for the participant to keep) of each of the following documents: the
study consent forms, bill of rights, HIPPA authorization form and self-certification of surrogate form. A
stamped envelope will also be provided to return the signed documents in. If requested, an electronic
copy will also be sent to the surrogate. The surrogate will be given ample time to consider and discuss
the study. No ancillary samples will be collected until verbal consent is received.
Ancillary specimens may be collected and processed after verbal consent. Signed consent will be obtained
after obtaining verbal consent. If signed consent is not received by the surrogate within 4 months of
receiving the specimen(s), the participant will be considered not enrolled and PHI will be removed from
records/ destroyed and banked specimens will be destroyed.
Outside non-relying site consent
Non-relying sites will consent research candidates and/or surrogates according to local IRB protocols.
Re-Consent for participants that gain capacity to consent after enrollment
Research candidates who were enrolled by surrogate consent while in the hospital will be re-contacted in
the case they re-gain capacity to give informed consent. We anticipate this to occur once the patient is no
longer hospitalized. Therefore, re-consent will be initiated with a phone call to explain the study to the
Study Protocol Page 34 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 30 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
research participant and give them the option to remain in the study or to withdraw. If the participant
wishes to be withdrawn, banked specimens will be destroyed and no further research will be conducted
using the specimens. However, any research already done using the specimens or data will be kept and
analyzed as part of the study. If the participant wishes to remain in the study, they will be asked to sign
new consent forms. Documents (2 of each: consent form, HIPPA authorization, and Bill of Rights) will be
mailed to the participant. One copy will be for the participant to keep for their personal records and the
second to sign and return.
* It is important that the people obtaining consent are qualified to do so. Briefly
describe the training and experience these individuals have in obtaining informed
consent: (REQUIRED)
At UCSF,
Hannah Sample, BS -- Study Coordinator, ~2 year experience in obtaining informed consent for research
studies
Amy Berger, MD -- internal medicine physician, hospitalist training, ~3 years experience in obtaining
informed consent for research studies
other faculty, fellows, residents on the Molecular Medicine, Neurology, Infectious Diseases consult
services -- clinical providers at UCSF who have been trained by the investigators on the details of the
CIAPM study and with at least 5 years experience in obtaining informed consent for research studies
11.9  * CONSENT COMPREHENSION: Indicate how the study team will assess and enhance the subjects'
understanding of study procedures, risks, and benefits prior to signing the consent form (check all
that apply): (REQUIRED)
 
Tip: Review the Consent Comprehension - Learning Notes in the Help bubble at the right for specific
questions that can be asked to assess comprehension, consider using the UCSF Decision-Making
Capacity Assesment Tool, and review our guidance on obtaining written or verbal informed
consent for more detail on how to conduct the assessment.
The study team will engage the potential participant in a dialogue, using open-ended questions about
the nature of the study or the experimental treatment, the risks and benefits of participating, and the
voluntary nature of participation
Potential participants will be asked or shown a series of questions to assess their understanding of
the study purpose, procedures, risks and benefits, as well as the voluntary nature of participation
(especially appropriate when the consent process happens online or through a mobile health app)
Other method (describe below):
Provide details of the other approaches that will be used, if using another method
to assess comprehension:
Subjects will be asked to explain back the risks, benefits and study protocols. All prospective subjects will
have a detailed neurological exam, part of which will entail a mental status exam in which multiple
cognitive domains are assessed. In addition, we will administer the attached Capacity Assessment Record
for Research Informed Consent. This document will insure that we assess and document whether the
potential research subject is able to make a choice whether to participate in the research protocol,
whether he/she shows understanding of the research protocol and its elements, including the
risks/benefits of participation, whether he/she is able to provide rational reasons for participating or not
participating the research protocol and whether he/she shows an appreciation of the personal
risks/benefits of participating or not participating in the protocol.
11.13  TIME: What is the estimated time commitment for participants (per visit and in total):
About 30-60 mins for consent. The rest of the study procedures involve processing and analysis but not
subject time. The 30-60 minutes for a follow up telephone call to confirm long-term outcome and final
diagnosis.
A blood draw shoud take about 5 minutes.
IMPORTANT TIP: Ensure this information is consistent with the
Study Protocol Page 35 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 31 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
information provided in the consent form.
12.0
Waiver of Consent/Authorization for Recruitment Purposes
This section is required when medical records may be reviewed to determine
eligibility for recruitment.
12.1  * PRACTICABILITY OF OBTAINING CONSENT PRIOR TO ACCESS: Study personnel need to access
protected health information (PHI) during the recruitment process and it is not practicable to
obtain informed consent until potential subjects have been identified: (REQUIRED)
Yes 
If no, a waiver of consent/authorization is NOT needed.
12.2  *  RISK TO PRIVACY: A waiver for screening of health records to identify potential subjects poses
no more than minimal risk to privacy for participants:
Yes 
If no, a waiver of authorization can NOT be granted.
12.3  * RIGHTS/WELFARE: Screening health records prior to obtaining consent will not adversely affect
subjects' rights and welfare:
Yes 
If no, a waiver of authorization can NOT be granted.
12.4  * IDENTIFIERS: Check all the identifiers that will be collected prior to obtaining informed consent:
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
Study Protocol Page 36 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 32 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
None
Note: HIPAA rules require that you collect the minimum necessary.
12.5  * HEALTH INFORMATION: Describe any health information that will be collected prior to obtaining
informed consent:
Name, MRN, dates, clinical history for the purposes of establishing eligibility based on suspected
diagnosis and clinical syndrome. Phone numbers may also be collected in order to contact non-local
surrogates or research candidates.
Note: HIPAA requires that you collect the minimum necessary.
12.6  * DATA RETENTION/DESTRUCTION PLAN: Describe your plan to destroy any identifiable data
collected to determine eligibility for recruitment. This should be done at the earliest opportunity. If
you plan to retain identifiable recruitment data, provide the justification for doing so:
Data on subjects who are not eligible or do not wish to participate will be destroyed. Patient name and
MRN will be kept on record in the secure research database so that patients who have declined
participation will not be approached again.
13.0
Surrogate Consent
13.1  PSYCHIATRIC SCREEN: Are any subjects inpatients on a psychiatric ward or mental health facility,
or on psychiatric hold:
No 
If Yes, use of surrogate consent for research is NOT allowed in California.
13.2  AREAS OF RESEARCH: Is this study related to the cognitive impairment, lack of capacity, or serious
or life-threatening diseases and conditions of the research subjects: 
Yes 
13.3  JUSTIFICATION: Explain why use of surrogates is necessary for completion of this study:
Many subjects to be enrolled in this study may be incapacitated with a serious illness, sedated, or
otherwise unable to provide informed consent.  For enrollment in this study, the use of surrogates with
durable power of attorney will be necessary for these subjects.
13.4  COGNITIVE ASSESSMENT:  Describe the plans for assessing the decision-making capacity of
prospective subjects:
Study Protocol Page 37 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 33 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
We will assess the decision-making capacity of prospective subjects by their condition (sedated,
intubated, or otherwise incapacitated patients will not be able to make decisions), including severity of
illness, and a clinician determination of whether they are able to provide informed consent.
13.5  POST-ENROLLMENT CONSENT PLANS: Describe the plans for obtaining consent from subjects who
regain ability to consent after a surrogate has given initial consent:
If subjects regain ability to consent after a surrogate has given initial consent, and are otherwise
accessible (e.g. still in the hospital), we will make every effort to obtain informed consent from the
subject directly.
13.6  
SURROGATE CONSENT REQUIREMENTS: Check to acknowledge:
Research takes place in California. All surrogates will complete the “Self-Certification of Surrogate
Decision Makers for Participation in Research” form.
Conscious subjects will be notified of the decision to contact a surrogate. If subjects object to study
participation, they will be excluded even if their surrogate has given consent.
Surrogates will not receive any financial compensation for providing consent.
If a higher-ranking surrogate is identified at any time, the investigators will defer to the higher-
ranking surrogate’s decision regarding the subject’s participation in the research.
For research taking place outside of California, explain how investigators will
confirm that surrogates are legally authorized representatives:
14.0
Risks and Benefits
14.1  RESEARCH-RELATED RISKS: Check if your study involves any of these specific research-related
risks to participants that may need to be disclosed in the consent form:
For interventional studies, risk that the regimen may be more harmful or less effective than other
available interventions
Risks associated with radiation exposure for imaging studies specifically for research purposes
Risks associated with the administration of contrast agent for imaging studies
Risks associated with withholding of treatment or discontinuation of current treatment (e.g., washout
period is required by the study protocol)
For randomized, placebo-controlled trials, possible temporary or permanent health consequences
from the deprivation of effective therapies during the placebo administration period
For studies involving a sham surgical procedure, the risk that participants may experience increased
morbidity without the possibility of benefit
Risks associated with modification or extension of a surgical procedure primarily for research
purposes (e.g. risks associated with prolonging anesthesia, time in the operating room, etc.)
Risk of pain or physical discomfort caused by the research intervention
Possible personal discomfort due to sensitive topics (stress, embarassment, trauma)
14.2  RISKS: Describe any anticipated risks and discomforts not listed above:
1. We will be analyzing surplus CSF, blood, other bodily fluids and biopsy tissue, which will not be able to
be returned to the subject for further clinical analysis.
2. It is possible that a pathogen will be identified using this approach, that upon additional clinical
Study Protocol Page 38 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 34 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
confirmation by the treating team, may need to be reported to public health authorities by law, which
could have implications for patient privacy.
3. There is a risk that information about taking part in a genetic study may influence insurance
companies and/or employers regarding your health. To further safeguard your privacy, genetic
information obtained in this study will not be placed in your medical record. Taking part in a genetic study
may also have a negative impact or unintended consequences on family or other relationships. If you do
not share information about taking part in this study, you will reduce this risk. Although your name will
not be with the sample, it will have other facts about you such as information about your medical history,
age and gender. These facts are important because they will help us learn if the factors that cause
neurologic disease to occur or get worse are the same or different based on these facts. Thus it is
possible that study finding could one day help people of the same race, ethnicity, or sex as you. 
However, it is also possible through these kinds of studies that genetic traits might come to be associated
with your group.  In some cases, this could reinforce harmful stereotypes.
4.  Drawing blood may cause temporary discomfort from the needle stick, bruising, and very rarely
infection.
14.3  
MINIMIZING RISKS: Describe the steps you have taken to minimize the risks/discomforts to
subjects. Examples include:
designing the study to make use of procedures involving less risk when appropriate
minimizing study procedures by taking advantage of clinical procedures conducted on the
study participants
mitigating risks by planning special monitoring or conducting supportive interventions for
the study
having a plan for evaluation and possible referral of subjects who report suicidal ideation
All clinical specimens will be obtained by trained clinical personnel according to standard operating
procedures, and the procedures will only be performed as clinically indicated.
14.4  RESOURCES: Describe the resources in place to conduct this study in a way that assures protection
of the rights and welfare of participants:
 
These resources typically include appropriately trained and qualified personnel (in terms
availability, number, expertise and experience), funding, space, equipment, and time to devote to
study activities.
 
Depending on the nature of the research study, investigators should consider the proximity or
availability of critical resources that may be essential to the safety and welfare of participants,
such as
the proximity of an emergency facility for care of participant injury
availability of psychological support after participation
resources for participant communication, such as language translation services
As described in the "Qualifications of Key Study Personnel" section, all research staff involved in this
project have extensive experience with research and patient care and understand the importance of
minimizing risks to study subjects. As described in the "Privacy" section, we have numerous protections
in place to insure subject privacy.
14.5  * BENEFITS: (REQUIRED)
Note: These are the benefits that the IRB will consider during their review. They are not necessarily
appropriate to include in the consent form.
Possible immediate and/or direct benefits to participants and society at
large (check all that apply):
Positive health outcome (e.g. improvement of condition, relief of pain, increased mobility, etc.)
Study Protocol Page 39 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 35 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Closer follow-up than standard care may lead to improved outcomes or patient engagement
Health and lifestyle changes may occur as a result of participation
Knowledge may be gained about their health and health conditions
Feeling of contribution to knowledge in the health or social sciences field
The research presents a reasonable opportunity to further the understanding, prevention, or
alleviation of a serious problem affecting the health or welfare of children
Other benefit (describe below)
None
14.6  RISK TO BENEFIT RATIO: Explain why the risks to subjects are reasonable in relation to anticipated
benefits, if any, to the participant or society:
The risk to subjects is minimal, principally loss of privacy (although every effort will be made to maintain
confidentiality, especially of genetic information).  Knowledge may be gained from the clinically validated
mNGS test about the infectious cause of their illness.
15.0
Confidentiality, Privacy, and Data Security
15.1  PROTECTING PRIVACY: Indicate how subject privacy will be protected:
Conduct conversations about the research in a private room
Ask the subject how they wish to be communicated with – what phone numbers can be called, can
messages be left, can they receive mail about the study at home, etc.
Take special measures to ensure that data collected about sensitive issues do not get added to their
medical records or shared with others without the subject’s permission
Other methods (describe below)
15.2  SENSITIVE DATA: Do any of the instruments ask about illegal or stigmatized behavior:
  Yes   
  No
15.3  CONSEQUENCES OF A LOSS OF PRIVACY OR CONFIDENTIALITY: Could a breach of privacy or
confidentiality  result in any significant consequences to participants, such as criminal or civil
liability, loss of state or federal benefits, or be damaging to the participant's financial standing,
employability, or reputation:
  Yes   
  No
15.4  EXTRA CONFIDENTIALITY MEASURES: Explain any extra steps that will be taken to assure
confidentiality and protect identifiable information from improper use and disclosure, if any:
Specimens and data will be coded. The "key" to this code will kept in RedCap. RedCap will only be
accessible to key study personnel and no identifying information will be shared with researchers not
directly involved in the study and who are listed as study personnel on this application.
15.5  * REPORTABILITY: Do you anticipate that this study may collect information that State or Federal
law requires to be reported to other officials, such as elder abuse, child abuse, or threat to self or
others: (REQUIRED)
Study Protocol Page 40 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 36 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
 Yes   
 No
The confidentiality and privacy section of the consent form should include
this as a possible risk of participation. 
 
* Describe the types of reportable information the research team may encounter
and provide the details of the reporting plan: (REQUIRED)
If there is suspicion for a concerning pathogen, the PI will contact the treating physician and/or clinical
laboratory to discuss the finding. Public health reporting may be indicated if confirmed by the clincial lab
and treating physician. The PI will not report research findings for public health reporting as these are
research findings.
15.6  CERTIFICATE OF CONFIDENTIALITY: Will this study obain a Certificate of Confidentiality:
  Yes   
  No
15.7  SHARING OF RESEARCH RESULTS: Will there be any sharing of EXPERIMENTAL research test results
with subjects or their care providers:
 Yes   
 No
Note: This is unusual and not recommended, particularly in cases where
the tests are carried out in a non-CLIA certified laboratory, the results
are of unproven clinical significance, or where there are not known
preventative strategies and/or treatments. If these are the most likely
scenarios for your study, you should check 'No.'  
 
If you have an incidental finding of clear clinical significance, call the
HRPP QIU at 415-476-1814 for a consult. 
Explain under what circumstances research results may be shared:
Results from the clinical mNGS test (CSF, plasma, or BAL) will be reported in the electronic medical
record and communicated to the treating clinician as this is a clinically validated test performed in the
UCSF Clinical Microbiology Laboratory.
For research results from non-validated specimen types (e.g. brain biopsy), a narrative results report will
be discused with the treating clinician detailing the candidate pathogen(s) found, research assay
methods, and limitations.  The discussion will include any testing available in CLIA-certified laboratories
for confirmation of the research result, if applicable.  The results will be marked specifically as "Research
use only not to be used for clinical purposes" and "Any results (positive or negative) do not exclude any
other causes for patient illness".  Thus, these research results will not be used for clinical purposes but
may be communicated to clinicians to guide additional CLIA-certified diagnostic testing.
15.8  * IDENTIFIERS: Will any personal identifiers be collected: (REQUIRED)
 Yes   
 No
Check all the identifiers that may be included:
Study Protocol Page 41 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 37 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
If publications from this study may include ANY photos or images of
patients - even without faces - either collected for research or from the
medical records, you are required to have each patient sign the 'Consent
for Photography / Authorization for Publication' form prior to submittal
for publication. Failure to obtain consent for publication may result in a
finding of Serious Non-compliance by the IRB and civil and criminal
penalties, including fines up to $1.5 million dollars for violation of the
HIPAA privacy protections if a participant complains.  
* Could study records include ANY photos or images (even 'unidentifiable'
ones): (REQUIRED)
 Yes   
 No
15.9  DATA DISCLOSURE: Will identifiable information be shared with outside groups:
  Yes   
  No
15.11  * DATA COLLECTION AND STORAGE: (check all that apply): (REQUIRED)
Collection methods:
Paper-based (surveys, logs, diaries, etc.)
Electronic case report forms (CRFs), such as OnCore or another clinical trial management portal
Web-based online surveys or computer-assisted interview tool
Mobile applications (mobile or tablet-based)
Wearable devices
Study Protocol Page 42 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 38 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Audio/video recordings
Other:
* What online survey tool will you use: (REQUIRED)
Qualtrics (Recommended)
RedCAP (Recommended)
Survey Monkey (NOT recommended and may require UCSF ITS Security review)
Other
* Data will be collected/stored in systems owned by (check all that
apply): (REQUIRED)
UCSF
SF VAMC
Amazon (Amazon Cloud)
Other academic institution
3rd party vendor (business entity)
Other (explain below)
* Do you have a contract or Data Use Agreement with a 3rd party for research
data collection, storage, access, and ownership: (REQUIRED)
 Yes   
 No
15.12  DATA SECURITY: Indicate how data are kept secure and protected from improper use and
disclosure (check all that apply):
 
NOTE: Whenever possible, do not store subject identifiers on laptops, PDAs, or other portable
devices. If you collect subject identifiers on portable devices, you MUST encrypt the devices.
Data are stored securely in My Research
Data are coded; data key is destroyed at end of study
Data are coded; data key is kept separately and securely
Data are kept in a locked file cabinet
Data are kept in a locked office or suite
Electronic data are protected with a password
Data are stored on a secure network
Data are collected/stored using REDCap or REDCap Survey
Data are securely stored in OnCore
15.13  * DATA SECURITY: Confirm below that you will keep data confidential: (REQUIRED)
 
I will keep any data sets that include identifiers secure and protected from improper use and
disclosure by using methods such as:
Physical Security – Keeping data in locked file cabinets, locked offices, locked suites, and
physically securing computers and servers.
Electronic Security – Following UCSF minimum security standards for electronic information
resources, which includes (but is not limited to): not storing identifiers on portable devices
like laptops or flash drives if they are unencrypted, encrypting portable devices, and storing
Study Protocol Page 43 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 39 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
data in password-protected files and on secure networks.
 
Yes 
15.15  HIPAA APPLICABILITY: Study data will be:
Derived from the Integrated Data Repository (IDR) or The Health Record Data Service (THREDS) at
SFGH
Derived from a medical record (e.g. APeX, OnCore, etc. Identify source below)
Added to the hospital or clinical medical record
Created or collected as part of health care
Obtained from the subject, including interviews, questionnaires
Obtained ONLY from a foreign country or countries
Obtained ONLY from records open to the public
Obtained from existing research records
None of the above
16.0
Financial Considerations
16.1  * PAYMENT: Will subjects be paid for participation, reimbursed for time or expenses, or receive any
other kind of compensation: (REQUIRED)
  Yes   
  No
16.4  COSTS TO SUBJECTS: Will subjects or their insurance be charged for any study activities:
  Yes   
  No
17.0
Qualifications of Key Study Personnel
17.1   
NOTE: This information is required and your application will be considered
incomplete without it. If this study involves invasive or risky procedures, or
procedures requiring special training or certification, please identify who will
be conducting these procedures and provide details about their qualifications
and training. Also identify each person who will be involved in the consent
process. Click the orange question mark for more information and examples.
Under qualifications, please include:
Academic Title
Institutional Affiliation (UCSF, SFGH, VAMC, etc.)
Department
Certifications
 
November, 2015 - NEW Definition of Key Study Personnel and CITI
Study Protocol Page 44 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 40 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Training Requirements:
UCSF Key Study Personnel include the Principal Investigator, other
investigators and research personnel who are directly involved in conducting
research with study participants or who are directly involved in using study
participants’ identifiable private information during the course of the
research. Key Personnel also include faculty mentors/advisors who provide
direct oversight to Postdoctoral Fellows, Residents and Clinical Fellows
serving as PI on the IRB application.
 
The IRB requires that all Key Study Personnel complete Human Subjects
Protection Training through CITI prior to approval of a new study, or a
modification in which KSP are being added. More information on the CITI
training requirement can be found on our website.  
 
KSP Name
Description of Study
Responsibilities - Briefly
describe what will each person
be doing on the study. If there
are procedures requiring special
expertise or certification,
identify who will be carrying
these out. Also identify who will
be obtaining informed consent.
Qualifications, Licensure, and
Training
Dr. Chiu, Charles Y MD
Principal investigator,
Supervision of next generation
sequencing techniques and
bioinformatic analysis of
sequencing data, patient
consent
UCSF Associate Professor of
Laboratory Medicine and
Medicine/Infectious Diseases;
Director, UCSF-Abbott Viral
Diagnostics and Discovery
Center; Associate Director,
UCSF Clinical Microbiology;
expert in pathogen discovery
techniques, next generation
sequencing and bioinformatics
Dr. DeRisi, Joseph, PhD
Supervision of next generation
sequencing techniques and
bioinformatic analysis of
sequencing data, patient
consent
UCSF Professor and Chair of
Biochemistry and Biophysics,
expert in pathogen discovery
techniques, next generation
sequencing and bioinformatics
Dr. Gelfand, Jeffrey MD
Patient recruitment, consent,
study design
UCSF Assistant Professor of
Neurology, UCSF Multiple
Sclerosis Center, expert on
neuroimmunological diseases,
Masters in Clinical Research
Dr. Wilson, Michael MD
Study design, perform next
generation sequencing on
clinical specimens and
bioinformatics analysis,
patient consent
UCSF Assistant Professor in
Residence in Neurology, UCSF
MS Center, expert in neuro-
infectious diseases
Langelier, Charles R
Study design, perform next
generation sequencing on
clinical specimens and
UCSF Infectious Diseases
fellow
Study Protocol Page 45 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 41 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
bioinformatics analysis,
patient consent
Chow, Felicia, MD
Study design, patient
recruitment, data analysis,
patient consent
UCSF Assistant Professor of
Neurology, Neurologist expert
in neuro-infectious diseases
Dr. Pleasure, Samuel M.D., PhD
Study design, autoantibody
screening, patient consent
UCSF Professor of Neurology,
Neurologist expert in
neuroimmunological diseases,
Neuroanatomist
Dr. Geschwind, Michael, MD,
PhD
Study design, data acquisition
and analysis, patient consent
UCSF Professor of Neurology,
neurologist expert in rapdily
progressive dementia
Sample, Hannah
Study coordinator; Patient
recruitment and consent;
specimen processing; study
database management
UCSF clinical research
coordinator
Dr. Chow, Eric, PhD
perform next generation
sequencing on clinical
specimens, data analysis
Director - Center for Advanced
Technology
UCSF Dept. of Biochemistry
and Biophysics
Samayoa, Erik L
perform next generation
sequencing on clinical
specimens
CLIA Lab technician, Chiu Lab
Naccache, Samia N
perform next generation
sequencing on clinical
specimens and bioinformatics
analysis; data manager; CLIA
technician running the mNGS
assay
PhD Bioinformatician, CLIA
Lab technician, Chiu Lab
Miller, Steven
Supervision of next generation
sequencing techniques and
bioinformatic analysis of
sequencing data
UCSF Associate Professor of
Laboratory Medicine, Director,
UCSF Clinical Microbiology
Federman, Scot M
next-generation sequencing
data analysis; running SURPI
bioinformatics pipeline
UCSF Programmer/Analyst III,
UCSF Department of
Laboratory Medicine
Stryke, Doug
next-generation sequencing
data analysis; running SURPI
bioinformatics pipeline
UCSF Programmer Analyst,
UCSF Department of
Laboratory Medicine
Berger, Amy
study design; enrolling
patients for NGS study;
obtaining consent
UCSF Resident Physician
Mccaleb, Kristen L
Study coordinator; Patient
recruitment and consent;
specimen processing; study
database management
UCSF Special Projects
Manager, 
UCSF Office of the Executive
Vice Chancellor & Provost
Pham, Elizabeth
Study Protocol Page 46 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 42 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
CLIA technician running the
clinical mNGS assay
UCSF Clin Lab Scientist
UCSF Department Laboratory
Medicine
Samayoa, Erik L
CLIA technician running the
clinical mNGS assay
UCSF Clin Lab Scientist
UCSF Department Laboratory
Medicine
Yu, Guixia
Sample biobanking and
aliquotting; running
confirmatory research assays
for the mNGS clinical test
UCSF SRA, UCSF Department
of Laboratory Medicine
18.0
Other Approvals and Registrations
18.1  * ADMINISTRATION OF RECOMBINANT DNA: Does this study involve administration of vaccines
produced using recombinant DNA technologies to human subjects (Help Link added Aug '15):
(REQUIRED)
  Yes   
  No
18.2  * HUMAN GENE TRANSFER: Does this study involve human gene transfer (NOTE: Requires NIH
Recombinant DNA Advisory Committee (RAC) review prior to IRB approval): (REQUIRED)
  Yes   
  No
18.4  OTHER APPROVALS: Indicate if this study involves other regulated materials and requires approval
and/or authorization from the following regulatory committees:
Institutional Biological Safety Committee (IBC)
Specify BUA #:
Chiu lab: BUA 49187-BU-01-INC; CLIA certificate 05D1024215
Institutional Animal Care and Use Committee (IACUC)
Specify IACUC #:
Controlled Substances
19.0
End of Study Application
19.1  
End of Study Application Form
 
To continue working on the Study Application: Click on the section you need to edit in the
left-hand menu. Remember to save through the entire Study Application after making
changes.
 
If you are done working on the Study Application:
Study Protocol Page 47 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:40 AM
iRIS: IRB Study Application
Page 43 of 43
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
 
Important: Before proceeding, please go back to Section 4.0 Initial Screening
Questions and Save and Continue through the form to make sure all the relevant
sections and questions have been included. If you've changed any answers since you
started, the branching may have changed. Your application will be incomplete and it
will have to be returned for corrections. 
 
Once you are sure the form is complete, click Save and Continue. If this is a new study, you
will automatically enter the Initial Review Submission Packet form, where you can attach
consent forms or other study documents. Review the Initial Review Submission Checklist
for a list of required attachments.
 
Answer all questions and attach all required documents to speed up your approval.
 
 
 
 
 
 
The UCSF IRB wants your feedback about this new form. Please
click the link to take a brief survey about the new application form.
Study Protocol Page 48 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 1 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
    Study Application (Version 1.16)
1.0
General Information
*Enter the full title of your study:
Precision Diagnosis of Acute Infectious Diseases
 
 
*Enter the study number or study alias
PDAID
* This field allows you to enter an abbreviated version of the Study Title to quickly identify this
study.
 
 
2.0
Add Department(s)
2.1 List departments and/or research programs associated with this study:
Primary
Dept?
Department Name
UCSF - 115001 - M_Biochemistry and Biophysics
UCSF - 135118 - M_CTSI-SOS
UCSF - 144075 - M_Laboratory Medicine
UCSF - 138300 - M_MEDICINE
UCSF - 140020 - M_Neurology
 
3.0
Assign key study personnel(KSP) access to the study
3.1 *Please add a Principal Investigator for the study:
 
Chiu, Charles Y MD
Select if applicable
Department Chair
Resident
Fellow
If the Principal Investigator is a Fellow, the name of the Faculty Advisor must be supplied below.
 
3.2 If applicable, please select the Research Staff personnel:
 
A) Additional Investigators
Study Protocol Page 49 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 2 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Berger, Amy 
 Other Investigator
Chow, Eric D PhD, PhD 
 Other Investigator
Chow, Felicia, MD 
 Other Investigator
Derisi, Joseph L. PhD 
 Co-Principal Investigator
Gelfand, Jeffrey MD 
 Other Investigator
Geschwind, Michael MD, PhD 
 Other Investigator
Langelier, Charles R 
 Other Investigator
Miller, Steven 
 Co-Principal Investigator
Naccache, Samia N 
 Other Investigator
Samayoa, Erik L 
 Other Investigator
Wilson, Michael R, MD 
 Co-Principal Investigator
B) Research Support Staff
Federman, Scot M 
 Biostatistician
Naccache, Samia N 
 Data Manager
Pham, Elizabeth 
 Technician
Samayoa, Erik L 
 Technician
Sample, Hannah 
 Study Coordinator
Stryke, Doug 
 Biostatistician
Weininger, Joshua K 
 Study Coordinator
Yu, Guixia 
 Technician
Zorn, Kelsey C 
 Study Coordinator
3.3 *Please add a Study Contact:
 
Chiu, Charles Y MD 
Derisi, Joseph L. PhD 
Study Protocol Page 50 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 3 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Mann, Jennifer 
Miller, Steven 
Sample, Hannah 
Wilson, Michael R, MD 
The Study Contact(s) will receive all important system notifications along with the Principal
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the Principal
Investigator themselves).
3.4 If applicable, please add a Faculty Advisor/Mentor:
 
3.5 If applicable, please select the Designated Department Approval(s):
 
Hauser, Stephen M.D. 
Department Chair
Lowell, Clifford A MD 
Department Chair
Add the name of the individual authorized to approve and sign off on this protocol from your
Department (e.g. the Department Chair or Dean).
4.0
Initial Screening Questions
Updated June 2017
4.1  * PROJECT SUMMARY: (REQUIRED)
Give a brief overview of this project (250 words or less). Tell us what this study is about, who is
being studied, and what it aims to achieve. If you have an NIH Abstract, paste it here:
 
Click on the orange question mark to the right for more detailed instructions.
Currently, up to 50% of hospitalized patients with pneumonia, sepsis, and encephalitis / meningitis are
treated without a laboratory-confirmed cause of their disease, resulting in delayed and ineffective
therapy, increased mortality, and excess healthcare costs.   Here we aim to use metagenomic next-
generation sequencing (mNGS) to provide the first-ever demonstration of precision medicine
for the diagnosis of acute infectious diseases in hospitalized patients, with immediate impact
on clinical care and patient outcomes.  Clinical validation of the mNGS assay in a licensed clinical
diagnostic laboratory (the UCSF Clinical Microbiology Laboratory) is complete for cerebrospinal fluid (CSF)
for the diagnosis of encephalitis / meningitis as of June 2016.  Validation is ongoing on plasma for sepsis,
and bronchoalveolar lavage (BAL) fluid for pneumonia is anticipated complete by June 2017, and Dec
2017, respectively.  In June 2016, we launched a prospective clinical study enrolling patients from 4 UC
hospitals (UCSF, UCLA, and UC Davis) to evaluate the performance of the clinically validated mNGS assay
relative to routine microbiological testing.  Patients will be consented for (1) review of their medical chart
and eventual publication, (2) blood draw for orthogonal laboratory testing and/or research, and (3)
collection and mNGS analysis of excess material from related sample types that have not been clinically
validated (e.g. brain biopsy). We will specifically evaluate how the mNGS results obtained from the
clinically validated test affect patient management and clinical outcomes.  Ultimately, we aim to deliver a
clinically reimbursable, self-sustaining genomic test for infectious diseases that will improve patient
outcomes long past the 1-year study time frame.  
4.2  * HUD DEVICE: (REQUIRED)
Study Protocol Page 51 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 4 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Does this application involve a Humanitarian Use Device (HUD):
No 
Yes, and it includes a research component 
Yes, and it involves clinical care ONLY 
4.3  * TYPE OF RESEARCH: (Click the Help link for definitions and guidance): (REQUIRED)
Biomedical research 
Social, behavioral, educational, and/or public policy research 
Hybrid - includes aspects of BOTH types of research (check this option if your research is mainly
social/behavioral but also involves specimen collection or blood draws to look at biological measures) 
4.4  * SUBJECT CONTACT: (REQUIRED)
Does this study involve ANY contact or interactions with participants:
Yes (including phone, email or web contact) 
No (limited to medical records review, biological specimen analysis, and/or data analysis) 
4.5  * RADIATION EXPOSURE: Does your protocol involve any radiation exposure to
patients/subjects EITHER from standard care OR for research purposes (e.g., x-rays, CT-scans,
DEXA, CT-guided biopsy, radiation therapy, or nuclear medicine including PET, MUGA or bone scans):
(REQUIRED)
  Yes   
  No
4.6  * RISK LEVEL: (REQUIRED)
What is your estimation of the risk level, including all screening procedures and
study activities (Help Text updated 9/13):
Minimal risk 
Greater than minimal risk 
4.7  * REVIEW LEVEL: (REQUIRED)
Requested review level (Click on the orange question mark to the right for definitions and
guidance):
Full Committee 
Expedited 
Exempt 
4.8  * EXPEDITED REVIEW CATEGORIES: (REQUIRED)
If you think this study qualifies for expedited review, select the regulatory categories that the
research falls under: (check all that apply)
Category 1: A very limited number of studies of approved drugs and devices
Category 2: Blood sampling
Study Protocol Page 52 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 5 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Category 3: Noninvasive specimen collection (e.g. buccal swabs, urine, hair and nail clippings, etc.)
Category 4: Noninvasive clinical procedures (e.g. physical sensors such as pulse oximeters, MRI,
EKG, EEG, ultrasound, moderate exercise testing, etc.)
Category 5: Research involving materials (data, documents, records, or specimens) that were
previously collected for either nonresearch or research purposes
Category 6: Use of recordings (voice, video, digital or image)
Category 7: Low risk behavioral research or research employing survey, interview, oral history, focus
group, program evaluation, human factors evaluation, or quality assurance methodologies
4.11  * CLINICAL TRIAL: (REQUIRED)
Is this a clinical trial? According to The World Health Organization (WHO) and the International
Committee of Medical Journal Editors (ICMJE) a clinical trial is:
Any research study that prospectively assigns human participants or groups of humans to
one or more health-related interventions to evaluate the effects on health outcomes.
ICMJE requires registration of a clinical trial in a public database (such as ClinicalTrials.gov) prior
to enrollment, for eventual publication of results in member biomedical journals.
Guidance: Public Law 110-85 requires that all investigators who perform an applicable clinical
trial must ensure that the trial is registered on a government web site called ClinicalTrials.gov.
 
The FDA requires registration for “applicable clinical trials,” defined as follows:
For any trials of drugs and biologics: controlled clinical investigations, other than Phase 1
investigations, of a product subject to FDA regulation.
For trials of biomedical devices: controlled trials with health outcomes of devices subject to
FDA regulation, other than small feasibility studies, and pediatric post-market surveillance.
For additional information on the ClinicalTrials.gov registration process at UCSF and the definition
of a clinical trial for purposes of registration, visit the ClinicalTrials.gov section of the UCSF Clinical
Research Resource HUB.
 Yes   
 No
Clinical Trial Registration
"NCT" number for this trial:
pending
If you don't yet have the NCT#, type 'Pending.' 
4.12  * CLINICAL TRIAL PHASE (REQUIRED)
Check the applicable phase(s) (Help Text updated 9/13):
Phase I
Phase II
Phase III
Phase IV
4.13  * INVESTIGATOR-INITIATED: (REQUIRED)
Is this an investigator-initiated study:
 Yes   
 No
Study Protocol Page 53 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 6 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
4.14  SCIENTIFIC REVIEW:
If this study has undergone scientific or scholarly review, please indicate which entity performed
the review (check all that apply):
Cancer Center Protocol Review Committee (PRC) (Full approval is required prior to final CHR approval
for cancer-related protocols.)
CTSI Clinical Research Services (CRS) Advisory Committee
CTSI Consultation Services
Departmental scientific review
Other:
* Specify Other: (REQUIRED)
California Initiative to Advance Precision Medicine
4.15  * STEM CELLS: (REQUIRED)
Does this study involve human stem cells (including iPS cells and adult stem cells), gametes or
embryos:
No 
Yes, and requires CHR and GESCR review 
Yes, and requires GESCR review, but NOT CHR review 
4.16  * FINANCIAL INTERESTS: (REQUIRED)
Do you or any other responsible personnel (or the spouse, registered domestic partner and/or
dependent children thereof) have financial interests related to this study:
 Yes   
 No
The Conflict of Interest Advisory Committee (COIAC) office may contact
you for additional information.
5.0
Funding
5.1  * FEDERAL FUNDING: (REQUIRED)
Is this study currently supported in whole or in part by Federal funding, even by a subcontract, OR
has it received ANY Federal funding in the past:
  Yes   
  No
5.2  * DoD INVOLVEMENT: Is this project linked in any way to the Department of Defense (DoD):
(REQUIRED)
  Yes   
  No
5.3  SPONSORS:
Identify all sponsors and provide the funding details. If funding comes from a Subcontract, please
list only the Prime Sponsor:
Study Protocol Page 54 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 7 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
External Sponsors:
 
 
View
Details
Sponsor Name
Sponsor Type
Awardee
Institution
Contract
Type:
UCSF RAS
"P
number"
or
eProposal
number 
UCSF
RAS
System
Award
Number
("A" +
6
digits) 
CALIF Governors Ofc of
Planning & Resrch 
02 
UCSF 
Grant 
P0509948  
Sponsor Name:
CALIF Governors Ofc of Planning & Resrch 
Sponsor Type:
02 
Sponsor Role:
Funding
Grant/Contract Number:
P0509948 
Awardee Institution:
UCSF 
Is Institution the Primary Grant
Holder:
Yes 
Contract Type:
Grant 
UCSF RAS "P number" or
eProposal number:
P0509948 
UCSF RAS System Award Number
("A" + 6 digits):
 
Grant Number for Studies Not
Funded thru UCSF:
 
Grant Title:
Clinical Implementation of Metagenomic Next-Generation
Sequencing for Precision Diagnosis of Acute Infectious Diseases 
PI Name:
(If PI is not the same as identified
on the study.)
Charles Y Chiu 
Significant Discrepancy:
 
If the funding is coming through UCSF and you don't know the
A or P number,  you can search the eProposal side for the
contract or grant (this does NOT replace adding the sponsor by
name above AND entering the A or P number):
Project Status
Proposal Number
Project Title
Principal Investigator
Submitted to Sponsor
P0509948
CIAPM Full Proposal
Charles Y Chiu MD
Clinical implementation of metagenomic next-
generation sequencing for precision diagnosis of
acute infectious diseases
ChiuC New NSF
BIGDATA 22Mar201 ...
Charles Y Chiu MD
Study Protocol Page 55 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 8 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Submitted to Sponsor
P0522592
BIGDATA: IA: Collaborative Research: Patient
Data-Driven Machine 
Learning for Diagnosis of Infectious Diseases
Submitted to Sponsor
P0526430
Dr. Gu_new K08_due
10/12/2017_ ...
Wei Gu, MD/PhD
Noninvasive Risk Stratification of Prostate Cancer
Using Cell-Free Nucleic Acids
Other Funding Sources and Unfunded Research - Gift,
Program, or Internal Funding (check all that apply):
Funded by gift (specify source below)
Funded by UCSF or UC-wide program (specify source below)
Specific departmental funding (specify source below)
Unfunded (miscellaneous departmental funding)
Unfunded student project
* List the gift, program, or departmental funding source: (REQUIRED)
Sandler-Bowes Foundation Award, UCSF Clinical Laboratory
6.0
Sites, Programs, Resources, and External IRB Review
6.1  UCSF AND AFFILIATED SITES (check all that apply):
UCSF (including Laurel Heights and all the other sites outside the main hospitals)
Parnassus
Mission Bay
China Basin
Mount Zion
Helen Diller Family Comprehensive Cancer Center
Langley Porter Psychiatric Institute
San Francisco General Hospital (SFGH)
SF VA Medical Center (SF VAMC)
Blood Centers of the Pacific (BCP)
Blood Systems Research Institute (BSRI)
Fresno Community Medical Center
Gallo
Gladstone
Jewish Home
Institute on Aging (IOA)
SF Dept of Public Health (DPH)
Research involving SFGH: You are required to obtain additional approvals
from the SFGH Dean's Office. Download the SFGH Protocol Application
Form and submit the completed form to the SFGH Dean's Office.
Study Protocol Page 56 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 9 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
6.2  LOCATIONS: At what locations will study visits and activities occur:
UCSF/Clinical Microbiology Laboratory
185 Berry Street, Suite #290
San Francisco, CA  94107
 
UCSF/Chiu Lab
185 Berry Street, China Basin 185
San Francisco, CA 94107
 
UCSF/DeRisi Lab
1700 4th Street
QB3 Room BH 401
San Francisco, CA 94158
 
UCSF/Pleasure Lab
Department of Neurology
675 Nelson Rising Lane, Room 260-270
San Francisco, CA 94158
 
UCSF/Oksenberg Lab
Department of Neurology
675 Nelson Rising Lane, Room 240-242
San Francisco, CA 94158
 
UCSF/ Center for Advanced Technology
Genentech Hall, Second floor, room S252
600 16th St.
San Francisco, CA 94158
 
UCLA Medical Center
 
UCD Medical Center
 
6.3  OFF-SITE PROCEDURES: Will any study procedures or tests be conducted off-site by non-UCSF
personnel:
 Yes   
 No
Please identify which procedures may be done off-site:
UC Davis and UCLA Medical Centers will serve as a major patient recruitment sites for the DAID study
outside of UCSF. UCD, UCLA, UCSD as well as all other clinical outside sites will be identifying eligible
patients and once consented, collecting patient clinical data and biospecimens relevant to the study. All
biospecimens will be shipped to UCSF and relevant clinical data will be uploaded into a RedCap project
maintained by the UCSF coordinating team and relying sites for their respective research candidates.
6.4  RESEARCH PROGRAMS:
Check any UCSF research programs this study is associated with:
Cancer Center
Center for AIDS Prevention Sciences (CAPS)
Global Health Sciences
Study Protocol Page 57 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 10 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Immune Tolerance Network (ITN)
Neurosciences Clinical Research Unit (NCRU)
Osher Center
Positive Health Program
6.5  * CTSI CRS SERVICES: (REQUIRED)
Will this study be carried out at one of the UCSF Clinical Research Services (CRS) units or utilize CRS
services:
  Yes   
  No
6.6  * MULTI-CENTER TRIAL: (REQUIRED)
Is this a multicenter research trial? By multi-center trial, we mean a study where the protocol is
developed by an industry sponsor, consortium, a disease-group, etc., who then selects sites across
the nation or in different countries to participate in the trial. The local sites do not have any control
over the design of the protocol. 
 Yes   
 No
Is UCSF the coordinating center:
 Yes   
 No
6.7  OTHER SITE TYPES: Check all the other types of sites not affiliated with UCSF with which you are
cooperating or collaborating on this project:
 
Do NOT check any boxes below if this is a multi-center clinical trial, UCSF is
just one of the sites, and neither UCSF nor its affiliates are the coordinating
center.
Other UC Campus
Other institution
Other community-based site
Foreign Country
Sovereign Native American nation (e.g. Navajo Nation, Oglala Sioux Tribe, Havasupai, etc.)
6.8  OTHER UC COLLABORATORS: Check any other UC campuses with which you are collaborating on this
research study:
UC Berkeley
UC Davis
Lawrence Berkeley National Laboratory (LBNL)
UC Irvine
UC Los Angeles
UC Merced
Study Protocol Page 58 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 11 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
UC Riverside
UC San Diego
UC Santa Barbara
UC Santa Cruz
6.10  * RELYING ON AN EXTERNAL IRB: Does this application include a request to rely on an a
central IRB (other than the NCI CIRB) or an external IRB (UC, commercial, or institutional):
(REQUIRED)
  Yes   
  No
6.11  UC RELIANCES: Are any of the above UC campuses requesting to rely on UCSF's IRB:
Yes
No
7.0
Outside Site Information
7.1  Outside Site Information
Click "Add a new row" to enter information for a site. Click it again to add a second site again to add a
third site, a fourth site, etc.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
University of California, Los Angeles
Contact name:
Dr. Jeffrey Klausner
Email:
JDKlausner@mednet.ucla.edu
Phone:
415 876 8901
Study Protocol Page 59 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 12 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
 Yes   
 No
If not, do NOT submit your application until after the other site has completed
this step.
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
UC Reliance Registry Application #1595
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Note: your application cannot be processed without the training
certificates.
Study Protocol Page 60 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 13 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
University of California, Davis
Contact name:
Dr. Christopher Polage
Email:
crpolage@ucdavis.edu
Phone:
(916) 734-3655
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
 Yes   
 No
If not, do NOT submit your application until after the other site has completed
this step.
Study Protocol Page 61 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 14 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
UC Reliance Registry #1595
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Note: your application cannot be processed without the training
certificates.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Syapse
Contact name:
Adam Jonas
Email:
adamj@syapse.com
Phone:
608.320.1042
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
Study Protocol Page 62 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 15 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
 Yes   
 No
If not, do NOT submit your application until after the other site has completed
this step.
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
Andi Barsan
Andrew Fisher
Maylee Wu
Preeti Bhat
Taylor Horwood
Tom Lemberg
Adam Jonas
Sonny Van
Stephen Mitchell
Syapse team is responsible for 1) facilitating the reporting of
metagenomic NGS data, 2) correlating clinical data extracted from the
Electronic Medical Record, alongside mNGS data from research samples
in a easily searchable database. In addition, Syapse provides the
software platform to enable the Precision Medicine Consult service; where
subject matter experts can offer clinical guidance to providers, in the
context of mNGS and other clinical information.
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Study Protocol Page 63 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 16 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Note: your application cannot be processed without the training
certificates.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
UC Berkeley
Contact name:
Brent Fulton
Email:
fultonb@berkeley.edu
Phone:
510-643-4102
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
Study Protocol Page 64 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 17 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
 Yes   
 No
If not, do NOT submit your application until after the other site has completed
this step.
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
Brent Fulton, PhD, MBA
 
Analysis of cost data for patients enrolled study (may have identifiers) 
Oversee analysis of de-identified cost data (Truven data set) 
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Note: your application cannot be processed without the training
certificates.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Children's National Medical Center
Contact name:
Roberta DeBiasi
Email:
RDebiasi@childrensnational.org
Phone:
Study Protocol Page 65 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 18 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
 Yes   
 No
If not, do NOT submit your application until after the other site has completed
this step.
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
Maggie Ryan
Patient recruitment and consent
Data entry
Clincian engagement
Roberta DeBiasi, MD
Local patient recruitment / enrollment / consenting
Collect clinical data from local medical records
Coordinate specimen handling and shipping to UCSF for processing
Participate in weekly Clinical Microbial Sequencing Board to discuss
clincal data from mNGS assay
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Study Protocol Page 66 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 19 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Note: your application cannot be processed without the training
certificates.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Children's Hospital Los Angeles
Contact name:
Jeffrey M. Bender, MD
Email:
jbender@chla.usc.edu
Phone:
323-361-2509
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Study Protocol Page 67 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 20 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Milliman
Contact name:
Susan Pantely
Email:
susan.pantely@milliman.com
Phone:
415-394-3756
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Study Protocol Page 68 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 21 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
St. Jude Children's Research Hospital, Inc.
Contact name:
Randall T. Hayden, M.D.
Email:
randall.hayden@stjude.org
Phone:
901-595-3525
For Federally-funded studies only, corresponding FWA#:
00000068
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
Request for UCSF to Serve As the IRB of Record
The non-affiliated site has reviewed UCSF's guidance "When UCSF Can Serve as
IRB of Record" and made an initial determination that UCSF's IRB can serve as
the IRB of record:
 Yes   
 No
If not, do NOT submit your application until after the other site has completed
this step.
List the collaborators and describe the scope of work that will be carried out at
the non-affiliated site:
Kim Allison, BSN, RN : Manager, Clinical Research Operations
Ronald Dallas, PhD : Clinical Research Scientist
Victoria Darling, BS : Clinical Research Assistant 
Randall Hayden, MD : Member, St. Jude Faculty; Director of Clinical & Molecular
Microbiology 
Study Protocol Page 69 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 22 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Gabriela Maron, MD, MS : Assistant Member, St. Jude Faculty
Naomi Ragsdale, BSN, RN : Clinical Research Associate
Tracey Stewart, BSN, RN : Director, Clinical Trials Management
Lauren Stronski, BSN, RN : Clinical Research Associate
Jennifer Vest, BSN, RN : Clinical Research Associate 
 
Scope of work: the team at St. Jude will screen inpatients and submit referrals
for this demonstration project. If inclusion criteria is met, the St. Jude's team
will consent patients and families and send specimens to UCSF for processing.
They will also be responsible for clinical data collection and input into the UCSF
RedCap database. Furthermore, the clinicians and treating teams of patients
included in this study will participate in weekly Clinical Microbial Sequencing
Board discussions. 
A letter from the non-affiliated site deferring IRB approval to the UCSF IRB is
attached:
 Yes   
 No
Note: your application cannot be processed without this letter.
Collaborators' training certificates for Human Subjects Training Course are
attached:
 Yes   
 No
Note: your application cannot be processed without the training
certificates.
Click here to view this form.
 
Outside Site Information
Non-UCSF affiliated site information:
Site name:
Children's Hospital Colorado
Contact name:
Kevin Messacar, MD
Email:
Kevin.Messacar@childrenscolorado.org
Phone:
(720) 777-6627
Study Protocol Page 70 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 23 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
For Federally-funded studies only, corresponding FWA#:
* The research at this site will be reviewed by:
The non-affiliated site's IRB or a private IRB 
The non-affiliated site is requesting UCSF to be the IRB of record for this
study 
The non-affiliated site is not engaged in the human subjects research and
has provided a letter of support 
If the other site's IRB approval letter is available now, attach it to the
application.  If the IRB approval letter is not yet available, submit it once you
receive it. 
Or, if the other site is not engaged in human subjects research, attach the
letter of support to your application.
8.0
Research Plan and Procedures
8.1  This new consolidated section requests information about:
Hypothesis
Aims
Study Design
Background and Significance
Preliminary Studies
Procedures
Statistical Methods
References
Later sections include:
Drugs and Devices
Sample Size, Eligibility, and Subjects
Recruitment and Consent
Risks and Benefits
Data and Safety Monitoring Plan
Confidentiality, Privacy and Security
Financial Considerations
Qualifications of Personnel
Other Approval and Registrations
8.2  HYPOTHESIS: Describe the hypothesis or what the study hopes to prove (Help Text updated 9/13):
We hypothesize that many clinical illnesses in the hospital (meningitis, encephalitis, sepsis, and
pneumonia) are caused by infectious agents but remain undiagnosed because current laboratory testing
lacks sensitivity and scope. Furthermore, we hypothesize clinical implementation of an mNGS assay in a
Study Protocol Page 71 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 24 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
licensed diagnostic laboratory (the UCSF Clinical Microbiology Laboratory) during the duration of the
demonstration project will result in more rapid and accurate diagnoses, decreased costs, and improved
clinical outcomes.
8.3  AIMS: List the specific aims:
This study is a prospective, multi-institutional study with the following specific aims post secimen
validation:
1. Compare the diagnostic yield of a newly clinically validated metagenomic next-generation
sequencing (mNGS) assay to standard microbiologic testing in 300 consented and enrolled
patients presenting with (1) acute meningitis and/or encephalitis, (2) sepsis, or (3) pneumonia at
4 hospitals in California and 1 in Washington, DC.
2. To collect clinical specimens for mNGS testing in a licensed diagnostic laboratory and excess
specimens or blood for orthogonal laboratory testing and/or research from patients with the
aforementioned illnesses.
3. To interpret clinical mNGS results in the context of a precision medicine board and clinical
interface
4. To evaluate impact of the mNGS assay on costs and clinical outcomes
8.4  DESIGN: Briefly describe the study design (e.g., observational, interventional, randomized, placebo-
controlled, blinded, cross-over, cross-sectional, longitudinal, pharmacokinetic, etc.):
 
This is a 1-year prospective cohort study which will enroll 300 patients at 5+ hospitals with encephalitis,
meningitis, sepsis, or pneumonia.  Patients will be enrolled if the clinical mNGS assay correpsonding to
the appropriate sample type -- cerebrospinal fluid (CSF) for encephalitis / meningitis (launched 6/2016),
plasma for sepsis (anticipated 6/2017), and bronchoalveolar lavage (BAL) fluid for pneumonia
(anticipated 12/2017) --- has been validated in the CLIA laboratory (the UCSF Clinical Microbiology
Laboratory). Accordingly, we anticipate that the majority of patients enrolled in the study will be
encephalitis and meningitis patients.  Patients will be consented for (1) clinical mNGS testing and review
of their electronic medical record (clinical, laboratory, and radiological data) and publication of their case
histories and (2) collection of blood and additional clinical samples that have not been validated for
clincial mNGS testing (e.g. brain biopsy) for the purpose of orthogonal clinical testing to confirm mNGS
results and biobanking to facilitate research on additional novel assay development (e.g. autoantibody
and host gene transcriptome profiling).  If additional clinical samples are to be used only for research
purposes and not for orthogonal clinical testing, then only available excess / surplus sample will be
collected.  As the research on transcriptome profiling will involve deposition of deidentified genetic data
into public databases, patients will be explicitly consented for release of their deidentified genetic
information.
 
After clinical mNGS testing is performed and results communicated to the patient and clinical provider, a
"precision medicine board" consisting of clinicians, laboratory directors, and research investigators will be
available to interpret mNGS results and recommend further diagnostic testing, management, and
treatment.  This board for infectious diseases is analogous to the tumor board in oncology. Members from
the treating team will be invited to paricipate in a voluntary survey both pre and post mNGS results being
reported. See survey in 'Other Study Documents'. We will also extract data from the electronic medical
record and evaluate the impact of the mNGS assay on costs and clinical outcomes as compared to a
subset of historical controls obtained by retrospective chart review of similar cases in the past for which
the mNGS assay was not available.
 
8.5  BACKGROUND AND SIGNIFICANCE: Briefly provide the background and significance of this study
(e.g. why is this study needed) (space limit: one half page):
If this is a first in humans study, please summarize the safety data from the
animal studies. For pediatric drug or device studies, please identify if this is the
first study in pediatric populations.  
Study Protocol Page 72 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 25 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
We aim to provide the first-ever demonstration of precision medicine for diagnosis of acute infectious
diseases in hospitalized patients, with the goal of directly impacting clinical care and improving patient
outcomes.  Existing methods fail to diagnose many life-threatening infections in a clinically relevant
timeframe, resulting in excessive health care costs and unnecessary morbidity and mortality.
 
Failure to obtain a laboratory-confirmed diagnosis for many acute infectious diseases directly contributes
to poor patient outcomes and a high cost burden to the health care system. Key areas of unmet clinical
need targeted by this proposal include neurological infections (encephalitis and meningitis), pneumonia,
and sepsis. The principal advantage of this approach is the ability to detect all viruses, bacteria, fungi,
and parasites in a single, standardized universal test, the clinically validated mNGS assay, directly from
diverse sample types such as cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL), and plasma. This
approach is comprehensive because all pathogens with the exception of prions are based on nucleic acid
(DNA/RNA).  Thus, a single shotgun sequencing test is able to simultaneously screen nearly all pathogens
directly from clinical samples, bypassing the "one bug, one test" traditional paradigm of infectious disease
diagnosis and maximizing the potential impact on patients with acute, life-threatening infections, where
time is of the essence.
 
Currently, up to 50% of hospitalized patients with pneumonia, sepsis, and encephalitis / meningitis are
treated empirically without a confirmed etiologic diagnosis, resulting in delayed or ineffective treatments,
increased mortality, and excess healthcare costs. For encephalitis, the annual disease burden in the U.S.
exceeds 20,000 hospitalizations with a high rate of long-term sequelae and mortality and $2.0 billion cost
to the healthcare system. Pneumonia and sepsis are associated with >43,000 avoidable deaths, 2.3
million excess patient days, and $8.1 billion in added costs each year. Metagenomic NGS, by providing a
more timely diagnosis in infected patients and the ability to "rule-out" infectious etiologies in patients
with non-infectious illness, has the potential to significantly reduce healthcare costs by decreasing
hospital lengths of stay and eliminating unnecessary treatments, procedures, and testing. Our NGS assay
also aligns perfectly with the Centers for Disease Control and Prevention (CDC) and President's Obama's
National Action Plan to Combat Antibiotic-Resistant Bacteria by enabling an early, specific diagnosis that
may obviate the need for empiric antibiotics and inform targeted, appropriate treatment, with the
potential to ultimately decrease antibiotic resistance in hospitals.
 
8.6  PRELIMINARY STUDIES: Briefly summarize any preliminary studies relevant to your proposed
research (space limit: one half page):
At UCSF, we have pioneered the use of unbiased metagenomic next-generation sequencing (mNGS) for
detection of all potential pathogens in a single assay, and have demonstrated its utility in saving the life
of a critically ill 14-year old boy with previously unrecognized neuroleptospirosis in a case report
published in the New England Journal of Medicine. We have further demonstrated the value of our mNGS
assay by identifying clinically significant pathogens in over 1,000 patients with severe, undiagnosed
pulmonary, blood and neurological infections.  We have also previously developed an automated sample-
to-answer pathogen identification pipeline named SURPI ("Sequence-based Ultra-Rapid Pathogen
Identification") to accelerate the speed of the bioinformatics analysis and ensure that NGS results will be
available in a fast enough time frame to impact patient care.
8.7  * TREATMENT PROTOCOL: Is this a treatment study, i.e. does this study intend to provide treatment
to individuals with a medical or psychological condition: (REQUIRED)
  Yes   
  No
8.8  * COMMON RESEARCH ACTIVITIES: Types of research activities that will be carried out. Check all
that apply and describe in more detail in the 'Procedures / Methods' section: (REQUIRED)
Interviews, questionnaires, surveys
Educational or cognitive tests
Focus groups
Observation
Study Protocol Page 73 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 26 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Non-invasive imaging or testing (MRI, EEG, pulse oximetry, etc.)
Administration of contrast agent
Imaging procedures or treatment procedures that involve radiation (x-rays, CT scans, CT-guided
biopsies, DEXA scans, MUGA or PET scan)
Biopsy conducted solely for research purposes
Use of placebo
Sham surgical procedure
Collection of data from wearable tech such as Fitbit, Apple Watch, Garmin, motion actigraphs, etc.)
Fitness tests or other exertion activities
Use of mobile health apps or other apps
Social media-based research activities
None of the above
8.9  * PROCEDURES / METHODS: (REQUIRED)
For clinical research, list all study procedures, tests and treatments
required for this study, including when and how often they will be
performed. If there are no clinical procedures, describe the research
activities.
 
If some of the activities would occur even if the person were not in the
study, as in the case of treatment or tests performed for diagnostic
purposes, clearly differentiate between those activities that will be
done solely for research purposes and those that are happening as part
of routine care.
 
Examples may include:
additional scans outside standard clinical diagnosis or monitoring
additional biopsies to collect tissue for research
extra clinic visits
extra lab tests not required for clinical care
If you have a procedure table, attach it to the submission with your other
study documents.
The investigators will seek to identify and enroll patients with a clinical syndrome that may have an acute
infectious etiology. Consent will follow procedures outlined under application section for recruitment and
consent.
 
The study investigators or site coordinator will review the medical record and abstract clinical, laboratory,
and radiographic data.
 
A RedCap survey will be used to collect basic demographic information, exposure/travel history, and
clinical information such as imaging results, labs, treatment history and clinical phenotype. The patient
may be asked directly by the study investigator or site coordinator to provide exposure/travel history,
however, most data will be obtained by reviewing the medical record.
 
All patients will have had the validated mNGS assay ordered clinically by a provider and the appropriate
sample (CSF, plasma, or BAL fluid) collected or added onto an existing collection for clinical testing at
Study Protocol Page 74 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 27 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
UCSF. Specimens will be shipped and processed at UCSF.
 
An additional sample (e.g. biopsy sample) that has not been clinically validated for mNGS testing may
also be collected for orthogonal diagnostic testing to confirm mNGS results and/or for research purposes.
Specimens must be excess / surplus sample to be used for research. Specimens will be shipped to UCSF.
 
A tissue bank will be established at UCSF for future research.
 
Research candidates will be asked to consent for collection of a venous blood sample of up to 30 ml or 1-
3 tubes. Blood collected will be processed to isolate peripheral blood mononuclear cells (PBMCs) and
serum for (1) orthogonal clinical validation of the mNGS assay, and/or (2) research analysis.
 
Blood draws will only be performed on patients who consent and who are 13 years and older. Blood
collections may be done on patients who are younger than 13, but only by adding 1-2 tubes to an already
scheduled blood draw, thus avoiding venipuncture solely for the research collection.
 
Subjects will also be consented to be re-contacted to provide short and longer-term follow-up to confirm
final diagnosis and outcome.
 
Sub-study: Plasma Validation for Patients with Sepsis
Plasma specimens from blood culture-positive patients are needed for validation of the mNGS assay for
pathogen detection from plasma in the CLIA-certified clinical laboratory.  A sub-study, limited in duration,
will be implemented at UCSF for specimen acquisition.
 
Specimens will be collected in coordination with the staff on the adult intensive care units at at 9ICU and
13ICU as well as the Adult Acute Care Unit on 15L. One tube of blood (4 – 10 mL) will be collected at the
time that blood cultures are ordered and sent as part of a workup for sepsis. This battery of tests and
work-up is sometimes completed prior to transfer to the 9 or 13 adult ICU (i.e. in the emergency
department) or will be initiated in the ED or the Adult Acute Care unit on 15L.
 
Plasma specimens will be transferred on ice to the Clinical Microbiology Laboratory at China Basin,
aliquoted by certified personnel, and frozen for validation studies. Within one week of the blood collection
occurring, an informational letter will be mailed to the address available in Apex. By default, patients will
be included in the study. If the patient or their family requests to be withdrawn, the sample held in the
Clinical Microbiology Laboratory at China Basin will be discarded and their research records will be
updated to reflect this. 
 
Sub-cohort of the validation cohort for plasma validation (sepsis):
In addition to the above mentioned cohort of patients who will be recruited to accrue validation plasma
samples, there will be a smaller number of cases from whom there will be interest to obtain remnant
specimens from the clinical lab (i.e. biopsy tissue, blood, other bodily fluid) in addition to an optional
blood draw for comparative study. These patients will be identified by either direct physician referral or by
working with the Microbiology/Pathology departments to identify tissue and/or bodily fluid from patients
of interest (i.e. culture positive abscess fluid). These patients will be approached for informed consent
and may be on units outside of the above mentioned units. Consent will be coordinated with permission
from the treatment team before approaching potential research candidates. 
8.11  INSTRUMENTS: List all questionnaires, surveys, interview, or focus group guides that will be used
for this study:
Given that many patients will be severely ill, we will utilize the standardized form, Capacity Assessment
Record for Research Informed Consent, to insure that subject capacity is assessed in a systematic
manner.
 
Patients will be requested to participate in a short questionnaire. This questionnaire will be administered
verbally at the time of consent and completed by either the patient or surrogate. This is a RedCap
questionnaire entitled 'Clinical Case History'. The patient will only be requested to provide information for
the following sections: patient information, exposures 1 month before onset, and travel 1 year before
onset. The patient or surrogate will not see the remaining sections of the survey. The treating physician
will be requested to complete the remainder of the survey. The information to be completed by the
treating physician will have already been gathered as part of the patient's routine work-up.
 
Providers will be requested for feedback before and after mNGS for pathogen detection results are
reported. Providers caring for the research participant will be identified through Apex and emailed and
Study Protocol Page 75 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 28 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
invitation to participate. Participation is not required, but encouraged. Once mNGS results are posted, a
second survey is sent to the same providers and any new treating team members identified by reviewing
the care team in Apex. 
Attach any unpublished instruments in the 'Other Study Documents'
section of the Initial Review Submission Packet form after completing the
study application. Published instruments should NOT be attached.
8.12  * BIOSPECIMEN COLLECTION: Are you drawing any blood or collecting other biosamples (e.g.
tissue, buccal swabs, urine, saliva, hair, etc.): (REQUIRED)
 Yes   
 No
* Could this study generate genetic data that may be broadly shared (e.g., submitted to
NIH in compliance with Genomic Data Sharing (GDS)/Genome-Wide Association
Studies (GWAS) requirements): (REQUIRED)
 Yes   
 No
Please make sure your consent form includes the recommended genomic
data sharing language. 
8.13  * TYPE OF SPECIMENS (check all that apply): (REQUIRED)
Blood
Tissue (describe below):
Existing/archival materials (name source below): ​
Other (describe below):
Describe and/or name source:
clinical mNGS testing at the UCSF Clinical Microbiology Laboratory: cerebrospinal fluid, plasma,
bronchoalveolar lavage fluid
 
blood draw: blood for PBMCs and serum/plasma
 
additional specimen types for orthogonal clinical validation or research (surplus): biopsy tissue, nasal
swabs, cyst / abscess fluid
 
8.14  * SPECIMENS ARE: (check all that apply): (REQUIRED)
Leftover specimens from a clinical diagnostic or therapeutic procedure
Specimens collected for research purposes only (including extra samples taken during a clinical
procedure)
Other
8.15  * DESTINATION: Specimens will ultimately be stored (check all that apply): (REQUIRED)
Outside Entity:
Study Protocol Page 76 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 29 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Cooperative group bank
NIH
Other university
Industry sponsor
Other
UCSF:
UCSF repository/bank being established under this protocol
Existing UCSF specimen repository/bank with CHR approval
Other location at UCSF (please describe)
Provide the name of the bank and iRIS approval number (if not being banked at
UCSF under this protocol). If you checked 'Other,' please provide the location or
lab:
Chiu Laboratory Biobank:
H9187-32565-02 Chiu, Charles Y MD 
Pathogen Detection and Discovery in Hospitalized Patients with Unexplained Acute or Chronic Illness
Clinical Microbiology Laboratory Biobank:
H52699-34941-01 Miller, Steven A 
Improved diagnosis of infectious meningitis / encephalitis using multiplex molecular methods
H52699-35006-01 Miller, Steven A 
Identification and characterization of infectious causes for respiratory infection
8.16  UCSF-BANK PHYSICAL LOCATION: The repository/bank is physically located at (list the address and
room number for all locations):
1. UCSF Clinical Microbiology Laboratory (Directors: Steve Miller and Charles Chiu), 185 Berry Street,
Suite 290, San Francisco, CA 94107
1. Chiu Lab, 185 Berry Street, Room 185, San Francisco, CA 94107
2.DeRisi Lab, 1700 4th Street, QB3 Room BH 401, San Francisco, CA 94158
3. Pleasure Lab, 675 Nelson Rising Ln. Room 260, San Francisco, CA 94158
8.18  * FUTURE SPECIMEN USE: Will any specimens or portions of specimens be retained after the study
is over for possible use in future research studies: (REQUIRED)
 Yes   
 No
8.19  * SPECIMEN BANKING - CONSENT METHOD: Consent for retaining specimens for future research
studies will be obtained via (check all that apply): (REQUIRED)
Specimen section within a main research study consent form
Separate specimen consent form
UCSF surgical consent form with tissue donation brochure
Study Protocol Page 77 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 30 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
8.20  * CLINICAL FOLLOW-UP DATA: Will clinical follow-up data be linked to specimens (i.e., will medical
record information continue to be abstracted after the specimen is collected): (REQUIRED)
 Yes   
 No
Provide duration of follow-up or 'indefinitely':
indefinitely
8.21  * UCSF-BANKED SPECIMENS - LINKING OF IDENTIFIERS: (REQUIRED)
Samples are completely de-identified before being added to the bank/repository. There is no way to
link the specimens back to the subjects.
Samples are coded and researchers are able to link the specimens to specific subjects.
Samples are stored with direct identifiers in the repository.
Explain under what circumstances identifiers may be released with specimens or
say none if identifiers will NEVER be released with specimens:
none. Only researchers directly involved in this study will have access to identifiers.
8.22  UCSF-BANKED SPECIMENS – IDENTIFIERS: List the identifiers that will be collected, stored, or
linked with the specimens:
Name
Date of birth
Social Security number
Medical record number
Address
Phone number
Email address
Other dates (dates of surgery, visit dates)
8.23  DISTRIBUTION: Specimens banked at UCSF may be made available to (check all that apply):
UCSF researchers
Non-UCSF researchers
Industry
None of the above - specimens will be retained and used within our own research program
8.24  UTILIZATION REVIEW: Is there a formal utilization review process for distribution of specimens:
  Yes   
  No
8.25  STATISTICAL METHODS: Briefly summarize the methods and types of analyses that will be
performed:
Study Protocol Page 78 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 31 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
The UCSF Clinical Microbiology Laboratory will process the clinical sample under validated standardized
operating procedures.  Bioinformatics analysis will be performed using the SURPI pipeline (Naccache, et
al., 2014).  We will also occasionally need to perform orthogonal clinical testing (serological, PCR testing)
or research polymerase chain reaction (PCR) testing for confirmation of results. Orthogonal testing will be
performed to confirm positive mNGS results or by recommendations from the Clinical Microbial
Sequencing Board. All data will be deidentified prior to submission and submitted to dbGaP (database of
Genotypes and Phenotypes), an NIH database which archives deidentified data beyond a controlled-
access firewall and makes such data only accessible to a limited number of investigators (see
http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap).
 
For the additional excess clinical samples used for research for the purposes of new assay development,
we will perform additional analyses including autoantibody profiling, human transcriptome profiling, and
probe-based sequencing enrichment.
8.26  REFERENCES: List only the 5-10 most relevant references (a separate bibliography can be attached
for reference purposes if this study involves novel approaches, agents, or an emerging technology
that the IRB may not be familiar with):
Goldberg B, Sichtig H, Geyer C, Ledeboer N, and Weinstock GM. (2015) Making the leap from
research laboratory to clinic: challenges and opportunities for next-generation sequencing in
infectious disease diagnostics. mBio 6(6):e01888-15.
Naccache SN, Federman S, Veeraraghavan N, Zaharia M, Lee D, Samayoa E, Bouquet J, Greninger
AL, Luk, KC, Enge B, Wadford DA, Messenger SL, Genrich GL, Pellegrino K, Grard G, Leroy E,
Schneider BS, Fair JN, Martinez MA, Isa P, Crump JA, DeRisi JL, Sittler T, Hackett, Jr. J, Miller S,
and Chiu CY. (2014) A cloud-compatible bioinformatics pipeline for ultra-rapid pathogen
identification from next-generation sequencing of clinical samples. Genome Research 24(7):1180-
9. (PMCID: PMC4079973).
Wilson MR, Naccache SN, Samayoa E, Biagtan M, Bashir H, Yu G, Salamat SM, Somasekar S,
Federman S, Miller S, Sokolic R, Garabedian E, CAndotti F, Buckley RH, Reed KD, Meyer TL,
Seroogy CM, Galloway R, Henderson SL, Gern JE, DeRisi JL, and Chiu CY. (2014) Actionable
diagnosis of neuroleptospirosis by next-generation sequencing. New England Journal of Medicine
370:2408-2017. (PMCID: PMC4134948).
Greninger AL, Naccache SN, Messacar K, Clayton A, Yu G, Somasekar S., Federman S, Stryke D,
Anderson C, Yagi S, Messenger S, Wadford D, Xia D, Watt JP, Van Haren K, Dominguez SR, Glaser
C, Aldrovandi G, and Chiu CY. (2015) A novel outbreak enterovirus D68 strain associated with
acute flaccid myelitis cases in the United States from 2012-2014: a retrospective cohort study.
Lancet Infectious Diseases S1473-3099(15)70093-93. E-pub ahead of print.
Naccache SN, Peggs KS, Mattes FM, Phadke R, Garson JA, Grant P, Samayoa E, Federman S, Miller
S, Lunn MP, Gant V, and Chiu CY. (2015) Diagnosis of neuroinvasive astrovirus infection in an
immunocompromised adult with encephalitis by unbiased next-generation sequencing. Clinical
Infectious Diseases 60(6):919-23. (PMCID: PMC4345816).
9.0
Drugs and Devices
9.1  * DRUGS AND/OR BIOLOGICS: Are you STUDYING any drugs and/or biologics that are either
approved or unapproved: (REQUIRED)
  Yes   
  No
Note: This question is frequently answered incorrectly. If any drugs or
biologics, approved or unapproved, are being administered under this
protocol, you should check 'Yes' unless you are absolutely sure that
NONE of the drugs are part of the research protocol. Tip: Ask the PI or
the sponsor if you are not sure how to answer this question.
Study Protocol Page 79 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 32 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
9.3  * MEDICAL DEVICES: Are you STUDYING any medical devices, in vitro diagnostics, or assays that are
either approved or unapproved:(REQUIRED)
 Yes   
 No
9.4  * NSR: Are you requesting a Non-Significant Risk (NSR) determination for an investigational
device: (REQUIRED)
 
Note: an NSR determination is different from an Investigational Device Exemption (IDE). Check the
Help link for more guidance on what types of devices can qualify for an NSR determination.
 Yes   
 No
* Explain why the use of the device in this study poses a non-significant
risk: (REQUIRED)
The$metagenomic$Next/Gen$Sequencing$(mNGS)$assay$for$pathogen$detec<on$$was$validated$for$clinical
use$as$a$laboratory/developed$(LDT)$test$in$the$CLIA/cer<ﬁed$UCSF$Clinical$Microbiology$Laboratory.$
Valida<on$studies$demonstrated$that$the$test$has$acceptable$performance$characteris<cs$for$use$in
pa<ent$diagnosis.$$These$studies$included$evalua<on$of$assay$sensi<vity,$speciﬁcity,$precision,$accuracy,
stability$and$interference.$$Accuracy$was$compared$to$a$composite$clinical$reference$standard$consis<ng
of$all$microbiologic$and$serologic$tes<ng$performed$on$the$cerebrospinal$samples.$$Because$not$all
samples$had$the$appropriate$conven<onal$tes<ng$done$to$be$able$to$conﬁrm$or$refute$mNGS$ﬁndings,
addi<onal$discrepancy$tes<ng$was$performed$as$needed.$$ANer$discrepancy$tes<ng,$the$performance$of
acceptable$samples$yielded$an$overall$sensi<vity$of$86.1%$and$speciﬁcity$of$97.9%.$$Due$to$the$diﬃculty
in$making$an$e<ologic$diagnosis$in$many$cases$of$meningi<s$/$encephali<s,$a$test$sensi<vity$of$80/90%
with$speciﬁcity$>95%$is$very$useful$in$pa<ent$management$decisions.
 
Over$the$course$of$the$Precision$Diagnosis$of$Acute$Infec<ous$Diseases$demonstra<on$project,,$each
case$is$discussed$with$a$team$of$leading$experts$in$neurology,$infec<ous$disease$and$microbiology
(CMSB,$“clinical$microbial$sequencing$board”).$$The$mNGS$ﬁndings$are$put$into$clinical$context,$and
appropriate$treatment$and$management$decisions$are$recommended$to$trea<ng$physicians.$$This$helps
to$ensure$that$proper$management$decisions$are$made$and$that$the$assay$results$are$interpreted
according$to$the$clinical$context,$thus$mi<ga<ng$risk$that$may$be$associated$with$diagnos<cs$provided
outside$of$the$healthcare$system$associated$with$the$pa<ent.
 
During$the$demonstra<on$project,$posi<ve$ﬁndings$by$mNGS$are$evaluated$using$orthogonal$tes<ng
(clinical$tes<ng$is$preferred$if$available,$or$research/based$PCR$conﬁrmatory$tes<ng)$to$assess$the
possibility$of$false/posi<ve$results.$However,$as$this$assay$u<lizes$signiﬁcant$advances$in$pathogen
detec<on$technology,$there$is$the$poten<al$to$detect$the$presence$of$a$pathogen$that$may$not$yet$be
detectable$via$other$diagnos<c$assays$(i.e.$detec<ng$a$virus$before$an<body$produc<on).
 
Poten<al$false/nega<ve$mNGS$results$(nega<ve$mNGS$assay$but$posi<ve$by$conven<onal$tes<ng)$are
also$reviewed$with$addi<onal$discrepancy$tes<ng$performed,$as$necessary.
 
The$results$of$the$mNGS$assay$do$not$solely$determine$the$need$for$therapy$or$other$pa<ent
interven<ons.$$Conven<onal$test$results$and$mNGS$results$are$used$in$the$proper$clinical$context$to
guide$therapy$decisions.$$Given$the$overall$mNGS$test$performance$during$clinical$laboratory$valida<on
studies,$expert$review$and$case$discussion,$and$the$use$of$discrepancy$tes<ng$as$needed,$the$mNGS
assay$(device)$as$performed$poses$a$non/signiﬁcant$risk$to$pa<ents.
Study Protocol Page 80 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 33 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
 
Attach any documentation you have from the manufacturer and/or FDA
to support this determination.
9.5  LIST THE DEVICES: List the medical devices or in vitro diagnostics to be studied or used. In the
device details screen you will be asked questions such as:
Whether the device is FDA approved or investigational
Medicare device category
If the device will be provided at no cost
If an IDE is necessary, the IDE number, and who holds the IDE
Risk category of the device
FDA status of the device
Please see the UCSF IRB website for more details about the use of devices in research, including the
Investigator Checklist for Significant Risk, Non-Significant Risk, and/or IDE Exempt Device Studies
 
Verification of IDE numbers: If the sponsor’s protocol does not list the IDE number, you must submit
documentation from the sponsor or FDA identifying the IDE number for this study. Attach this
documentation in the Other Study Documents section of the Initial Review Submission Packet.
 
If you have any correspondence from the FDA or sponsor regarding this device,
please attach it to the application.
 
View
Details
Device Name
Is the Device FDA
Approved
Is this a new
device or a new
use of an already
approved device
IDE Number
mNGS IVD for diagnosis of
infectious diseases 
No 
Yes 
 
Manufacturer/Supplier of Device
University of California, San Francisco 
Medicare Category
A
B
Where will the Devices Be Stored
 
Will Devices be supplied at no
Cost
Yes 
Is this a HUD (HDE)
No 
HDE Number
 
Is the Device FDA Approved
No 
Is this a new device or a new use
of an already approved device
Yes  
Is an IDE necessary
No  
IDE Number
 
Who holds the IDE
N/A  
IDE Details
The in vitro diagnostic under study (mNGS for diagnosis of
infectious disease) will be performed as a laboratory-developed
test in the UCSF clinical laboratory. As a laboratory-developed
test, FDA approval or IDE registration are not required. The
primary purpose of the test is to diagnose patients enrolled in
the study.  
Study Protocol Page 81 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 34 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
In the opinion of the sponsor,
select the level of risk associated
with this device
No Significant Risk  
9.6  * Is this an expanded access or compassionate use protocol, meaning the primary purpose is to
diagnose, monitor or treat a patient's condition, rather than the collection of safety and efficacy data
of the experimental agent: (REQUIRED)
  Yes   
  No
10.0
Sample Size and Eligibility Criteria
10.1  ENROLLMENT TARGET: How many people will you enroll:
500
 If there are multiple participant groups, indicate how many people will be in each
group:
200- neurology patients 
300- sub-study for plasma validation of mNGS for pathogen detection (sepsis patients w/ no patient
contact)
10.2  TOTAL PARTICIPANTS: For multicenter studies, how many people will be enrolled in total:
 
600
10.3  SAMPLE SIZE JUSTIFICATION: Explain how and why the number of people was chosen. For multi-
site studies, this is referring to the number that will be enrolled across all sites:
300 participants is the target enrollment for this project to demonstrate the utility of this new diagnostic
assay. We anticipate the majority of patients to be hospitalized at UCSF (200), with another 100 enrolled
at UCLA and UCD.
 
The sub-study for specimen acquisition for plasma validation will obtain samples from approximately 300
patients receiving sepsis work-up. A small number (approximately 10) of plasma samples on correlated
blood culture negatives will be held for validation studies. Plasma samples correlated to positive blood
cultures will be held for validation studies (approximately 30). The remaining plasma specimens will not
be held (approximately 260). 
10.4  * PARTICIPANT AGE RANGE: Eligible age ranges: (REQUIRED)
0-6 years
7-12 years
13-17 years
18-64 years
65+
Study Protocol Page 82 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 35 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
10.5  * STUDY POPULATIONS: Data will be collected from or about the following types of people (check
all that apply): (REQUIRED)
Inpatients
Outpatients
Family members or caregivers
Providers
People who have a condition but who are not being seen as patients
Healthy volunteers
Students
Staff of UCSF or affiliated institutions
None of the above
10.6  * SPECIAL SUBJECT GROUPS: Check the populations that may be enrolled: (REQUIRED)
Children / Minors
Subjects unable to consent for themselves
Subjects unable to consent for themselves (emergency setting)
Subjects with diminished capacity to consent
Subjects unable to read, speak or understand English
Pregnant women
Fetuses
Neonates
Prisoners
Economically or educationally disadvantaged persons
None of the above
If not already addressed in the Background and Significance questions in the
Research Plan section or elsewhere, explain why it is appropriate to include
the types of subjects checked above in this particular study:
The majority of the subjects involved in this study will have neurological illness, with the minority having
sepsis.
 
Central nervous system infections and autoimmune diseases can affect cognition. Therefore, subjects
who are unable to consent for themselves, an appropriate surrogate will be approached and given the
opportunity to consent on the patient’s behalf.
 
Undiagnosed CNS infections and autoimmune diseases are a major problem in pediatrics. Therefore we
do not wish to exclude pediatrics or neonates.
 
While we anticipate very few if any pregnant women to be in this study, we would like to include them in
the case that a pregnant women were to develop neuroinflammatory disease requiring hospitalization.
Describe the additional safeguards that have been included in the study to protect
the rights and welfare of these subjects and minimize coercion or undue
influence:
Here are some examples:
evaluating capacity to consent for individuals who may be decisionally
Study Protocol Page 83 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 36 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
impaired (specify how)
calibrating payment amounts to be non-coercive for the financially
disadvantaged
conducting more in-depth evaluations of subjects’ understanding of the
study and the voluntary nature of participation
involving advocates in the consent process
More information and other safeguards are described here: Vulnerable Subject
Populations and Recruiting Staff and Students.
Capacity assessment and consent from surrogate decision-maker if subjects do not have capacity for
consent. If capacity improves, subjects will be re-contacted for their consent. For age < 18 years, the
protocol requires assent (if the patient has capacity) as well as parental/guardian consent.
10.7  INCLUSION CRITERIA:  Briefly describe the population(s) that will be involved in this study.
Include anyone that data will be collected from or about (e.g. patients, healthy controls,
caregivers, providers, administrators, students, parents, family members, etc.):
Inclusion criteria for this study is any patient with acute onset of encephalitis and/or meningitis (phase
1), sepsis (phase 2), and pneumonia (phase 3). Information will be gathered about these patients. Some
data may be collected on family members or other sick contacts of the patient. This will only be for
information gathering that may help explain or identify the infectious etiology.
10.8  EXCLUSION CRITERIA: List any exclusion criteria (e.g. reasons why someone would not be included
in the study):
We will not include patients with a psych hold (5150 or 5250), prisoners or UC employees or students or
close associates of the key personnel on the study.
10.9  * RESEARCH CONDUCTED ON PATIENT CARE WARDS: Do any study activities take place on patient
care units at UCSF medical facilities: (REQUIRED)
 Yes   
 No
Attach a letter of acknowledgement for the study from the involved
patient care manager. If you don't know who the patient care manager
is, click here to send an email to the nursing group.
11.0
Inclusion of Minors in Research
11.1  REGULATORY CATEGORIES OF RESEARCH: Select all the regulatory categories that apply:
No greater than minimal risk (45 CFR 46.404, 21 CFR 50.51)
Greater than minimal risk but presenting prospect of direct benefit (45 CFR 46.405, 21 CFR 50.52)
Greater than minimal risk (though only a minor increase over minimal risk) and no prospect of direct
benefit but likely to yield generalizable knowledge about the subjects disorder or condition (45 CFR
46.406, 21 CFR 50.53)
Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate
a serious problem affecting the health or welfare of children (45 CFR 46.407, 21 CFR 50.54)
Study Protocol Page 84 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 37 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Explain why the research in this study falls under the above category or
categories:
The greatest risk to the patients is the potential loss of privacy.
 
It is possible, although unlikely, that this research could indicate an infection where infection control
measures are needed in order to protect public health. In these cases, we will contact the treating team
of the participant and the hospital infection control physicians. These people will be responsible for
determining how to proceed with the participant’s care, which could include sending additional tests
and/or moving the participant to a separate hospital room to keep a possible infection from spreading.
11.2  
MINORS CONSENTING: Will this study enroll minors who can legally consent for themselves (as in
the case of emancipated minors or minors being treated for pregnancy or drug use without their
parents knowing). This is different from agreeing to be in the study even when their parents are
the ones providing 'official' consent, which we refer to as 'providing assent':
Note: This is very rare and the answer is usually 'No.'
  Yes   
  No
11.3  
PARENTAL PERMISSION VS. WAIVER: Please review the guidance to see under what circumstances
the IRB can waive parental permission.
Parental permission will be obtained
Waiver of parental permission is requested: The waiver meets the provisions for a waiver of consent
(i.e., the research poses minimal risk, it could not practicably be carried out without the waiver of
parental permission, AND the waiver will not adversely affect the rights and welfare of the minor
participants (45 CFR 46.116(d))
Waiver of parental permission is requested: Parental permission is not a reasonable requirement to
protect the minor (e.g. neglected or abused children) or parental knowledge of the study may
endanger the health or welfare of the minor (45 CRF 46.408(c))
Provide details on the other protections that will be in place:
Minors will be approached for assent. Parents or legal guiardians will approached for informed, signed
consent.
11.4  ASSENT OF MINORS OR WAIVER: Please review the guidance to see under what circumstances the
IRB can waive assent.
Assent of children developmentally and psychologically able to provide assent will be obtained
Waiver of assent is requested: The capability of some or all of the children is so limited that they
cannot reasonably be consulted
Waiver of assent is requested: The research holds out a prospect of direct benefit that is important to
the health or well-being of the children and is available only in the context of the research
Waiver of assent is requested: The activities involving the minor are limited to chart review or the
something equally innocuous
Waiver of assent is requested: It is not culturally appropriate to involve the minor in the decision to
participate (e.g. some foreign research)
Provide a brief justification for the waiver:
Study Protocol Page 85 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 38 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
As this study will be primarily enrolling participants with neurological disease, it is anticipated that many,
if not most, children will be too ill to engage in an assent discussion with the research staff. If it is
determined by the treating team, family members, and/or the study personnel, the assent discussion
may be waived. However, parental and/or guardian consent will always be obtained prior to enrollment.
11.5  DOCUMENTATION OF PERMISSION AND ASSENT: (select all that will be used):
Permission form addressed to the parents
Simplified assent form addressed to the child, 7-12 years old (parents get separate form)
Assent form addressed to the child, 13 years and older (for subjects and parents)
Assent form addressed to the child, 13 years and older (parents get separate form)
Check one:
One parent's signature will be obtained 
Two parents' signatures will be obtained 
If this study is approvable under regulatory category .405 and you plan to get permission from only one
parent, explain why you think one parent's permission is sufficient:
11.6  WARDS OF THE STATE: Might this study enroll wards of the state:
 Yes   
 No
11.7  WARDS JUSTIFICATION: It is appropriate to enroll wards in this study because:
This study is minimal risk and access to the clinical diagnostic test, currently only available in congruence
with research participation, and its associated potential benefit to the patient, outweigh the risks. 
12.0
Recruitment and Consent
12.1  * RECRUITMENT METHODS: What kinds of methods will be used to identify potential participants
for recruitment (check all that apply): (REQUIRED)
Medical records review
Recruitment registry
Re-contact of participants from the investigators' previous studies
Referrals from colleagues (attach the 'Dear Colleague' letter or other recruitment materials you will
provide to colleagues)
Referrals from the community / word of mouth
Advertisements (flyers, brochures, radio or t.v. ads, posting on clinical research sites or social media,
presentation of the study at community events/media, etc.)
Online recruiting tool such as TrialSpark
CTSI Recruitment Services unit
Other method (describe below)
12.2  * SEARCHING OF MEDICAL RECORDS: (REQUIRED)
Study Protocol Page 86 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 39 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Whose patients are they:
Investigators' own patients or patients seen within the same practice
Patients not under the care of the investigators
How and by whom will records be accessed and searched (check all that apply):
Self-search in APeX or other medical records source
Self-search using UCSF's Research Cohort Selection Tool
CTSI Consultation Service Recruitment Services
UCSF Academic Research Services (ARS)
University of California Research Exchange (UC ReX)
Other method (describe below)
12.3  DETERMINATION OF ELIGIBILITY: How, when, and by whom will eligibility for recruitment be
determined:
 
Treating clinicians on the infectious disease, neurology, and critical care services will refer patients with
infectious disease syndromes. At that point, the Study Investigator, co-Investigators or Study Coordinator
will review the patient's clinical information to determine whether they are eligible for the study. The
Study Investigator, co-Investigator or Study Coordinator will then approach and consent the patient (or
his/her surrogate decision maker) for the study.
 
Similarly, the Study Investigator, co-Investigator, or Study Coordinator will screen patients in APeX for
eligibility. If patients meet criteria, the primary treating team will be contacted for permission to approach
and discuss the study with the potential research candidate. The Study Investigator, co-Investigator or
Study Coordinator will approach for possible consent.
 
A RedCap Referral survey will be used to assist with determining patient eligibility. This will be submitted
to either the CRC, PI, or co-PI to review and determine eligibility prior to approaching patients for
consent.
 
Sepsis sub-study: eligibility will be determined by meeting clinical criteria for sepsis or sirs (i.e. low blood
pressure, increased heart rate, fever, etc). Blood samples will be collected near the time of the first blood
culture, non-acute/well-established/managed cases of sepsis will not be included. 
12.4  * INITIATION OF CONTACT: Who initiates contact (check all that apply): (REQUIRED)
Investigators/study team
UCSF recruitment unit (e.g. CTSI Consultation Services)
Potential participant
Other (explain below)
12.5  * HOW IS CONTACT INITIATED: (check all that apply): (REQUIRED)
In person
Phone
Letter / email
Website or app
Other (explain below)
Study Protocol Page 87 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 40 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Attach the telephone recruitment script in the Other Study Documents
section of the Initial Review Submission Packet Form. If potential
participants will initiate contact, attach the telephone screening script
that will be used to provide more information about the study and
determine if callers are eligible to participate.
Attach the recruitment letter or email template in the Other Study
Documents section of the Initial Review Submission Packet Form.
12.6  RECRUITMENT PLAN: Based on the checkboxes you chose above, please provide a narrative
describing your recruitment plan. We want to know:
Who is conducting the search for potential participants, and how?
How are potential subjects being approached for recruitment? By whom, and when?
If there will be more than one participant group (e.g. patients, healthy controls, caregivers, family
members, providers, etc.), provide details about the recruitment plans for each group.
(Recommended length - 100-250 words)
Potential participants will be identified by treating clinicians who have ordered the clinical UCSF mNGS
and referred the patient to opt into research participation. mNGS test ordering may happen before or
after enrollment criteria is reviewed, or before or after patient consent. Patients will only be included in
the study and have mNGS performed if they meet criteria and consent to the study. Study team members
will also review medical records for potential subjects that meet criteria and engaging treating teams to
determine eligibility. 
 
Subjects will be approached by their treating clinician(s) in the context of their ongoing clinical care (e.g.
at the treating medical center).
 
Sepsis sub-study: information letter will be mailed within one week of blood draw occuring. 
 
Providers will be recruited for feedback (pre and post mNGS results) by an emailed survey. Treating team
members will be identified by reviewing the EMR of the study participants. 
12.7  * CONSENT METHODS: How will permission to participate (i.e., informed consent) be obtained from
each potential participant. If there will be multiple groups and different plans for consenting each,
check all that apply. See the orange Help bubble to the right for more detailed guidance.
 
Participants will (check all that apply): (REQUIRED)
Sign a consent form at the end of the consent discussion (signed consent)
Provide online 'eConsent' using DocuSign or another E-Signature system
Click through a link in a survey or email after reading about the study and then complete the study
online (electronic consent)
Be told about the study and be given a handout/information sheet and be asked if they agree to
participate (verbal consent)
Complete the study activities and turn in materials, as in the case of a completed survey that is
placed in a drop box or mailed to the study team (implied consent)
Not be able to provide consent and will have a family member consent for them, as in the case of a
critically ill or unconscious patient (surrogate consent)
Not be able to provide consent (emergency waiver of consent - allowed for minimal risk research or
greater than minimal risk research with an approved community consultation plan)
Not know about the study, as in the case of chart reviews or observations of public behavior (waiver
of consent)
Other method (describe below)
Study Protocol Page 88 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 41 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Attach your consent form, information sheet, or electronic consent text in
the Informed Consent Documents section of the Initial Review
Submission Packet Form.
12.8  * CONSENT PROCESS: Describe the process for obtaining informed consent, including details such
as who will have the consent discussion and when participants will be asked to sign the consent
form in relation to finding out about the study: (REQUIRED)
 
We encourage researchers to review our guidance on obtaining and documenting informed
consent.
If there are multiple groups being consented differently, provide details about the consent
process for each group.
If you are relying on verbal or implied consent, provide details about how that will happen.
For studies using online recruitment and consent or consent via mail, provide details here.
As this study coincides with the release of the new UCSF metagenomic Next-Generation Sequencing
(mNGS) test, candidates and/or surrogates will be approached for possible consent to the study after
the mNGS clinical test has been ordered by the treating team.
 
UCSF Research Candidate with Capacity to Consent
The PI or other study key personnel will approach the research candidate and invite them to learn more about
the study. The PI or study key personnel will describe the study and the research candidate will be given ample
time to ask questions and consider their choice. Written informed consent will only be obtained when the
candidate feels comfortable proceeding with the study. A photocopy of the signed consent documents will be
provided to the candidate after they have been signed.
 
Specimens may be sent to the Clinical Microbiology Lab at UCSF for mNGS prior to the patient being
approached for possible consent. However, ancillary specimens will not be obtained prior to candidate consent.
 
Some research candidates will be discharged or transferred before informed consent may be obtained. In
these instances, the site PI or other study key personnel will reach out the research candidate by phone and
invite them to participate in the study. If the candidate is interested to participate and verbally OKs sending
their specimen for testing and the review of medical records, they will be included in the study.
 
Copies of the consent forms will then be mailed or sent via DocuSign to the candidate to sign and return. If
signed documentation is not received within 4 months from enrollment, the candidate will be withdrawn from
the study.
 
UCSF Surrogate Consent
Some research candidates will not be able to provide informed consent due to altered mental status or
cognitive impairment caused by their illness. Surrogates who are local and able to meet the study personnel at
bedside will be consented in person. The study PI or other key personnel will approach the surrogate at the
hospital to explain the research study and invite them to give consent on behalf of the research candidate. The
surrogate will be given ample time to discuss and ask questions. They surrogate will complete the “Self-
Certiﬁcation of Surrogate Decision Makers for Potential Subject's Participation in University of California
Research”. When ready to sign the documents, they will sign the consent documents and be provided a
photocopy of the signed forms.
 
 
Surrogates who are not local or unable to meet the study personnel at the hospital, may be contacted and
invited to learn more about the study over the phone. Surrogate contact information will be gathered from
either the electronic medical record, the treating physician, or by contacting the nurse, case manager or other
hospital staff involved in caring for the research candidate. The PI or other study personnel will reach out to the
surrogate by phone to explain the research study and invite them to give consent on behalf of the research
candidate. If the surrogate provides verbal consent, ancillary specimens may be collected after this initial
Study Protocol Page 89 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 42 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
contact with the surrogate, including a blood draw. At the time of initial verbal consent the study personnel will
invite the surrogate to meeti at the hospital to review and sign the consent documents.
 
If they are unable to meet in person, copies of the consent forms will then be mailed or sent via DocuSign to
the surrogate to sign and return. The surrogate will be given ample time to consider and discuss the study. No
ancillary samples will be collected until verbal consent is received.
 
Ancillary specimens may be collected and processed after verbal consent. Signed consent will be obtained
after obtaining verbal consent. If signed consent is not received by the surrogate within 4 months of receiving
the specimen(s), the participant will be considered not enrolled and PHI will be removed from records/
destroyed and banked specimens will be destroyed.
 
Specimens may be sent to the Clinical Microbiology Lab at UCSF for mNGS prior to the patient being
approached for possible consent.
 
Outside Relying Site Research Candidate with Capacity to Consent
Outside relying sites will similarly ordering the clinical mNGS test and subsequently or simultaneously be
approaching candidates for possible consent to the research study.
 
The relying outside site PI or other study key personnel will approach the research candidate and invite them
to learn more about the study. The PI or study key personnel will describe the study and the research
candidate will be given ample time to ask questions and consider their choice. Written informed consent will
only be obtained when the candidate feels comfortable proceeding with the study. A photocopy of the signed
consent documents will be provided to the candidate after they have been signed.
 
Specimens may be sent to the Clinical Microbiology Lab at UCSF for mNGS prior to the patient being
approached for possible consent. However, ancillary specimens will not be obtained prior to candidate consent.
 
Some research candidates will be discharged or transferred before informed consent may be obtained. In
these instances, the site PI or other study key personnel will reach out the research candidate by phone and
invite them to participate in the study. If the candidate is interested to participate and verbally Okays sending
their specimen for testing and the review of medical records, they will be included in the study.
 
Copies of the consent forms will then be mailed or sent via DocuSign to the candidate to sign and return. If
signed documentation is not received within 4 months from enrollment, the candidate will be withdrawn from
the study.
 
 
 
Outside Relying Site Surrogate Consent
Some research candidates at outside sites will not be able to provide informed consent due to altered mental
status or cognitive impairment caused by their illness. Surrogates who are local to the relying sites and able to
meet the local study personnel at bedside will be consented in person. The local study PI or other key
personnel will approach the surrogate at the hospital to explain the research study and invite them to give
consent on behalf of the research candidate. The surrogate will be given ample time to discuss and ask
questions. They surrogate will complete the “Self-Certiﬁcation of Surrogate Decision Makers for Potential
Subject's Participation in University of California Research”. When ready to sign the documents, they will sign
the consent documents and be provided a photocopy of the signed consent form, HIPPA auth, and Bill Rights.
One version of the consent document will be used at all sites.
 
Surrogates who are not local or unable to meet the local study personnel at the hospital, may be contacted and
invited to learn more about the study over the phone. Surrogate contact information will be gathered from
either the electronic medical record, the treating physician, or by contacting the nurse, case manager or other
hospital staff involved in caring for the research candidate. The local PI or other study personnel will reach out
to the surrogate by phone to explain the research study and invite them to give consent on behalf of the
research candidate. If the surrogate provides verbal consent, ancillary specimens may be collected after this
initial contact with the surrogate, including a blood draw. At the time of initial verbal consent the study
personnel will invite the surrogate to meeti at the hospital to review and sign the consent documents.
Study Protocol Page 90 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 43 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
 
If they are unable to meet in person, copies of the consent forms will then be mailed or sent via DocuSign to
the surrogate to sign and return. The surrogate will be given ample time to consider and discuss the study. No
ancillary samples will be collected until verbal consent is received.
 
Ancillary specimens may be collected and processed after verbal consent. Signed consent will be obtained
after obtaining verbal consent. If signed consent is not received by the surrogate within 4 months of receiving
the specimen(s), the participant will be considered not enrolled and PHI will be removed from records/
destroyed and banked specimens will be destroyed.
 
 
 
Outside non-relying site consent
Non-relying sites will consent research candidates and/or surrogates according to local IRB protocols.
 
Re-Consent for participants that gain capacity to consent after enrollment
Research candidates who were enrolled by surrogate consent while in the hospital will be re-contacted in the
case they re-gain capacity to give informed consent. We anticipate this to occur once the patient is no longer
hospitalized. Therefore, re-consent will be initiated with a phone call to explain the study to the research
participant and give them the option to remain in the study or to withdraw. If the participant wishes to be
withdrawn, banked specimens will be destroyed and no further research will be conducted using the
specimens. However, any research already done using the specimens or data will be kept and analyzed as
part of the study. If the participant wishes to remain in the study, they will be asked to sign new consent forms.
Documents (2 of each: consent form, HIPPA authorization, and Bill of Rights) will be mailed to the participant.
One copy will be for the participant to keep for their personal records and the second to sign and return.
 
Sepsis sub-study:
All patients from whom a blood sample has been collected (regarless of use in research) will be mailed an
information letter within one week of blood sample collection. Letter will include study contact information
and a return envelope. If the patient wishes to be excluded from the study, they will check 'withdraw' on
the information letter and return in the envelope provided. By default, cases will be included if criteria is
met unless otherwise requested by the patient or appropriate surrogate. 
 
Sub-cohort of the validation cohort for plasma validation (sepsis):
 
Same as 'UCSF Research Candidate with Capacity to Consent' and 'UCSF Surrogate Consent' as described
above (substituting research mNGS for clinical mNGS). 
* It is important that the people obtaining consent are qualified to do so. Briefly
describe the training and experience these individuals have in obtaining informed
consent: (REQUIRED)
At UCSF,
Hannah Sample, BS -- Study Coordinator, ~2 year experience in obtaining informed consent for research
studies
Amy Berger, MD -- internal medicine physician, hospitalist training, ~3 years experience in obtaining
informed consent for research studies
other faculty, fellows, residents on the Molecular Medicine, Neurology, Infectious Diseases consult
services -- clinical providers at UCSF who have been trained by the investigators on the details of the
CIAPM study and with at least 5 years experience in obtaining informed consent for research studies
 
 
12.9  * CONSENT COMPREHENSION: Indicate how the study team will assess and enhance the subjects'
understanding of study procedures, risks, and benefits prior to signing the consent form (check all
that apply): (REQUIRED)
 
Tip: Review the Consent Comprehension - Learning Notes in the Help bubble at the right for specific
questions that can be asked to assess comprehension, consider using the UCSF Decision-Making
Capacity Assesment Tool, and review our guidance on obtaining written or verbal informed
Study Protocol Page 91 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 44 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
consent for more detail on how to conduct the assessment.
The study team will engage the potential participant in a dialogue, using open-ended questions about
the nature of the study or the experimental treatment, the risks and benefits of participating, and the
voluntary nature of participation
Potential participants will be asked or shown a series of questions to assess their understanding of
the study purpose, procedures, risks and benefits, as well as the voluntary nature of participation
(especially appropriate when the consent process happens online or through a mobile health app)
Other method (describe below):
Provide details of the other approaches that will be used, if using another method
to assess comprehension:
 
Subjects will be asked to explain back the risks, benefits and study protocols. All prospective subjects will
have a detailed neurological exam, part of which will entail a mental status exam in which multiple
cognitive domains are assessed. In addition, we will administer the attached Capacity Assessment Record
for Research Informed Consent. This document will insure that we assess and document whether the
potential research subject is able to make a choice whether to participate in the research protocol,
whether he/she shows understanding of the research protocol and its elements, including the
risks/benefits of participation, whether he/she is able to provide rational reasons for participating or not
participating the research protocol and whether he/she shows an appreciation of the personal
risks/benefits of participating or not participating in the protocol.
12.11  * NON-ENGLISH CONSENT METHOD: Indicate which method(s) you will use to consent non-
English speaking subjects: (REQUIRED)
Preferred Method—Consent form and other study documents will be available in the subject’s primary
language Personnel able to discuss participation in the patient’s language will be present for the
consent process.
Short-Form—A qualified interpreter will translate the consent form verbally, and subjects will be given
the Experimental Subject’s Bill of Rights in their primary language, following instructions in Those
Who do not Read, Speak or Understand English for required witnessing and signatures
* Explain how you will maintain the ability to communicate with non-English
speakers throughout their participation in the study: (REQUIRED)
We expect non-English speaking consent to be a minority of our cohort. Given the minimal risk this study
poses, we fell that this approach will be sufficient. An interpreter (either available by phone or in-person)
will be used for consenting and all follow-up contact.
12.12  * WAIVER OF DOCUMENTATION OF SIGNED CONSENT: Select the regulatory category under which
the IRB may waive the requirement to obtain signed consent for this study:
The only record linking the subject and the research would be the consent document and the principal
risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked
whether they want documentation linking them with the research. 46.117(c) (1)  
The research presents no more than minimal risk of harm to subjects and involves no procedures for
which written consent is normally required outside of the research context. 46.117(c) (2)  
12.13  TIME: What is the estimated time commitment for participants (per visit and in total):
About 30-60 mins for consent. The rest of the study procedures involve processing and analysis but not
subject time. The 30-60 minutes for a follow up telephone call to confirm long-term outcome and final
diagnosis.
 
Study Protocol Page 92 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 45 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
A blood draw shoud take about 5 minutes.
IMPORTANT TIP: Ensure this information is consistent with the
information provided in the consent form.
13.0
Waiver of Consent/Authorization for Recruitment Purposes
This section is required when medical records may be reviewed to determine
eligibility for recruitment.
13.1  * PRACTICABILITY OF OBTAINING CONSENT PRIOR TO ACCESS: Study personnel need to access
protected health information (PHI) during the recruitment process and it is not practicable to
obtain informed consent until potential subjects have been identified: (REQUIRED)
Yes 
If no, a waiver of consent/authorization is NOT needed.
13.2  *  RISK TO PRIVACY: A waiver for screening of health records to identify potential subjects poses
no more than minimal risk to privacy for participants:
Yes 
If no, a waiver of authorization can NOT be granted.
13.3  * RIGHTS/WELFARE: Screening health records prior to obtaining consent will not adversely affect
subjects' rights and welfare:
Yes 
If no, a waiver of authorization can NOT be granted.
13.4  * IDENTIFIERS: Check all the identifiers that will be collected prior to obtaining informed consent:
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Study Protocol Page 93 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 46 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
None
Note: HIPAA rules require that you collect the minimum necessary.
13.5  * HEALTH INFORMATION: Describe any health information that will be collected prior to obtaining
informed consent:
Name, MRN, dates, clinical history for the purposes of establishing eligibility based on suspected
diagnosis and clinical syndrome. Phone numbers may also be collected in order to contact non-local
surrogates or research candidates.
Note: HIPAA requires that you collect the minimum necessary.
13.6  * DATA RETENTION/DESTRUCTION PLAN: Describe your plan to destroy any identifiable data
collected to determine eligibility for recruitment. This should be done at the earliest opportunity. If
you plan to retain identifiable recruitment data, provide the justification for doing so:
Data on subjects who are not eligible or do not wish to participate will be destroyed. Patient name and
MRN will be kept on record in the secure research database so that patients who have declined
participation will not be approached again.
14.0
Waiver of Consent/Authorization
(August, 2013)
14.1  * IMPACT OF WAIVER ON RIGHTS AND WELFARE: I affirm that subjects' rights and welfare will not
be adversely affected by waiving informed consent:
Yes 
14.2  * PRACTICABILITY: It is not practicable to conduct the research without the waiver of consent /
authorization because (check all that apply):
Many subjects are no longer being followed at the institution or are deceased
The attempt to contact subjects poses a greater risk than this study
The large number of records required makes it impracticable to contact all potential subjects
The researchers do not know the identity of the study subjects and therefore cannot contact them
The data being used was collected under a different IRB-approved study and subjects gave their
consent for data to be used in research of this type
14.3  * INFORMING SUBJECTS POST-PARTICIPATION: Will subjects be provided with pertinent
information after their participation:
Study Protocol Page 94 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 47 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
  Yes   
  No
14.4  * IDENTIFIERS: Are you recording identifiers in the research records: (REQUIRED)
 Yes   
 No
*  Describe your plan to destroy the identifiers at the earliest opportunity
consistent with the research or provide a health or research justification for
retaining the identifiers, or indicate and explain that retention is required by law:
(REQUIRED)
For mNGS sepsis validation sub-study: MRNs will be recorded in order to link to blood culture results. 
15.0
Surrogate Consent
15.1  PSYCHIATRIC SCREEN: Are any subjects inpatients on a psychiatric ward or mental health facility,
or on psychiatric hold:
No 
If Yes, use of surrogate consent for research is NOT allowed in California.
15.2  AREAS OF RESEARCH: Is this study related to the cognitive impairment, lack of capacity, or serious
or life-threatening diseases and conditions of the research subjects: 
Yes 
15.3  JUSTIFICATION: Explain why use of surrogates is necessary for completion of this study:
Many subjects to be enrolled in this study may be incapacitated with a serious illness, sedated, or
otherwise unable to provide informed consent.  For enrollment in this study, the use of surrogates with
durable power of attorney will be necessary for these subjects.
15.4  COGNITIVE ASSESSMENT:  Describe the plans for assessing the decision-making capacity of
prospective subjects:
We will assess the decision-making capacity of prospective subjects by their condition (sedated,
intubated, or otherwise incapacitated patients will not be able to make decisions), including severity of
illness, and a clinician determination of whether they are able to provide informed consent.
15.5  POST-ENROLLMENT CONSENT PLANS: Describe the plans for obtaining consent from subjects who
regain ability to consent after a surrogate has given initial consent:
For all sites, UCSF study staff will coordinate re-consent procedures. 
 
Research candidates who were enrolled by surrogate consent while in the hospital will be re-contacted in
case they re-gain capacity to give informed consent. We anticipate this to occur once the patient is no
longer hospitalized. If, based on chart review, the participant has clearly regained capacity to consent,
study staff will reach out by phone to discuss the study and give them the option to remain in the study
Study Protocol Page 95 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 48 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
or to withdraw. If the participant wishes to be withdrawn, banked specimens will be destroyed and no
further research will be conducted using the specimens. However, any research already done using the
specimens or data will be kept and analyzed as part of the study. If the participant wishes to remain in
the study, they will be asked to sign new consent forms. Documents (2 of each: consent form, HIPPA
authorization, and Bill of Rights) will be mailed to the participant. One copy will be for the participant to
keep for their personal records and the second to sign and return.
 
If study staff are not able to reach the participant via phone, a letter (‘re-consent letter’) will be mailed to
the address of record, along with 2 copies of the consent forms. One copy will be for the participant to
keep for their personal records and the second to sign and return. No further attempts to reach the
participant will be made after 1 phone call and 1 letter.
 
If it is not clear from review of the medical chart whether the participant has regained the ability to
consent, contact will be initiated with the surrogate decision maker via phone. Staff will call the surrogate
to inquire about the participant’s mental status. If they have regained mental capacity, staff will reach out
to the participant directly for consent following the procedures outlined above.
 
If the surrogate is not reachable via phone call, staff will mail a letter inquiring as to the mental status of
the participant along with a form to complete summarizing the participant’s status (‘surrogate check in
letter’, ‘participant status form’). If the ‘participant status form’ comes back indicating that the participant
has regained mental capacity, staff will reach out to the participant directly for consent following the
procedures outlined above. No further attempts to reach the surrogate or participant will be made after 1
phone call and 1 letter. 
 
Study staff will not attempt to contact surrogates or participants if they become aware (through chart
review or physician notification) that the patient has passed away.
15.6  
SURROGATE CONSENT REQUIREMENTS: Check to acknowledge:
Research takes place in California. All surrogates will complete the “Self-Certification of Surrogate
Decision Makers for Participation in Research” form.
Conscious subjects will be notified of the decision to contact a surrogate. If subjects object to study
participation, they will be excluded even if their surrogate has given consent.
Surrogates will not receive any financial compensation for providing consent.
If a higher-ranking surrogate is identified at any time, the investigators will defer to the higher-
ranking surrogate’s decision regarding the subject’s participation in the research.
For research taking place outside of California, explain how investigators will
confirm that surrogates are legally authorized representatives:
Non California sites: Children's National Medical Center & St. Jude Children's Research Hospital : 
 
Children enrolled at these site will be consented by the parents or legal guardians. The appropriate
surrogates will be indentified by the local treating team caring for the patients. 
16.0
Risks and Benefits
16.1  RESEARCH-RELATED RISKS: Check if your study involves any of these specific research-related
risks to participants that may need to be disclosed in the consent form:
For interventional studies, risk that the regimen may be more harmful or less effective than other
available interventions
Risks associated with radiation exposure for imaging studies specifically for research purposes
Risks associated with the administration of contrast agent for imaging studies
Risks associated with withholding of treatment or discontinuation of current treatment (e.g., washout
Study Protocol Page 96 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 49 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
period is required by the study protocol)
For randomized, placebo-controlled trials, possible temporary or permanent health consequences
from the deprivation of effective therapies during the placebo administration period
For studies involving a sham surgical procedure, the risk that participants may experience increased
morbidity without the possibility of benefit
Risks associated with modification or extension of a surgical procedure primarily for research
purposes (e.g. risks associated with prolonging anesthesia, time in the operating room, etc.)
Risk of pain or physical discomfort caused by the research intervention
Possible personal discomfort due to sensitive topics (stress, embarassment, trauma)
16.2  RISKS: Describe any anticipated risks and discomforts not listed above:
1. We will be analyzing surplus CSF, blood, other bodily fluids and biopsy tissue, which will not be able to
be returned to the subject for further clinical analysis.
 
2. It is possible that a pathogen will be identified using this approach, that upon additional clinical
confirmation by the treating team, may need to be reported to public health authorities by law, which
could have implications for patient privacy.
 
3. There is a risk that information about taking part in a genetic study may influence insurance
companies and/or employers regarding your health. To further safeguard your privacy, genetic
information obtained in this study will not be placed in your medical record. Taking part in a genetic study
may also have a negative impact or unintended consequences on family or other relationships. If you do
not share information about taking part in this study, you will reduce this risk. Although your name will
not be with the sample, it will have other facts about you such as information about your medical history,
age and gender. These facts are important because they will help us learn if the factors that cause
neurologic disease to occur or get worse are the same or different based on these facts. Thus it is
possible that study finding could one day help people of the same race, ethnicity, or sex as you. 
However, it is also possible through these kinds of studies that genetic traits might come to be associated
with your group.  In some cases, this could reinforce harmful stereotypes.
 
4.  Drawing blood may cause temporary discomfort from the needle stick, bruising, and very rarely
infection.
 
 
16.3  
MINIMIZING RISKS: Describe the steps you have taken to minimize the risks/discomforts to
subjects. Examples include:
designing the study to make use of procedures involving less risk when appropriate
minimizing study procedures by taking advantage of clinical procedures conducted on the
study participants
mitigating risks by planning special monitoring or conducting supportive interventions for
the study
having a plan for evaluation and possible referral of subjects who report suicidal ideation
All clinical specimens will be obtained by trained clinical personnel according to standard operating
procedures, and the procedures will only be performed as clinically indicated.
16.4  RESOURCES: Describe the resources in place to conduct this study in a way that assures protection
of the rights and welfare of participants:
 
These resources typically include appropriately trained and qualified personnel (in terms
availability, number, expertise and experience), funding, space, equipment, and time to devote to
study activities.
 
Depending on the nature of the research study, investigators should consider the proximity or
Study Protocol Page 97 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 50 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
availability of critical resources that may be essential to the safety and welfare of participants,
such as
the proximity of an emergency facility for care of participant injury
availability of psychological support after participation
resources for participant communication, such as language translation services
As described in the "Qualifications of Key Study Personnel" section, all research staff involved in this
project have extensive experience with research and patient care and understand the importance of
minimizing risks to study subjects. As described in the "Privacy" section, we have numerous protections
in place to insure subject privacy.
16.5  * BENEFITS: (REQUIRED)
Note: These are the benefits that the IRB will consider during their review. They are not necessarily
appropriate to include in the consent form.
Possible immediate and/or direct benefits to participants and society at
large (check all that apply):
Positive health outcome (e.g. improvement of condition, relief of pain, increased mobility, etc.)
Closer follow-up than standard care may lead to improved outcomes or patient engagement
Health and lifestyle changes may occur as a result of participation
Knowledge may be gained about their health and health conditions
Feeling of contribution to knowledge in the health or social sciences field
The research presents a reasonable opportunity to further the understanding, prevention, or
alleviation of a serious problem affecting the health or welfare of children
Other benefit (describe below)
None
16.6  RISK TO BENEFIT RATIO: Explain why the risks to subjects are reasonable in relation to anticipated
benefits, if any, to the participant or society:
The risk to subjects is minimal, principally loss of privacy (although every effort will be made to maintain
confidentiality, especially of genetic information).  Knowledge may be gained from the clinically validated
mNGS test about the infectious cause of their illness.
17.0
Confidentiality, Privacy, and Data Security
17.1  PROTECTING PRIVACY: Indicate how subject privacy will be protected:
Conduct conversations about the research in a private room
Ask the subject how they wish to be communicated with – what phone numbers can be called, can
messages be left, can they receive mail about the study at home, etc.
Take special measures to ensure that data collected about sensitive issues do not get added to their
medical records or shared with others without the subject’s permission
Other methods (describe below)
17.2  SENSITIVE DATA: Do any of the instruments ask about illegal or stigmatized behavior:
Study Protocol Page 98 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 51 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
  Yes   
  No
17.3  CONSEQUENCES OF A LOSS OF PRIVACY OR CONFIDENTIALITY: Could a breach of privacy or
confidentiality  result in any significant consequences to participants, such as criminal or civil
liability, loss of state or federal benefits, or be damaging to the participant's financial standing,
employability, or reputation:
  Yes   
  No
17.4  EXTRA CONFIDENTIALITY MEASURES: Explain any extra steps that will be taken to assure
confidentiality and protect identifiable information from improper use and disclosure, if any:
Specimens and data will be coded. The "key" to this code will kept in RedCap. RedCap will only be
accessible to key study personnel and no identifying information will be shared with researchers not
directly involved in the study and who are listed as study personnel on this application.
17.5  * REPORTABILITY: Do you anticipate that this study may collect information that State or Federal
law requires to be reported to other officials, such as elder abuse, child abuse, or threat to self or
others: (REQUIRED)
 Yes   
 No
The confidentiality and privacy section of the consent form should include
this as a possible risk of participation. 
 
* Describe the types of reportable information the research team may encounter
and provide the details of the reporting plan: (REQUIRED)
If there is suspicion for a concerning pathogen, the PI will contact the treating physician and/or clinical
laboratory to discuss the finding. Public health reporting may be indicated if confirmed by the clincial lab
and treating physician. The PI will not report research findings for public health reporting as these are
research findings.
17.6  CERTIFICATE OF CONFIDENTIALITY: Will this study obain a Certificate of Confidentiality:
  Yes   
  No
17.7  SHARING OF RESEARCH RESULTS: Will there be any sharing of EXPERIMENTAL research test results
with subjects or their care providers:
 Yes   
 No
Note: This is unusual and not recommended, particularly in cases where
the tests are carried out in a non-CLIA certified laboratory, the results
are of unproven clinical significance, or where there are not known
preventative strategies and/or treatments. If these are the most likely
scenarios for your study, you should check 'No.'  
 
If you have an incidental finding of clear clinical significance, call the
HRPP QIU at 415-476-1814 for a consult. 
Study Protocol Page 99 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 52 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Explain under what circumstances research results may be shared:
Research results from non-validated specimen types (e.g. brain biopsy), a narrative results report will be
discused with the treating clinician detailing the candidate pathogen(s) found, research assay methods,
and limitations.  The discussion will include any testing available in CLIA-certified laboratories for
confirmation of the research result, if applicable.  The results will be marked specifically as "Research use
only not to be used for clinical purposes" and "Any results (positive or negative) do not exclude any other
causes for patient illness".  Thus, these research results will not be used for clinical purposes but may be
communicated to clinicians to guide additional CLIA-certified diagnostic testing.
 
 
17.8  * IDENTIFIERS: Will any personal identifiers be collected: (REQUIRED)
 Yes   
 No
Check all the identifiers that may be included:
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
If publications from this study may include ANY photos or images of
patients - even without faces - either collected for research or from the
medical records, you are required to have each patient sign the 'Consent
for Photography / Authorization for Publication' form prior to submittal
for publication. Failure to obtain consent for publication may result in a
finding of Serious Non-compliance by the IRB and civil and criminal
penalties, including fines up to $1.5 million dollars for violation of the
HIPAA privacy protections if a participant complains.  
* Could study records include ANY photos or images (even 'unidentifiable'
Study Protocol Page 100 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 53 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
ones): (REQUIRED)
 Yes   
 No
17.9  DATA DISCLOSURE: Will identifiable information be shared with outside groups:
  Yes   
  No
17.11  * DATA COLLECTION AND STORAGE: (check all that apply): (REQUIRED)
Collection methods:
Paper-based (surveys, logs, diaries, etc.)
Electronic case report forms (CRFs), such as OnCore or another clinical trial management portal
Web-based online surveys or computer-assisted interview tool
Mobile applications (mobile or tablet-based)
Wearable devices
Audio/video recordings
Other:
* What online survey tool will you use: (REQUIRED)
Qualtrics (Recommended)
RedCAP (Recommended)
Survey Monkey (NOT recommended and may require UCSF ITS Security review)
Other
* Data will be collected/stored in systems owned by (check all that
apply): (REQUIRED)
UCSF
SF VAMC
Amazon (Amazon Cloud)
Other academic institution
3rd party vendor (business entity)
Other (explain below)
* Do you have a contract or Data Use Agreement with a 3rd party for research
data collection, storage, access, and ownership: (REQUIRED)
 Yes   
 No
17.12  DATA SECURITY: Indicate how data are kept secure and protected from improper use and
disclosure (check all that apply):
 
NOTE: Whenever possible, do not store subject identifiers on laptops, PDAs, or other portable
devices. If you collect subject identifiers on portable devices, you MUST encrypt the devices.
Study Protocol Page 101 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 54 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Data are stored securely in My Research
Data are coded; data key is destroyed at end of study
Data are coded; data key is kept separately and securely
Data are kept in a locked file cabinet
Data are kept in a locked office or suite
Electronic data are protected with a password
Data are stored on a secure network
Data are collected/stored using REDCap or REDCap Survey
Data are securely stored in OnCore
17.13  * DATA SECURITY: Confirm below that you will keep data confidential: (REQUIRED)
 
I will keep any data sets that include identifiers secure and protected from improper use and
disclosure by using methods such as:
Physical Security – Keeping data in locked file cabinets, locked offices, locked suites, and
physically securing computers and servers.
Electronic Security – Following UCSF minimum security standards for electronic information
resources, which includes (but is not limited to): not storing identifiers on portable devices
like laptops or flash drives if they are unencrypted, encrypting portable devices, and storing
data in password-protected files and on secure networks.
 
Yes 
17.15  HIPAA APPLICABILITY: Study data will be:
Derived from the Integrated Data Repository (IDR) or The Health Record Data Service (THREDS) at
SFGH
Derived from a medical record (e.g. APeX, OnCore, etc. Identify source below)
Added to the hospital or clinical medical record
Created or collected as part of health care
Obtained from the subject, including interviews, questionnaires
Obtained ONLY from a foreign country or countries
Obtained ONLY from records open to the public
Obtained from existing research records
None of the above
Unless a waiver of Authorization is granted, in addition to the consent
form, participants will need to sign UCSF Research Subject Authorization
Form (HIPAA Form). NEW REQUIREMENT - This form should be uploaded
in the Other Study Documents section of the Initial Review Submission
Packet Form. Failure to obtain HIPAA Authorization for research is one of
the most common findings from QIU Routine Site Visits. Your IRB
approval letter will include instructions about HIPAA requirements
specific to your study.
If derived from a medical record, identify source:
Study Protocol Page 102 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 55 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
APeX
17.16  * HIPAA - PERMISSION TO ACCESS SENSITIVE DATA: Does the research require access to any of
the following types of health information from the medical record: (check all that apply)
(REQUIRED)
Drug or alcohol abuse, diagnosis or treatment
HIV/AIDS testing information
Genetic testing information
Mental health diagnosis or treatment
None of the above
Important note: Ensure that participants initial the corresponding line(s)
in Section C of the HIPAA authorization form during the consent process.
18.0
Financial Considerations
18.1  * PAYMENT: Will subjects be paid for participation, reimbursed for time or expenses, or receive any
other kind of compensation: (REQUIRED)
  Yes   
  No
18.4  COSTS TO SUBJECTS: Will subjects or their insurance be charged for any study activities:
  Yes   
  No
19.0
Qualifications of Key Study Personnel
19.1   
NOTE: This information is required and your application will be considered
incomplete without it. If this study involves invasive or risky procedures, or
procedures requiring special training or certification, please identify who will
be conducting these procedures and provide details about their qualifications
and training. Also identify each person who will be involved in the consent
process. Click the orange question mark for more information and examples.
Under qualifications, please include:
Academic Title
Institutional Affiliation (UCSF, SFGH, VAMC, etc.)
Department
Certifications
 
November, 2015 - NEW Definition of Key Study Personnel and CITI
Training Requirements:
UCSF Key Study Personnel include the Principal Investigator, other
investigators and research personnel who are directly involved in conducting
Study Protocol Page 103 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 56 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
research with study participants or who are directly involved in using study
participants’ identifiable private information during the course of the
research. Key Personnel also include faculty mentors/advisors who provide
direct oversight to Postdoctoral Fellows, Residents and Clinical Fellows
serving as PI on the IRB application.
 
The IRB requires that all Key Study Personnel complete Human Subjects
Protection Training through CITI prior to approval of a new study, or a
modification in which KSP are being added. More information on the CITI
training requirement can be found on our website.  
 
KSP Name
Description of Study
Responsibilities - Briefly
describe what will each person
be doing on the study. If there
are procedures requiring special
expertise or certification,
identify who will be carrying
these out. Also identify who will
be obtaining informed consent.
Qualifications, Licensure, and
Training
Dr. Chiu, Charles Y MD
Principal investigator,
Supervision of next generation
sequencing techniques and
bioinformatic analysis of
sequencing data, patient
consent
UCSF Associate Professor of
Laboratory Medicine and
Medicine/Infectious Diseases;
Director, UCSF-Abbott Viral
Diagnostics and Discovery
Center; Associate Director,
UCSF Clinical Microbiology;
expert in pathogen discovery
techniques, next generation
sequencing and bioinformatics
Dr. DeRisi, Joseph, PhD
Supervision of next generation
sequencing techniques and
bioinformatic analysis of
sequencing data, patient
consent
UCSF Professor and Chair of
Biochemistry and Biophysics,
expert in pathogen discovery
techniques, next generation
sequencing and bioinformatics
Dr. Gelfand, Jeffrey MD
Patient recruitment, consent,
study design
UCSF Assistant Professor of
Neurology, UCSF Multiple
Sclerosis Center, expert on
neuroimmunological diseases,
Masters in Clinical Research
Dr. Wilson, Michael MD
Study design, perform next
generation sequencing on
clinical specimens and
bioinformatics analysis,
patient consent
UCSF Assistant Professor in
Residence in Neurology, UCSF
MS Center, expert in neuro-
infectious diseases
Langelier, Charles R
Study design, perform next
generation sequencing on
clinical specimens and
bioinformatics analysis,
patient consent
UCSF Infectious Diseases
fellow
Chow, Felicia, MD
Study design, patient
recruitment, data analysis,
patient consent
UCSF Assistant Professor of
Neurology, Neurologist expert
in neuro-infectious diseases
Study Protocol Page 104 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 57 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
Dr. Pleasure, Samuel M.D., PhD
Study design, autoantibody
screening, patient consent
UCSF Professor of Neurology,
Neurologist expert in
neuroimmunological diseases,
Neuroanatomist
Dr. Geschwind, Michael, MD,
PhD
Study design, data acquisition
and analysis, patient consent
UCSF Professor of Neurology,
neurologist expert in rapdily
progressive dementia
Sample, Hannah
Study coordinator; Patient
recruitment and consent;
specimen processing; study
database management
UCSF clinical research
coordinator
Dr. Chow, Eric, PhD
perform next generation
sequencing on clinical
specimens, data analysis
Director - Center for Advanced
Technology
UCSF Dept. of Biochemistry
and Biophysics
Samayoa, Erik L
perform next generation
sequencing on clinical
specimens
CLIA Lab technician, Chiu Lab
Naccache, Samia N
perform next generation
sequencing on clinical
specimens and bioinformatics
analysis; data manager; CLIA
technician running the mNGS
assay
PhD Bioinformatician, CLIA
Lab technician, Chiu Lab
Miller, Steven
Supervision of next generation
sequencing techniques and
bioinformatic analysis of
sequencing data
UCSF Associate Professor of
Laboratory Medicine, Director,
UCSF Clinical Microbiology
Federman, Scot M
next-generation sequencing
data analysis; running SURPI
bioinformatics pipeline
UCSF Programmer/Analyst III,
UCSF Department of
Laboratory Medicine
Stryke, Doug
next-generation sequencing
data analysis; running SURPI
bioinformatics pipeline
UCSF Programmer Analyst,
UCSF Department of
Laboratory Medicine
Berger, Amy
study design; enrolling
patients for NGS study;
obtaining consent
UCSF Resident Physician
Pham, Elizabeth
CLIA technician running the
clinical mNGS assay
UCSF Clin Lab Scientist
UCSF Department Laboratory
Medicine
Samayoa, Erik L
CLIA technician running the
clinical mNGS assay
UCSF Clin Lab Scientist
UCSF Department Laboratory
Medicine
Yu, Guixia
Sample biobanking and
aliquotting; running
confirmatory research assays
UCSF SRA, UCSF Department
of Laboratory Medicine
Study Protocol Page 105 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 58 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
for the mNGS clinical test
Zorn, Kelsey C
Consent patients, assist with
specimen collection, data
management
UCSF Clinical Research
Coordinator, Dept of
Biochemistry and Biophysics
20.0
Other Approvals and Registrations
20.1  * ADMINISTRATION OF RECOMBINANT DNA: Does this study involve administration of vaccines
produced using recombinant DNA technologies to human subjects (Help Link added Aug '15):
(REQUIRED)
  Yes   
  No
20.2  * HUMAN GENE TRANSFER: Does this study involve human gene transfer (NOTE: Requires NIH
Recombinant DNA Advisory Committee (RAC) review prior to IRB approval): (REQUIRED)
  Yes   
  No
20.4  OTHER APPROVALS: Indicate if this study involves other regulated materials and requires approval
and/or authorization from the following regulatory committees:
Institutional Biological Safety Committee (IBC)
Specify BUA #:
Chiu lab: BUA 49187-BU-01-INC; CLIA certificate 05D1024215
Institutional Animal Care and Use Committee (IACUC)
Specify IACUC #:
Controlled Substances
21.0
End of Study Application
21.1  
End of Study Application Form
 
To continue working on the Study Application: Click on the section you need to edit in the
left-hand menu. Remember to save through the entire Study Application after making
changes.
 
If you are done working on the Study Application:
 
Important: Before proceeding, please go back to Section 4.0 Initial Screening
Questions and Save and Continue through the form to make sure all the relevant
sections and questions have been included. If you've changed any answers since you
started, the branching may have changed. Your application will be incomplete and it
will have to be returned for corrections. 
Study Protocol Page 106 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5/25/18, 10:43 AM
iRIS: IRB Study Application
Page 59 of 59
https://iris.ucsf.edu/Study_App.jsp?FORM_MODE=PRINT_HTML&tab=full
 
Once you are sure the form is complete, click Save and Continue. If this is a new study, you
will automatically enter the Initial Review Submission Packet form, where you can attach
consent forms or other study documents. Review the Initial Review Submission Checklist
for a list of required attachments.
 
Answer all questions and attach all required documents to speed up your approval.
 
 
 
 
 
 
The UCSF IRB wants your feedback about this new form. Please
click the link to take a brief survey about the new application form.
Study Protocol Page 107 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

4.  SUMMARY OF CHANGES TO THE ORIGINAL STUDY PROTOCOL 
 
 
Approval 
date 
Summary of modiﬁcations 
1.2 
3/01/16 
Initial approval of study application. UCSF as IRB of record, UC Davis and UCLA approved as relying sites.  
1.3 
5/25/16 
Changes to consent documents:  
• 
removed language that allowed for participants to have the UCSF mNGS test done without participation in 
the research study. This initial demonstration project will limit access only those who are in the study (meet 
criteria and are willing to consent).  
Changes to Application: 
• 
section 3- updated study personnel 
• 
section 7 updated personnel for outside site; Syapse 
• 
section 11 included referral form that we will use to determine eligibility for study 
Attached docs: 
• 
referral survey 
• 
CITI training certification for new Syapse team member 
• 
revised consents 
 
1.4 
6/10/16 
Updated study personnel  
 
1.5 
6/20/16 
This modification is being submitted because of a glitch in the iRIS system. Our vulnerable populations were 
accidentally removed from the application. They have been added again here on the new form. Discussion has been had 
with Karen Chao and Liz Tioupine. 
Section 1: DAID-> PDAID 
Section 3: removed Kristen McCaleb 
Section 5: CIAPM is listed as funding (this has always been the case) 
Section 6: removed SFGH, this is still in process, will add them at a later date 
Section 9: changed to No, this has never been true and was an error. 
Section 10: added justification for enrollment numbers 
Added minors, pregnant women, non-English speakers, patients unable to consent themselves, and the economically 
disadvantaged (this was in the original application form, but glitched out with section 9.6 being selected ‘yes’) 
Section 11: inclusion of minors 
Section 12: added UC ReX 
Section 12: consent method for non-English speakers 
Section 16: Added where we are obtaining PHI 
Section 16/ 14: defined PHI, sensitive data 
Section 18: removed Kristen McCaleb 
 
1.7 
8/19/16 
This modification includes changes to the consent documents, the addition of one study personnel, and includes 
consenting subjects who have been discharged or transferred. 
  
Changes to consent:  
No major changes 
Minor changes in language, presentation, and organization 
These changes are being submitted via the request of our UCLA collaborators in hopes it will make the consent more 
understandable for study participants 
  
Changes to application: 
Section 3: two team members added 
Section 12: adding consent for patients who have been transferred or discharged 
Section 18: qualifications for KSP 
Study Protocol Page 108 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

1.9 
1//3/17 
Section 4.1—updated information to reflect finished validation of CSF (June 2016) and pending validation of serum and 
BAL.  
Section 4.9—yes, Clinical Trial, pending final posting. 
Section 4- indicated ‘yes’ to financial conflict of interest 
  
1) The SURPI-PLUS software used for analysis of sequencing data in the study has been disclosed to the UCSF Industry 
and Technology Alliances (UCSF ITA) and is under copyright as disclosure SF2014-090 
2)The SURPI-PLUS algorithms, including analysis, interpretation, and visualization components, is the subject of a 
patent application titled “Pathogen Detection Using Next-Generation Sequencing”, filed 9/21/2016, and superseding the 
non-provisional U.S. patent application No. 62/221,574 filed 9/21/2015. 
3)The terms “SURPI”, “SURPI+”, “SURPI-PLUS”, and “SURPIrt” have been trademarked by UCSF, filed with the 
United States Patent and Trademark Office with statement of use 7/19/16 
4)The positive and negative controls used in the assay have been disclosed as case number SF2016-185, entitled 
“Microbial Standard Reference Materials for Pathogen Detection” 
  
Section 6.1 added SFGH 
Section 6.3 updated information on sites 
Section 7.1- updated information for CNMC, Dr. Goldberg has recused as site PI, Dr. DeBiasi will now be site PI 
7.1 added Milliman, St. Jude and Children's Hospital Colorado 
Section 8- updated information stated 
Section 9.3 non-significant risk information  
Section 11- added wards of the state. There is a current patient who is a foster child, whom we would like to enroll in the 
study as they have acute encephalitis and access to the clinical diagnostic could potentially benefit this patient.  
Section 12- updated wording 
Section 12.8 added DocuSign for remote consenting  
Section 14.6 updated surrogate consent info 
Section 16.7 removed info about clinical test, not relevant for IRB 
  
__________CONSENT________ 
  
CNMC: removed Dr. Goldberg as contact from these documents, updated to include DeBiasi’s contact information (all 3 
CNMC consents) 
  
UCSF consents: removed Dr. Goldberg (CNMC collaboration is using a separate consent), updated statement that 
addressed accuracy of test to state “clinical utility” of test. Added statement regarding patent.  
  
______ATTACHED DOCUMENTS_______ 
  
attached are IAA for ST. Jude, CITI certs for St. Jude team and CNMC team, as well as letter of support from Milliman 
(not engaged in human subjects research). Also attached IRB documents for Children's Hospital Colorado (independent 
IRB review and approval for collaboration)  
1.10 
2/22/17 
Section 3- updated staff (originally added in study management prior to modification) 
Section 3.3- added another contact (Jenn Mann) 
Section 4.1 3 UCs-> 4UCs (adding UCSD) 
  
Section 5.3 This change may have been an error—the P number is now pulled into the application 
Section 6.3 adding UCSD 
Section 6.8- checked UCSD 
Consent form: added UCSD contact info to adult/adolescent form  
 
 
 
1.16 
8/17/17 
Application: 
8.4 added provider survey to procedures 
15.5 updated and detailed re-consent procedure for patients who were enrolled via surrogate 
  
Consent Documents:  
1. Submitting an adult consent form for St Jude (currently only a minors consent form is available for St Jude)  
  
Other Study Documents: 
1-2. Submitting the provider pre and post test result surveys 
3. Added phone script for re-consent to surrogate 
4. Added phone script for re-consent to participant 
5. Added re-consent letter to participants 
Study Protocol Page 109 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

6. Added re-consent letter to surrogates 
7. Added Status Update Form 
 
1.17 
12/18/17 
Section 3: removed Jenn Mann as study contact, other personnel changes pulled from study management tab 
Section 7.1 Outside sites—added new coordinator for CNM 
Other Documents: 
CITI cert for new CNMC coordinator who will be doing data collection / chart review 
 
 
 
Study Protocol Page 110 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

5.  REGULATORY COMMITTEE APPROVALS 
 
The UCSF Clinical Microbiology Laboratory, a CLIA-licensed facility, operates under CLIA with 
certiﬁcate 05D1024215 and undergoes regular inspections by CAP and CLIA. The Chiu research 
laboratory is able to analyze research samples collected from patients under active BUA (Biological 
Use Authorization) 49187-BU-01-INC. 
 
This was a multisite study with the following IRB approvals: 
 
UC Reliance 1595-3 
• 
Coordinating Center 
o University of California, San Francisco 
o 15-18425 
• 
Relying Sites through UC BRAID 
o University of California, Davis 
o University of California, Los Angeles 
o University of California, Berkeley  
o University of California, San Diego 
 
Relying Sites (UCSF IRB, not under UC BRAID) 
• 
Children’s National Medical Center 
• 
Zuckerberg San Francisco General Hospital 
• 
St Jude Children’s Research Hospital  
 
Collaborating Sites with independent IRB review 
• 
Children’s Hospital Los Angeles 
• 
Children’s Hospital Colorado  
 
This study was submitted as version 1.0 on 12/8/15 and approved by the UCSF IRB as study number 
15-18425 after proposed clariﬁcations to the protocol as version 1.2 on 3/1/2016. The ﬁrst study 
patients were enrolled on 6/15/2016 under protocol version 1.4 which was approved on 6/10/16.   
 
Study Protocol Page 111 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

6.  STATISTICAL ANALYSIS PLAN 
 
6.1.  Original Statistical Analysis Plan 
 
This was a one-year, multicenter, prospective cohort study in which subjects were enrolled based 
on a particular exposure (i.e. idiopathic meningitis +/- encephalitis and/or myelitis) and then followed 
over time to assess for the occurrence of the outcome (i.e. results of CSF mNGS testing).  Prospective 
enrollees were identified by physician referral, computerized provider order entry, patient chart review, or 
screening of daily EMR reports (Supplementary Appendix). Given funding and clinical testing capacity 
constraints, sample size estimates (n=300) were based on convenience without formal statistical 
considerations. The target condition was idiopathic meningitis, encephalitis, and/or myelitis in patients 
undiagnosed at time of enrollment. The index test was the CSF mNGS assay, and the reference standard 
was a composite of conventional testing and orthogonal confirmatory testing of mNGS-only positive 
results, either with respect to all clinical testing or direct detection (i.e. non-serologic) testing of CSF 
only. 
 
Performance measures (sensitivity, specificity, positive predictive value (PPV), and negative 
predictive value (NPV)) were calculated using standard formulas for proportions, and 95% confidence 
intervals for these proportions were determined using Wilson’s method. The primary analysis was a 
comparison of the performance of the mNGS assay versus conventional (direct detection) testing using 
the composite results of direct detection testing of CSF, including orthogonally confirmed mNGS results, 
as the reference standard. Secondary analyses included 2x2 contingency analyses of other comparative 
performance measures and calculations of diagnostic yield (the number and proportion of infectious 
diagnoses made by mNGS or conventional testing).  
 
The original statistical analysis plan may also be viewed as part of original IRB protocol on page 
27. 
 
 6.2.  Final Statistical Analysis Plan 
 
This was a one-year, multicenter, prospective cohort study in which subjects were enrolled based on 
a particular exposure (i.e. idiopathic meningitis +/- encephalitis and/or myelitis) and then followed over 
time to assess for the occurrence of the outcome (i.e. results of CSF mNGS testing).  Prospective 
enrollees were identified by physician referral, computerized provider order entry, patient chart review, or 
screening of daily EMR reports (Supplementary Appendix). Given funding and clinical testing capacity 
constraints, sample size estimates (n=300) were based on convenience without formal statistical 
considerations. The target condition was idiopathic meningitis, encephalitis, and/or myelitis in patients 
undiagnosed at time of enrollment. The index test was the CSF mNGS assay, and the reference standard 
was a composite of conventional testing and orthogonal confirmatory testing of mNGS-only positive 
results, either with respect to all clinical testing or direct detection (i.e. non-serologic) testing of CSF 
only.  
 
As gold standard reference results for diagnosis of meningitis and encephalitis was not available 
(due to the varying extent of diagnostic testing done at each hospital, lack of detailed performance 
characteristics for each test performed locally, and lack of availability of comprehensive gold standard 
testing for meningitis and encephalitis), obtaining unbiased estimates of sensitivity and specificity was 
not possible. Thus, the comparative performance measures of mNGS relative to conventional testing are 
reported as positive percent agreement (PPA) and negative percent agreement (NPA) to the composite 
reference standard, in accordance with statistical guidance from the FDA. PPA and NPA were calculated 

using standard formulas for proportions, and 95% confidence intervals for these proportions were 
determined using Wilson’s method. 
 
The primary analysis was a comparison of the performance of the mNGS assay versus 
conventional (direct detection) testing using the composite results of direct detection testing of CSF, 
including orthogonally confirmed mNGS results. Secondary analyses included 2x2 contingency analyses 
of the PPA and NPA of the mNGS assay relative to other combinations of conventional diagnostic testing 
including serology and test results from other tissue types. 
  
The final statistical analysis plan may also be viewed as part of the final IRB protocol on page 78. 
 
6.3.  Summary of Changes to the Statistical Analysis Plan  
 
In the Institutional Review Board (IRB)-approved protocol titled “Study Protocol for the PDAID 
Trial”, clinical trials registration number NCT02910037, one of the primary outcomes is described as an 
assessment of clinical mNGS assay performance (sensitivity, specificity, positive predictive value, and 
negative predictive value). These performance measures are also mentioned in the document as an 
explanation for why the use of the device in the study (the clinical mNGS assay) poses a non-significant 
risk. 
 
During the course of peer review, it was brought up that obtaining unbiased estimates of 
sensitivity and specificity was not possible as gold standard reference results for diagnosis of meningitis 
and encephalitis were not available. Thus, the comparative performance measures of mNGS relative to 
conventional testing are calculated and reported in the paper as positive percent agreement (PPA) and 
negative percent agreement (NPA) to the composite reference standard, in accordance with statistical 
guidance from the FDA (“Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic 
Tests – Guidance for Industry and FDA Staff”, Food and Drug Administration, U.S. Department of 
Health and Human Services, issued March 13th, 2007).  
 

7.     APPENDIX 
 
7.1.  Enrollment Flow Chart 
 
 
 
 
 
XXX enrolled
in study
XXX not enrolled
XXX do not meet
criteria for enrollment
XXX meet criteria
for enrollment
• XXX chart review
• XXX physician referral
• XXX automated electronic
       medical records report
• XXX provider order entry
•  XXX inadequate
        sample volume
• XX decline to
        participate 
• XXX unable to contact
          patient / surrogate
Study Protocol Page 114 | Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis