Prenatal Precision Medicine (NSIGHT2): A Randomized, Blinded, Prospective Study of the Clinical Utility of Rapid Genomic Sequencing for Infants in the Acute-care Setting
Phase: NA
Conditions: Genetic Diseases, Genetic Syndrome, Mendelian Disorders
Sponsor: Rady Pediatric Genomics & Systems Medicine Institute

 
 
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UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Form Version date: 
9/30/2013
1.
PROJECT TITLE 
Study #: 161983 
Perinatal Precision Medicine (NSIGHT2): A randomized, blinded, prospective study of the clinical utility of 
rapid genomic sequencing for infants in the acute-care setting 
2. 
PRINCIPAL INVESTIGATOR
Stephen F. Kingsmore, MD, DSc  
CEO and President of Rady Children’s Institute for Genomic Medicine (RCIGM)  
3. 
FACILITIES 
Rady Children’s Institute for Genomic Medicine 
Rady Children’s Hospital (RCHSD) – All locations 
Rady Children’s Clinical Genomics Laboratory 
University of California at San Diego 
 
4. 
ESTIMATED DURATION OF THE STUDY
Enrollment in Rady Children's Hospital acute care settings to begin in 2017 and to continue through 2019, with 
follow-up including chart review of outcomes through 2025. 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph)
This study will seek to determine if rapid genomic sequencing improves outcomes for acutely ill infants. We 
will enroll up to 1,000 acutely ill infants in a prospective, randomized, blinded study to either rapid Whole 
Genome Sequencing (WGS) or rapid Whole Exome Sequencing (WES, which is 2% of the genome and ~2-fold 
less expensive). Outcomes will be measured both by objective clinical measures and family perceptions 
(patient/family centered outcomes). Primary analysis of WGS or WES will be in infants alone. Secondary 
analysis, in infants who do not receive a diagnosis, will be of families – ideally trios (mother, father and 
affected infant), which is ~2-fold more expensive. Trios will be analyzed within the same randomization arm 
(WGS or WES). This study is designed to quantify which acutely ill infants benefit from rapid genomic 
sequencing, by how much they benefit, how they benefit, which rapid genomic sequencing method is superior, 
and the cost effectiveness of such testing. 
 
6.
SPECIFIC AIMS
Specific Aim 1. Determine if, and by how, much rapid WGS is associated with better outcomes than rapid 
WES in acutely ill infants. The null hypothesis is that both tests are equivalent. This may occur, for example, if 
the diagnosis rate is similar or the additional diagnoses from WGS do not alter clinical management. 
 
Specific Aim 2. Determine if and by how much rapid WGS is associated with better perceived outcomes in 
parents of acutely ill infants than rapid WES in acutely ill infants. The null hypothesis is that both tests are 

 
 
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equivalent. In addition, this will be the first study to examine the family-centered outcomes of rapid genomic 
sequencing, and particularly in Hispanic/Latino families. 
 
Specific Aim 3. To compare diagnostic rates, time to diagnosis, and outcomes of rapid genome-wide 
sequencing compared with historical matched cases who received standard care before genome-wide 
sequencing was available. The null hypothesis is that genome wide sequencing does not increase diagnosis rate, 
time to diagnosis or outcomes. 
 
Specific Aim 4. To compare diagnostic rates of singleton analysis versus familial analysis (ideally trio) and the 
cost-effectiveness of each testing method (rapid singleton WGS, rapid singleton WES, rapid trio WGS and 
rapid trio WES). The null hypothesis is that adding familial sequencing data does not significantly increase 
diagnostic yield. 
 
7. 
BACKGROUND AND SIGNIFICANCE 
15% of the 4 million infants born in the US each year are admitted to a Neonatal Intensive Care Unit (NICU) or 
Pediatric Intensive Care Unit (PICU) for diagnosis and treatment of an acute illness. Approximately 6% of 
infants born in San Diego county are admitted to the RCHSD Level IV NICU or regional PICU. Genetic 
diseases are common among infants in ICUs, although precise prevalence data does not exist. There are more 
than 8,000 defined genetic diseases. Malformations and genetic disorders are the leading cause of infant 
mortality, NICU mortality and PICU mortality in the US. One study in a large children's hospital reported that 
51% of infant deaths were from a malformation and/or a genetic disorder. 19% of deaths in the PICU of a large 
children’s hospital were due to genetic diseases. Our experience suggests that up to 40% of level IV NICU 
infants may benefit from rapid WGS for genetic disease diagnosis. However, studies to date have been limited 
to a small proportion of NICU admissions, and may therefore be subject to ascertainment bias.  
Newborn Screening (NBS), although variable by state, identifies 44 diseases within several weeks of birth, 
primarily inborn errors of metabolism (IEM) that collectively affect 0.3% of newborns. Typically, these 
diseases are asymptomatic at birth. NBS is not designed to diagnose genetic conditions in acutely ill infants, but 
rather to screen the population. However, IEMs are detected in 1.5% of NICU infants, and are associated with 
~20% mortality. Rapid diagnosis of IEMs by NBS allows timely institution of treatment that saves thousands of 
Quality Adjusted Life Years (QALY) and Disability Adjusted Life Years (DALY) per year. The QALY is a 
generic measure of disease burden, including both the quality and the quantity of life lived. It is used in 
economic evaluation to assess the value of medical interventions. One QALY equates to one year in perfect 
health. Likewise, the DALY is a measure of overall disease burden, expressed as the number of years lost due 
to ill-health, disability or early death. IEMs represent the tip of the genetic disease iceberg in NICU and PICU 
infants, but it is not known whether broad use of genomic sequencing in such infants would save additional 
QALYs and DALYs.  
Other than IEMs and common chromosomal diseases (e.g. Down syndrome and 22q11 microdeletion 
syndrome), ascertainment rates of genetic diseases in NICUs and PICUs are low. Serial, single gene sequencing 
is the current standard for molecular diagnosis of genetic diseases for acutely ill infants. However, it is usually 
too slow for clinical utility in these sick infants as time-to-result for each test is >4 weeks, and more typically 6 
- 26 weeks. Sequential testing may take years. Rapid WGS and WES allow simultaneous testing of most of the 
8,000 known genetic disorders within 1 week. 
Due to lack of methods for rapid molecular diagnosis, NICU and PICU treatment of genetic diseases is usually 
empiric. We recently invented WGS with time-to-result of ~26 hours, providing a method for timely diagnosis 
in acutely ill infants.  In the only published study of rapid WGS (with our prior 2-day protocol), we found that 

 
 
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20 (57%) of 35 enrolled infants received a diagnosis by rapid trio WGS, in contrast to 9% using all 
conventional testing methods. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a rapid WGS 
diagnosis, four (20%) had diagnoses with strongly favorable effects on management, and six (30%) started 
palliative care. However, ascertainment of eligible infants was delayed, and the median diagnosis was at day of 
life ~50. This impacted the effect of diagnosis on outcomes since 100-day mortality was 57% (12 of 21) in 
infants with a genetic diagnosis. This was not a randomized controlled study, infants were selected based on 
likelihood of having an actionable genetic diagnosis, and all infants received both WGS and conventional tests. 
Thus, this study was not designed to determine the maximum improvement in outcomes achievable nor the 
proportion of NICU infants who benefit. The diagnostic variants affected coding regions of genes, and therefore 
would potentially have been detected by WES (rather than WGS). The most common mechanism was de novo 
mutation causing dominant disorders, which are much more difficult to identify by singleton than trio testing. 
Recently we implemented rapid (3 days) trio WGS at RCIGM. For 4 months we have enrolled acutely ill 
infants at RCHSD in the protocol “Genomic Biorepository: Protocol for the Collection, Storage, Analysis, and 
Distribution of Biological Samples, Genomic and Clinical Data (IRB #160468)”. Among 35 families with 
acutely infants nominated, 29 (83%) were enrolled. The fastest time to diagnosis was 41 hours from blood draw 
to communication of provisional diagnosis. On average, diagnosis occurred within one week. At time of 
submission, WGS had been interpreted in 29 families with 30 symptomatic infants, yielding informative data in 
28. 15 (53%) of infants received diagnoses. In 14 (50%), the initial diagnosis was by rapid trio WGS. 13 
patients had single nucleotide variants and two had structural variants. The leading mechanism of disease was 
de novo mutations causing dominant genetic disorders. Only two patients received diagnoses prior to 
completion of rapid trio WGS. Following diagnosis by rapid trio WGS, clinical management changed in 12 
(43% of infants tested). Of these, medications were changed in 9 (32%) infants; One infant avoided needless 
major surgery; Palliative care was initiated in two infants with > $6M potential healthcare savings. This data 
replicated our published previous experience at Children’s Mercy Hospital in Kansas City, but was remarkable 
since enrollment was much broader at RCHSD (namely, the 4 or 5 infants with greatest need of a definitive 
diagnosis each week). 
Additionally, we recently concluded the first randomized, controlled, partially blinded, prospective trial of the 
28-day diagnostic yield of rapid trio WGS plus conventional testing versus conventional testing in acutely ill 
NICU infants (the NIH-funded “NSIGHT” study). While the results are still being evaluated, we found that 
patients in the control arm of the study also received genetic diagnoses through next-generation sequencing, 
including WES and WGS, upon unblinding of neonatologists. Similarly, we observed a cross-over rate for 
compassionate use of WGS of 10%. Nevertheless, we found that the 28-day rate of diagnosis was 5 of 33 (15%) 
in the control arm and 14 of 32 in the rapid trio WGS arm (44%, p<0.01). Thus, provisionally, we conclude that 
rapid trio WGS has greater 28-day diagnostic yield than conventional testing. This study was not designed to 
evaluate clinical utility. 
Finally, a group that we are collaborating with in Melbourne Australia published a study of 80 children <2 
years of age with likely genetic diseases. Singleton WES yielded a 58% rate of diagnosis. WES is four-fold less 
expensive than WGS, and singleton testing is 2-fold less expensive than trios. Their enrollment criteria favored 
children with a positive family history, which enriched for infants with recessive diseases (which are readily 
identified by singleton testing). While de novo mutations were the leading cause of diagnosis in their study, 
recessive diseases were much more common in their cohort than other studies. They utilized WES at standard 
speed (~6 month time to diagnosis), and thus their study was not well designed to assess clinical utility. 
These studies, which comprise the literature to date, demonstrate that rapid WGS significantly increases the rate 
of diagnosis and time to diagnosis compared with traditional testing. As yet, however, no randomized 

 
 
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controlled study has compared the rate of diagnosis of WGS and less costly WES, nor of trio versus less costly 
singleton testing. It is no longer acceptable to have randomization to a control arm that delays reporting of 
results up to 12 weeks (such as routine speed WGS or WES). Furthermore, although data from studies to date 
shows clinical utility of WGS or WES, it is not yet clear what the specific indications for such testing should be 
in acutely ill infants, nor whether WGS or WES are associated with improved outcomes. Furthermore, both the 
cost of WGS and WES, and their clinical utility, increase as time to result decreases. The optimal match of 
timeliness and cost effectiveness are not yet known. Finally, it not clear whether patient and family perceptions 
of improved outcomes match those of physicians. Therefore, we propose to examine standard and family-
centered outcomes in acutely ill infants receiving rapid WGS or rapid WES as a first-line test. 
Little data exists on the clinical utility of rapid genomic sequencing for cost-effectiveness modeling of 
interventions initiated in the early days to weeks of life. Studies have shown that NBS decreases morbidity and 
mortality because it provides rapid screening at birth for diseases that benefit from early treatment. 
Additionally, rapid genomic diagnosis of critically ill babies may diagnose lethal disorders, enabling initiation 
of palliative care, potentially decreasing physical suffering to the infant, and prioritizing bonding with family 
members rather than futile heroic interventions. Studying the clinical impact of WGS or WES for acutely ill 
infants compared with historic controls will provide information on the incidence of genetic disease in this 
population and help determine how WGS and WES benefit acutely ill infants, their families and their clinical 
care providers. Likewise, we will attempt to aggregate data for QALYs and DALYs to analyze the clinical 
utility of genomic sequencing, in addition to clinician surveys of utility, and to assess economic impact of 
testing over the lifetime of each patient. 
Rapid WES is ~2-fold less expensive than rapid WGS but has at least one additional day of time to results. 
There is no data comparing the diagnostic or clinical utility of WES and WGS. WES is the only genome wide 
sequencing test routinely covered by insurers. In addition, as noted above, all of our rapid WGS cases could 
theoretically have been detected by WES. Conversely, although WES can analyze the coding regions of nearly 
all potentially disease causing genes, we believe that WGS is superior, despite its higher costs, due to its ability 
to detect de novo variants, structural variants (SV), and to interrogate regions of extreme GC content. WGS 
provides coverage of non-coding variants that can be clinically identified as definitely disease causing. As such, 
we believe an analysis of diagnostic rates between the two types of tests will show that WGS does in fact 
provide more diagnoses than WES. However, such increases in diagnoses may not lead to an increase in 
changes in care as the variants that can be detected only by WGS may be less amenable to specific therapeutic 
interventions. The primary goal of this study is to evaluate which method provides the optimal outcomes in 
acutely ill infants with likely genetic diseases. However, we anticipate that we may also – in subsequent 
amendments – retrospectively re-analyze these samples to determine if WGS or WES has superior ability to 
yield pharmacogenomic and secondary findings related to childhood-onset conditions. In subsequent 
amendments, families may potentially be asked for their opinions on receiving such additional testing results, if 
available, following the discharge of their child. As pharmacogenomics knowledge grows, the need for 
informed drug choice and dose will be crucial in effectively managing critically ill patients and preventing 
secondary harm. In particular, we anticipate a future amendment to examine the prevalence of the genetic 
predisposition to hearing loss following the administration of aminoglycosides, an antibiotic very commonly 
used in NICUs. 
The incidence of genetic diseases in acutely ill infants receiving NICU and PICU care is unknown since no 
large scale genomic sequencing study has been performed in this population. While genetic diseases are known 
to be a leading cause of death among infants, the impact of timely diagnosis in acutely ill infants on clinical 
care of these diseases is unknown. We propose a prospective, randomized study to compare outcomes in up to 
1,000 acutely ill babies, all of whom will receive some form of genomic sequencing. We will use genomic 

 
 
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sequencing to prospectively test the hypothesis that rapid WGS confers significantly better outcomes to a 
subset of ill neonates/infants and their families than rapid WES or current clinical practice (clinical diagnosis 
and standard diagnostic tests).  Molecular diagnostic yield, time to diagnosis and changes in management will 
be secondary outcomes. 
8. 
PROGRESS REPORT 
This study has resulted in 23 publications to date: 
1. 
Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in 
children with suspected genetic diseases. Clark MM, Stark Z, Farnaes L, Tan TY, White SM, Dimmock D, Kingsmore SF. NPJ 
Genom Med. 2018 Jul 9;3:16. 
2. 
Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. Farnaes L, Hildreth A, Sweeney 
NM, Clark MM, Chowdhury S, Nahas S, Cakici JA, Benson W, Kaplan RH, Kronick R, Bainbridge MN, Friedman J, Gold JJ, Ding 
Y, Veeraraghavan N, Dimmock D, Kingsmore SF. NPJ Genom Med. 2018 Apr 4;3:10. 
3. 
The case for early use of rapid whole-genome sequencing in management of critically ill infants: late diagnosis of Coffin-
Siris syndrome in an infant with left congenital diaphragmatic hernia, congenital heart disease, and recurrent infections. Sweeney 
NM, Nahas SA, Chowdhury S, Campo MD, Jones MC, Dimmock DP, Kingsmore SF; RCIGM Investigators. Cold Spring Harb Mol 
Case Stud. 2018 Jun 1;4(3).  
4. 
The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically 
ill infants. Petrikin JE, Cakici JA, Clark MM, Willig LK, Sweeney NM, Farrow EG, Saunders CJ, Thiffault I, Miller NA, Zellmer L, 
Herd SM, Holmes AM, Batalov S, Veeraraghavan N, Smith LD, Dimmock DP, Leeder JS, Kingsmore SF. NPJ Genom Med. 2018 
Feb 9;3:6. 
5. 
Rapid whole-genome sequencing identifies a novel <i>AIRE</i> variant associated with autoimmune polyendocrine 
syndrome type 1. Sanford E, Watkins K, Nahas S, Gottschalk M, Coufal NG, Farnaes L, Dimmock D, Kingsmore SF; RCIGM 
Investigators. Cold Spring Harb Mol Case Stud. 2018 Jun 1;4(3). 
6. 
Rapid whole-genome sequencing identifies a novel <i>GABRA1</i> variant associated with West syndrome. Farnaes L, 
Nahas SA, Chowdhury S, Nelson J, Batalov S, Dimmock DM, Kingsmore SF; RCIGM Investigators. Cold Spring Harb Mol Case 
Stud. 2017 Sep 1;3(5). 
7. 
Rapid whole-genome sequencing identifies a novel homozygous <i>NPC1</i> variant associated with Niemann-Pick type 
C1 disease in a 7-week-old male with cholestasis. Hildreth A, Wigby K, Chowdhury S, Nahas S, Barea J, Ordonez P, Batalov S, 
Dimmock D, Kingsmore S; RCIGM Investigators. Cold Spring Harb Mol Case Stud. 2017 Sep 1;3(5). 
8. 
Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research. Manolio TA, Fowler DM, Starita 
LM, Haendel MA, MacArthur DG, Biesecker LG, Worthey E, Chisholm RL, Green ED, Jacob HJ, McLeod HL, Roden D, Rodriguez 
LL, Williams MS, Cooper GM, Cox NJ, Herman GE, Kingsmore S, Lo C, Lutz C, MacRae CA, Nussbaum RL, Ordovas JM, Ramos 
EM, Robinson PN, Rubinstein WS, Seidman C, Stranger BE, Wang H, Westerfield M, Bult C. 
Cell. 2017 Mar 23;169(1):6-12. 
9. 
Genomic newborn screening: public health policy considerations and recommendations. Friedman JM, Cornel MC, 
Goldenberg AJ, Lister KJ, Sénécal K, Vears DF; Global Alliance for Genomics and Health Regulatory and Ethics Working Group 
Paediatric Task Team. BMC Med Genomics. 2017 Feb 21;10(1):9. 
10. 
Newborn Sequencing in Genomic Medicine and Public Health. Berg JS, Agrawal PB, Bailey DB Jr, Beggs AH, Brenner SE, 
Brower AM, Cakici JA, Ceyhan-Birsoy O, Chan K, Chen F, Currier RJ, Dukhovny D, Green RC, Harris-Wai J, Holm IA, Iglesias B, 
Joseph G, Kingsmore SF, Koenig BA, Kwok PY, Lantos J, Leeder SJ, Lewis MA, McGuire AL, Milko LV, Mooney SD, Parad RB, 
Pereira S, Petrikin J, Powell BC, Powell CM, Puck JM, Rehm HL, Risch N, Roche M, Shieh JT, Veeraraghavan N, Watson MS, 
Willig L, Yu TW, Urv T, Wise AL. Pediatrics. 2017 Feb;139(2). pii: e20162252. 
11. 
Clinical detection of deletion structural variants in whole-genome sequences. Noll AC, Miller NA, Smith LD, Yoo B, Fiedler 
S, Cooley LD, Willig LK, Petrikin JE, Cakici J, Lesko J, Newton A, Detherage K, Thiffault I, Saunders CJ, Farrow EG, Kingsmore 
SF. NPJ Genom Med. 2016 Aug 3;1:16026. 
12. 
USE OF GENOME DATA IN NEWBORNS AS A STARTING POINT FOR LIFE-LONG PRECISION MEDICINE. 
Brenner SE, Kingsmore S, Mooney SD, Nussbaum R, Puck J. Pac Symp Biocomput. 2016;21:568-75. 
13. 
Whole-Exome Sequencing and Whole-Genome Sequencing in Critically Ill Neonates Suspected to Have Single-Gene 
Disorders. Smith LD, Willig LK, Kingsmore SF. Cold Spring Harb Perspect Med. 2015 Dec 18;6(2):a023168. 
14. 
Newborn testing and screening by whole-genome sequencing. Kingsmore SF. Genet Med. 2016 Mar;18(3):214-6.  
15. 
Rapid whole genome sequencing and precision neonatology. Petrikin JE, Willig LK, Smith LD, Kingsmore SF. Semin 
Perinatol. 2015 Dec;39(8):623-31. 
16. 
A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization. Thiffault 
I, Speca DJ, Austin DC, Cobb MM, Eum KS, Safina NP, Grote L, Farrow EG, Miller N, Soden S, Kingsmore SF, Trimmer JS, 
Saunders CJ, Sack JT. J Gen Physiol. 2015 Nov;146(5):399-410. 
17. 
MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates. Guimier A, Gabriel 
GC, Bajolle F, Tsang M, Liu H, Noll A, Schwartz M, El Malti R, Smith LD, Klena NT, Jimenez G, Miller NA, Oufadem M, Moreau 
de Bellaing A, Yagi H, Saunders CJ, Baker CN, Di Filippo S, Peterson KA, Thiffault I, Bole-Feysot C, Cooley LD, Farrow EG, 

 
 
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Masson C, Schoen P, Deleuze JF, Nitschké P, Lyonnet S, de Pontual L, Murray SA, Bonnet D, Kingsmore SF, Amiel J, Bouvagnet P, 
Lo CW, Gordon CT. Nat Genet. 2015 Nov;47(11):1260-3.  
18. 
A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Miller NA, 
Farrow EG, Gibson M, Willig LK, Twist G, Yoo B, Marrs T, Corder S, Krivohlavek L, Walter A, Petrikin JE, Saunders CJ, Thiffault 
I, Soden SE, Smith LD, Dinwiddie DL, Herd S, Cakici JA, Catreux S, Ruehle M, Kingsmore SF. Genome Med. 2015 Sep 30;7:100.  
19. 
Emergency medical genomes: a breakthrough application of precision medicine. Kingsmore SF, Petrikin J, Willig LK, Guest 
E. Genome Med. 2015 Jul 30;7(1):82.  
20. 
Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of 
diagnostic and clinical findings. Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, Soden SE, Cakici JA, Herd 
SM, Twist G, Noll A, Creed M, Alba PM, Carpenter SL, Clements MA, Fischer RT, Hays JA, Kilbride H, McDonough RJ, 
Rosterman JL, Tsai SL, Zellmer L, Farrow EG, Kingsmore SF. Lancet Respir Med. 2015 May;3(5):377-87. 
21. 
CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and 
methylglutaconic aciduria. Saunders C, Smith L, Wibrand F, Ravn K, Bross P, Thiffault I, Christensen M, Atherton A, Farrow E, 
Miller N, Kingsmore SF, Ostergaard E. Am J Hum Genet. 2015 Feb 5;96(2):258-65.  
22. 
Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A2 γ recapitulate the 
mitochondriopathy of the homologous null mouse. Saunders CJ, Moon SH, Liu X, Thiffault I, Coffman K, LePichon JB, Taboada E, 
Smith LD, Farrow EG, Miller N, Gibson M, Patterson M, Kingsmore SF, Gross RW. Hum Mutat. 2015 Mar;36(3):301-6. 
23. 
Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. 
Soden SE, Saunders CJ, Willig LK, Farrow EG, Smith LD, Petrikin JE, LePichon JB, Miller NA, Thiffault I, Dinwiddie DL, Twist G, 
Noll A, Heese BA, Zellmer L, Atherton AM, Abdelmoity AT, Safina N, Nyp SS, Zuccarelli B, Larson IA, Modrcin A, Herd S, Creed 
M, Ye Z, Yuan X, Brodsky RA, Kingsmore SF. Sci Transl Med. 2014 Dec 3;6(265):265ra168. 
9. 
RESEARCH DESIGN AND METHODS
Summary of design 
A prospective, randomized, controlled, blinded trial to evaluate the comparative outcomes and effectiveness 
(clinical utility, perceived family utility, and cost effectiveness) of two methods of rapid genomic sequencing 
(WGS and WES) and two methods of analysis (singleton probands and familial trios) in acutely ill infants. 
Enrollment in this study includes enrollment into a Newborn/Infant biorepository and co-enrollment into the 
Genomic Biorepository: Protocol for the Collection, Storage, Analysis, and Distribution of Biological Samples, 
Genomic and Clinical Data (IRB #160468). Historic controls will be obtained from a separate retrospective 
chart review study following IRB approval. 
Acutely ill infant inpatients who have an undiagnosed illness, and their families, will be eligible to participate 
in the study.  We will enroll up to 1,000 infants. Locally, the study population will be recruited from Rady 
Children’s Hospital (RCH) inpatient population, primarily the NICU, PICU and cardiovascular intensive care 
unit (CVICU), with a smaller population presenting to other hospital in-patient services. Recruitment will be 
targeted at the RCH main campus, but it may include referrals from satellite locations in the RCH network 
(particularly the RCH NICU network throughout San Diego County). All patients will continue to receive 
routine care as clinically indicated, including the state NBS and other genetic testing as determined by their 
treating providers. Half of the affected study participants will be randomized to receive rapid WGS and the 
other half will receive rapid WES. Each arm will initially be analyzed using the patient’s (proband’s) sample 
only. If a proband-only analysis fails to yield a diagnosis, genomic data from the biological family members 
(typically parents), when available, will be used to supplement analysis (trio analysis). Occasionally, a second 
affected sibling may be available for family analysis. Not infrequently, the father is not available for study. 
Similarly, we anticipate the need for targeted genetic analysis of biological parents, and possibly other family 
members, to confirm diagnostic results and/or provide additional information regarding inheritance. 
Recruitment, Enrollment and Sample Collection: 
Enrollment will be sought within the first 96 hours following admission to RCH or an RCH network ICU or 
within 96 hours of meeting eligibility criteria for the study if the infant was not previously eligible. The 
clinicians will typically confirm study eligibility and make a referral to the research staff. The research staff 

 
 
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will approach the families and provide them with a brief summary of the study, including a study brochure (see 
appendix), research team contact information, and consent documents if requested. Families may also receive 
additional study information and potentially consent at the initial time or the study staff will leave the materials 
and follow up the next day. Families will be given the option to opt-out as a part of the study brochure, which 
may be given to the clinical staff or the research staff at any time. A decision to opt-out will require families to 
re-contact the research team directly should they change their minds.  
Informed consent and permission will be sought for the patients and biological parents. Other family members, 
affected or unaffected, may be asked to enroll as well to assist with analysis. Other family members may 
include children or adults. Blood will be collected from patients and family members following informed 
consent. An order for “RCIGM Research Testing”, at no charge, will be placed in the medical record of each 
participant for sample collection and tracking purposes. The order will be marked as “Completed” at the 
conclusion of the analysis. A second clinical order will be entered, at no charge, for clinical confirmation of the 
research results. The results of the clinical confirmation will be entered into the affected child (or children if 
there are multiple affected individuals in one family) medical record(s) (see Return of Results below).  
Following informed consent, subjects will have blood drawn for nucleic acid (DNA and possibly RNA) 
isolation at the time of enrollment in the study. All maximum blood sample volumes will be determined by the 
patient’s weight in a volume per kg calculation. A minimum of 0.5 ml (up to 3 ml) will be collected from the 
admitted patients by their clinical nursing staff when scavenged blood/DNA is not available. Volume will 
depend on the size of the patient and other clinical lab draw volumes at the time of collection. Up to 6 ml of 
blood will be collected from adult participants by trained research staff. Priority will be given to clinical lab 
samples over research samples.  Buccal smears and saliva may be collected in addition to blood or in lieu of 
blood; heel-prick blood spots, additional blood, urine and left over fluid and tissue samples, if available, may 
also be collected and stored in the Rady Children’s Clinical Genome Center as part of the Genomic 
Biorepository (Study 160468). The latter samples will not involve invasive sampling, and are helpful for 
diagnosis in cases, for example, of mitochondrial diseases and somatic mutations. Samples scavenged from 
other clinical testing and/or other research studies (such as the RUB) will be determined based on the 
participant’s clinical presentation and symptoms. It is impossible to say at this time what amounts and sample 
types will be collected due to the large number of genetic diseases being studied. 
We may collect additional samples for functional studies needed to confirm genetic results. The sample 
amounts, types and additional family members who may be requested to provide additional samples will be 
determined on a case-by-case basis. Whenever possible, previously obtained clinical samples and/or samples 
stored in the Genomic Biorepository and/or RUB will be scavenged to avoid unnecessary patient blood draws. 
If additional samples are required that are not available from other studies or left-over clinical samples, families 
will be contacted regarding these research-only additional samples. The specific sample type and amount will 
be discussed with each family and permission will be requested prior to any additional research-only sample 
collection. Additional samples that may be collected for research-only purposes include blood, buccal swabs, 
saliva, non-invasive stool collection, and/or a clean-catch urine specimen. The study team will coordinate 
collection of such samples, and whenever possible, will coordinate these collections to overlap with routine 
clinical care. No charges will be applied for research-only sample collection. We may also use non-invasive 
methods of DNA collection to test the sample accuracy against whole blood. 
Randomization and DNA Analysis 
Patients and their family members who consent to participate will be randomized to receive either rapid Whole 
Genome Sequencing (WGS) or rapid Whole Exome Sequencing (WES). DNA will be extracted and rapid 
genomic sequencing will occur per Standard Operating Procedures within the Rady Children’s Clinical 

 
 
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Genome Center and in accordance with the Genomic Biorepository (Study 160468). Genomic data will be 
analyzed using the clinical features and symptoms as extracted from the patient’s medical record, reported by 
clinicians, and/or by physical exam by research staff. 
Stage One Analysis: 
The initial symptom-driven analysis will be conducted on the patient’s sample only (singleton analysis). 
Stage Two Analysis: 
If a diagnosis is not found promptly (within 24 hours) via a singleton analysis, the family (or any combination 
of parents and/or other family members) will be analyzed using the same technology that the patient was 
randomized to receive. Dependent upon logistics and the acuity of the patient’s illness, we may generate trio 
genomic sequences simultaneously or in stages (singleton then parental duo). 
Other Analysis: 
Some family members may have targeted sequencing and analysis done to confirm results and/or provide 
additional inheritance information of singleton analysis results. 
Data analysis will follow the standards set by the clinical diagnostic laboratory and in line with 
recommendations from the American College of Medical Genetics (ACMG). Currently, a minimum of two 
expert data analysts will be responsible for analyzing the DNA variants following genomic sequencing. 
Analysts will be rotated among qualified RCIGM staff, including but not limited to laboratory directors, genetic 
counseling staff, trained medical and research staff. One of the analysts will then compile a report to be 
reviewed by the Molecular Pathology Laboratory Directors, Shareef Nahas or Shimul Chowdhury, or the 
Medical Director, David Dimmock. 
We anticipate that in rare cases a newborn may be so ill that the team lacks equipoise that the child can wait for 
the estimated ten day turnaround time of our send-out exome testing. In these rare cases, the PI, or his delegate, 
will decide if the child is not eligible for randomization. These children will remain in the research study 
throughout the entirety of the study, but they will receive in-house ultra-rapid whole genome sequencing by the 
RCIGM laboratory in lieu of either a rapid genome or rapid exome (both anticipated to be 10 day turn-arounds). 
For the purpose of study analysis, these subjects will be treated as excluded from randomization and analyzed 
as a separate category.  
Return of Results 
All findings: Follow up with the patient's family of testing results will be guided by the clinical care team. All 
subjects who receive results as a part of this study may be offered the opportunity to follow-up with licensed 
genetic counselors and/or medical staff from the genome institute to discuss the return of results in-person. This 
post-test genetic counseling will be available to all subjects as a part of this study and may be done in the in-
patient setting, over the telephone or other telecommunication device, or in an out-patient setting. These post-
test counseling visits will be documented in the subject’s RCHSD EHR, but there will not be any billing or 
charges associated with these visits. All genetic counseling sessions (including any pre-test counseling, 
generation of a pedigree, or post-test follow-up contact) with our licensed research team will be documented in 
the patient’s EHR to facilitate communication amongst clinical teams. Such sessions are in addition to any 
clinically indicated counselling or testing which will be performed and billed as appropriate by the clinical 
genetics team and other clinical providers. If the findings pertain to someone who is not a patient in the hospital 
system, in addition to our counselling, we will ask the subject to identify a provider to whom the results can be 

 
 
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returned. 
Primary findings: Pathogenic and likely pathogenic variants (as determined by ACMG guidelines) that relate in 
part or in whole to the patient’s current phenotype will be reported into the patients’ medical record. In the case 
of positive study findings that may be diagnostic, confirmatory clinical diagnostic testing will be performed on 
the proband and, when warranted, segregation analysis on other family members. Following this confirmation, 
a standard clinical diagnostic report will be placed in the patient's medical record, and the nominating physician 
will be contacted. In the event that an affected family member, such as a sibling, is also a patient of the 
enrolling hospital system, clinical results will also be returned to that patient’s medical record. In the event that 
clinical genomic sequencing is done by a CLIA accredited laboratory these negative results will be treated as 
clinical-grade and will be placed in the affected subject’s medical record indicating the symptoms used for 
analysis, the testing done, and the limitations of the results at this time. 
Negative findings: Although the intention of the study is to return symptom-driven results to the medical 
record, the clinical report for confirmation of symptom-driven findings may include negative findings of 
testing. We believe this negative clinical testing result is clinically relevant and should not be withheld as it 
may be pertinent to patient care and future testing. This testing will preferentially use FDA approved in vitro 
diagnostics tests where available. In this situation the entirety of the approved test, not just the target variant 
information will be returned. Similarly, clinical confirmation may be required by an outside laboratory; results 
reported by this outside laboratory may include variants of unknown significance, genome-wide negative 
results and/or secondary findings per the clinical lab’s testing protocol. These results will be placed in the 
patient’s medical record to reflect the clinical testing ordered. Clinical tests required for confirmation of 
research results will be charged to this research study. 
Secondary findings: Whenever possible, this study will not report secondary findings. That is, the laboratory 
will not intentionally seek to evaluate disease status or predisposition beyond attempting to identify the cause of 
the child’s current health issues. Similarly, other information, identified as a result of the testing but not 
relevant to the clinical question, such as family relations not being as stated and adult onset conditions will not 
be returned. In accordance with standard care for clinical laboratories, we will report clinically that no 
pathogenic results were found related to the patient’s specific symptoms. This report will include a list of the 
symptoms used, the type of testing, and the limitations of the testing. Parents and family members of the 
affected patient may also be enrolled in this study for the purpose of comparing genetic variants with the 
affected patient. Similarly to the proband the data will not be evaluated to specifically find carrier information, 
disease status or predisposition beyond that required to identify the cause of disease in the proband. Only in the 
event that an immediately life-threatening illness is inadvertently found, such as familial hypercholesterolemia, 
will results be returned to family members. In this rare event, the family member will be asked to identify a 
clinician to whom our team may return these results. Genetic inheritance patterns and reoccurrence risks will be 
included in the patient’s results and genetic counsellors will be available to all families enrolled in this study as 
well as to support their physicians. 
As noted above it is the intention of the team to not evaluate the genome for “secondary findings”. However it 
is possible that federal or local rules change more strongly recommending analysis of the genome for other such 
findings or there is s future research interest in such analysis. The team will therefore seek to identify families 
that would not want to be contacted in the future to specifically enroll in a study evaluating the return of such 
secondary findings. If families opt out of such contact, they still may be contacted in the future about primary 
study questions but will not be approached to consent for future studies about secondary findings return. 
 
Preliminary Reports – In instances where a diagnosis suggests an intervention that needs to be implemented 

 
 
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prior to the time required for orthogonal confirmation to potentially avoid morbidity or mortality, the diagnosis 
will be communicated to the clinical team verbally and a preliminary clinical report will be placed into the 
medical record. This will be amended or updated when orthologous testing is completed. A preliminary clinical 
report allows greater access and better adoption of the genomic test information for physicians in EMRs. 
Additionally, evidence in the literature and internally at RCIGM have shown that data generated from whole 
genome sequencing (WGS) is equivalent, or even superior in certain instances, to orthogonal methods in terms 
of sensitivity and specificity. In over 150 diagnoses at RCIGM since inception in 2016, all clinically significant 
variants have undergone successful orthogonal confirmation. All results are generated in the CAP-accredited, 
CLIA-certified RCIGM-Clinical Genome Center or collaborating clinically accredited laboratories under the 
guidance and oversight of the laboratory director. Thus, the preliminary report can be viewed as a preliminary 
clinical report. 
Incidental - During the course of the phenotype-driven analysis, if a pathogenic variant is identified that is 
medically actionable and does not overlap with the patient’s reported phenotype, the variant will be 
reported.  Consensus by at least one laboratory director and one RCIGM staff physician must be obtained and 
documented that the possible benefits of reporting the incidental finding of interest exceeds the potential harms. 
Clinically significant variants incidentally ascertained in genes associated with a medically actionable condition 
will be reported as incidental findings if appropriate consent for return of incidental findings has been obtained. 
Reporting of incidental findings will be reported as stated in the RCIGM clinical laboratory guidelines. Criteria 
for consideration include, but are not limited to: available evidence of pathogenicity of the variant, medical 
actionability of the condition of interest, and the benefit:risk ratio of potential medical interventions. 
VUS - A “variant of uncertain significance” is one for which there is insufficient current evidence to determine 
if the variant is disease causing (i.e. clinically significant). This may be due to a lack of available evidence 
supporting pathogenicity or conflicting evidence currently exists. Universally, diagnostic reference laboratories 
performing whole genome sequencing and whole exome sequencing as commercial diagnostic tests report 
variants that are classified by the American College of Medical Genetics as “variants of uncertain significance” 
in genes that are implicated in human disease. Per RCIGM clinical laboratory standard operating procedures, 
selected VUS’s will be placed in a separate table in the report and verbiage will state that additional testing and 
clinical correlation will be required to re-classify the variant as clinically significant. Consensus by at least one 
laboratory director and one RCIGM staff physician must be obtained and documented that the possible benefits 
of reporting the VUS of interest exceeds the potential harms. This type of reporting is necessary as often the 
physicians treating the patients are best positioned to conduct follow up testing and further examinations to 
provide adequate and timely follow-up for a VUS result.  
Surveys: 
Family Surveys:  
After enrollment into the research study, families will have a brief survey administered assessing their trust in 
medical providers (see appendix). In-person surveys will be given the option to take the survey on paper 
independently or administered by research staff verbally. Families for whom a translated survey is not available 
will have the survey administered using an interpreter. Families will receive two follow-up surveys (see 
appendix) assessing decisional regret and perceived benefits or harm of testing. The first follow-up survey will 
be administered within one week of the return of results (including the return of no results), and the second 
follow-up survey will be administered approximately one year after enrollment. If families are still in the 
hospital at the time of follow-up, research staff will attempt to meet the families bedside to conduct the survey. 
For families that are no longer in-patient at the time of follow-up, research staff will attempt to contact families 
by phone prior to administration of follow-up surveys and families will be offered the choice to decline further 

 
 
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surveys at that time. Barring a verbal decline for further surveys, families will have the choice to take the 
survey electronically e.g. via a REDCap survey or by phone. Families who chose the electronic survey will be 
told that if the survey is not completed within 72 hours, the research staff will contact them to conduct the 
survey by phone, with a possible second contact at a scheduled time. 
Clinician Surveys: 
Within one week of the return of results (including the return of no results), clinicians caring for the patient will 
be asked to complete a brief survey (see appendix) regarding the clinical utility of genomic testing. The surveys 
may be administered in-person on paper or independently completed on paper or via email messaging to the 
providers’ secured RCHSD or UCSD electronic mail account. Surveys will contain the minimum information 
required to identify the child in which the testing focuses on. It aims to identify what, if any, changes were 
made to the immediate management of the patient as a result of testing as well as general utility from the 
diagnosis. As these surveys are directed at obtaining clinical information about the patients and not assessing 
the clinicians as research subjects, the clinicians will not be enrolled as a part of this study. A second study of 
clinicians may be performed under a separate protocol in the future. 
 
Data Sharing and Privacy: 
Samples that undergo clinical confirmation will be labeled as such and stored with identifiers for future 
confirmation and tracking. Following return of results, all other samples will have patient identifiers removed 
and be labeled with a research study ID and a second unique sample identifier. These unique identifiers will be 
linked with a Master List within the Rady Children’s Institute for Genomic Research. The Master List will be 
password protected with access limited to research staff only. The Master List may take the form of an Excel 
file housed on an internal secure shared drive, with limited access, and/or a password protected, limited access 
REDCap database administered by RCH. Samples will also be tracked using the Rady Children’s Clinical 
Genome Center’s Laboratory Information Management System (LIMS) system.  
Patient data will be stored securely in this HIPAA compliant sample tracking system separate from the 
electronic medical record. RCIGM is collaborating with researchers at UCSD; therefore data will be stored on 
the UCSD servers as well as the RCIGM servers. Researchers at UCSD will contribute expertise relevant to all 
aims of the study, especially to the ethical, social, and behavioral impacts and implications of newborn 
sequencing research. They will contribute expertise from previous studies of patient and physician response to 
genome sequencing for disease diagnosis, as well as attitudes and preferences about the personal genomic 
information for research. Researchers will analyze data collected from surveys of patients and physicians, draft 
manuscripts that report on findings from those data, and contribute to the design of future empirical studies 
focused on the ethical, social, and behavioral impacts of newborn genome sequencing. 
Biorepositories: 
Sample testing, storage and analysis will adhere to the RCIGM Genomic Biorepository protocol, IRB# 160468. 
Following the clinical storage of samples in accordance with RCIGM CLIA laboratory requirements, all data 
and samples from participants in this study will be stored for future research. Coded and/or de-identified data 
will be shared with the RCIGM Genomic Biorepository (IRB# 160468). 
Participants in this study will also be included in the Genomic Biorepository (IRB# 164068). Under this 

 
 
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protocol nucleic acids may be isolated and prepared for genomic sequencing with Standard Operating 
Procedures (SOP) at the Genomic Institute. Familial samples (for example, mother, father, affected or 
unaffected siblings) will also be obtained, and nucleic acids will also be sequenced per the Genomic 
Biorepository’s SOP, as indicated, to assist in diagnosis of the acute medical condition in the infant. All 
sequencing and sample data will be stored by the Genomic Biorepository (IRB #160468). Clinical information 
will be shared with the Genomic Biorepository including referring clinician details, testing, symptoms, age of 
symptom onset and relevant medical and family history. All future research and data sharing will be regulated 
through the Genomic Biorepository protocol. 
Similarly, this study will operate as a Newborn/Infant Biorepository. De-identified data collected from this 
study will be shared and aggregated with other sites participating in this or similar future research studies 
administered by the Rady Children’s Institute for Genomic Research collecting genotypic and phenotypic data 
from infants. It is anticipated that a protocol mirroring this study will be made available as a multi-site research 
study hosted by Rady Children’s Institute for Genomic Research subject to RCHSD/UCSD and Local IRB 
approval in the near future.  
Data and sample sharing among researchers is key to enhancing the scientific community’s understanding of 
genomics. De-identified data from this Newborn Biorepository will also be shared with public databases such 
as Clinvar and dbGAP as well as other research databases like the Longitudinal Pediatric Data Resource 
(LPDR) hosted by the Newborn Screening Translational Research Network (NBSTRN). Samples and data will 
be stored in the Rady Children’s Institute for Genomic Research and Rady Children’s Clinical Genome Center 
laboratory. The research team will review all cases to ensure that the phenotypic data and genotypic data being 
shared with other researchers as well as in publications and public databases are not individually identifiable. In 
rare cases where this information is determined to be identifiable, the research team will seek out specific 
permission from the family to release this information for the advancement of scientific understanding. 
Optional Questions: 
Participants will also be offered the optional question to allow for the use of photographs as a part of this study. 
The RCH policy regarding the use of photography will be followed and the release form will be signed at the 
time photographs are taken. Photography may be used for publications. Whenever possible, the identifying 
features will be blocked. Names and other personal health identifiers will not be released as a part of 
publications. If, in the future, photographs are to be used for research purposes to test new technologies, 
including algorithms designed to identify phenotypic features, the PI will submit a separate protocol and obtain 
approval from the IRB for such research activity. Phenotypic features identified with this technology, as well as 
other phenotypic data collected from the medical record and patient assessments, may be shared with both 
public databases as well as in publications.  
Opt-Out for Incidental Findings 
Families will be given the opportunity to opt-out of receiving actionable incidental results. In the event that our 
analysis incidentally finds a pathogenic variant for which a treatment or intervention exists to improve 
morbidity and/or mortality, families may choose to receive this additional information. We will not be 
intentionally looking for results unrelated to the primary cause of disease (secondary findings). All findings will 
be confirmed using an appropriate standard clinical testing method prior to the return of such results.  Affected 
adult individuals will also be given the option to have their symptom-driven diagnosis reported clinically. All 
adults who are not patients at Rady Children’s Hospital will be provided copies of their clinical results and 
advised to follow-up with their primary care provider. Results will be returned by, or on the instruction of, a 

 
 
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licensed clinical geneticist or genetic counsellor. These results will be discussed with both clinicians and the 
affected individual or their legal guardian following confirmation.  
Unaffected subjects enrolled in this study will only receive results if they do not opt-out for incidental results. 
In the event that results are returned to unaffected participants who are not patients at Rady Children’s Hospital, 
the participants will be provided with their results directly and advised to follow-up with their primary care 
provider. DNA from unaffected individuals and family members enrolled will be used primarily for comparison 
to the proband. Return of results will include inheritance patterns and risk for reoccurrence with Genetic 
Counsellors and/or Board Certified Clinical Geneticists available for families enrolled in this study. 
Clinical Information Collection 
 
Patient clinical information 
We will collect patient identifiers (name, date of birth, family contact information, names, dates of birth, 
medical record numbers), demographic information (race, ethnicity, zip code at birth), birth information (birth 
history, APGAR score, interventions at birth, newborn screening results, pregnancy complications), clinical and 
phenotypic information (clinical symptoms, clinical presentations, lab values, imaging results, clinician notes, 
family histories and pedigrees), genetic testing information (types of tests ordered, test order and result dates, 
results of testing), and billing information (diagnostic codes,  billing data, DRG data). After consent, 
information will be collected for this study at the following time points: at birth, at enrollment, at (or following) 
return of results, at time of significant clinical events and post significant clinical events (if any), at hospital 
discharge, at death if it occurs, at one year, and annually throughout the duration of this study. Additional data 
may be collected for long-term follow-up through the Genomic Biorepository to assess changes in the patient’s 
medical condition and to possibly re-analyze sequences for symptom-driven diagnoses. This is often necessary 
to track disease progression, changes to clinical presentation and to correlate symptoms with genomic findings 
in light of new knowledge of genetic diseases.  
 
Sequencing information  
All specific sequencing information will be kept in the Genome Biorepository per their protocol.  We will 
collect quality metrics for each study run, run time length, total amount of data generated, and average 
coverage. 
 
Data Analysis: 
 
Aggregate demographic and clinical information will be characterized and analyzed. Measures of outcomes and 
clinical utility will be determined for both arms of the study. Outcome measures will include Quality Adjusted 
Life Years saved, Disability Adjusted Life Years, mortality and severe morbidity.  Clinical utility measures will 
include changes in medications, surgeries, diets, and other interventions, including institution of palliative care. 
Measures of diagnostic utility will also be collected (rate of diagnosis, type of diagnosis, time to diagnosis, 
completeness of diagnosis). Family perceptions of benefit and/or harm will be measured and results will be 
correlated to diagnoses and clinical reports of testing utility. Singleton versus family analysis diagnostic rates 
will be analyzed. Cost-effectiveness modelling will be developed. Utilization of genetic counseling and/or 
clinical genetics will be measured. The time spent consenting families will be measured as a baseline for future 
research. 
 
This study will monitor parental feedback annually. In the event that a family states that this testing caused 
harm, additional information will be sought. Whenever possible, trends will be identified and changes to the 
research protocol will be submitted for IRB approval if harm can be mitigated.  The study team will contact the 

 
 
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IRB in the event that 25% or more of the families enrolled perceived the testing to be harmful. 
 
10. HUMAN SUBJECTS 
Up to 1000 acutely ill infants and their families will be randomized to receive rapid whole genome sequence 
versus rapid whole exome sequencing.  We anticipate that we will enroll up to 2500 family members related to 
the 1000 acutely ill neonates and infants.  
 
Multi-site enrollment: 
 RCH will enroll ~1000 infants per year for an estimated total enrollment of ~250 to be enrolled and 
analyzed by the end of the NIH administrative supplement period ending September 2019. 
 Additional funding will be provided by Rady Children’s Institute for Genomic Medicine. 
CMH will consult on Ethical, Legal and Social Implications of genomic testing in infants through their 
Pediatric Bioethics Center. 
 Additional sites may be recruited to ensure enrollment goals are being met. 
 
Sample size determination  
Preliminary results indicate that rapid trio WGS will result in a change in clinical utility index (CUI) ~50% of 
cases (a key secondary outcome).  We propose that WES must yield a CUI of 40% or lower to justify the cost 
differential between WGS and WES.  Using α=0.05, we can achieve a power of 80% with 325 patient per arm, 
well below our proposed 500 patients per arm. Preliminary results indicate that rapid trio WGS is associated 
with 2.9 QALYs saved per infant tested (a key primary outcome). No similar analysis has been performed for 
WES. Additional patients, therefore, increase our power to assess differences in outcomes, and also 
compensates for technical or other issues that may cause some sample to be unanalyzable.  Notably, we have 
proposed multiple measures of outcomes and clinical utility in addition to QALYs and CUI, respectively, and 
our power calculations do not correct for multiple testing. We feel this is acceptable for two reasons: First, 
these outcome variables are not completely independent making a Bonferroni correction overly conservative.  
Second, as there is little preexisting data on this subject, we felt a less conservative approach often utilized in 
preliminary studies is appropriate. 
 
Affected Participant Inclusion Criteria 
Individual in whom one of the following criteria is met: 
1. Acutely ill inpatient of less than 4 months of age and within 96 hours of admission 
2. Acutely ill inpatient of less than 4 months of age and within 96 hours of development of an abnormal 
response to standard therapy for an underlying condition 
3. Acutely ill inpatient of less than 4 months of age and within 96 hours of development of clinical feature 
or laboratory test value suggestive of a genetic condition 
4. Biological relative of an infant enrolled in this study 
 
Affected Participant Exclusion Criteria  
Inpatients of greater than 4 months of age, or who do not meet any of the inclusion criteria, or with:  
1. Neonatal infection or sepsis with normal response to therapy 
2. Isolated prematurity 
3. Isolated unconjugated hyperbilirubinemia 
4. Hypoxic Ischemic Encephalopathy with clear precipitating event 
5. Previously confirmed genetic diagnosis that explains their clinical condition (i.e. have a positive genetic 
test) 
6. Isolated Transient Neonatal Tachypnea  
7. Permission is unable to be obtained by a legal guardian or court-appointed representative within 96 

 
 
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hours of becoming eligible for enrollment. 
8. Nonviable neonates- newborns less than 28 days of life with a modified code status (only full code 
patients may be enrolled). 
 
Family Members of Affected Participants Inclusion Criteria 
Family members are eligible for participation in this study if the following criterion is met: 
1. Presumed genetically related to a patient participant eligible for the study under section Affected 
Participant. 
For participants over the age 18, they must be able to provide consent or have a legal guardian able to provide 
consent. For participants under age 18 who have not achieved emancipation, a legal guardian must be available 
to provide permission, and children who are 7 to 17 years of age will also be required to assent for this research 
unless not required per IRB SOP regarding child assent.  
 
Family Members of Affected Participants Exclusion Criteria 
Family members are ineligible for participation in this study if: 
1. They are known to not be genetically related to the patient participant 
2. They are a member of a protected research population unless they are a neonate and meet criteria for 
enrollment as a patient participant under section Affected Participant. 
 
Clinicians 
As the clinicians caring for enrolled patients are being surveyed to return clinical feedback regarding their 
patients only, we request a waiver of consent as the clinicians themselves are not the subject of our research.  
 
Vulnerable Populations 
Enrollment will include the following vulnerable populations: neonates, those with cognitive disabilities, 
pediatric patients, minorities, and employees. Vulnerable populations, specifically pediatric patients, those with 
cognitive disabilities, newborns, and pediatric patients are being included so that they may benefit by receiving 
to a diagnosis and/or better understanding of their medical condition. Sample collection will be coordinated 
with clinical care whenever possible. All information will be stored de-identified. Only clinically-confirmed 
diagnoses will be reported to the medical record. As such, we believe this study to be of minimal risk to the 
participants.  
 
Minorities will be sought to aid in the diversification of study population. Consents will be translated to 
accommodate the most common foreign language(s), and UCSD approved and translated short-forms will be 
used in lieu of full translations to allow for the inclusion of the most diverse population possible. If no short 
forms are available for the family’s preferred language, consent will be obtained through a certified interpreter 
and documented on the English consent form. In the event a short form is used, UCSD informed consent policy 
will be followed regarding the documentation and consenting process.  The full consent form will be translated 
and after approval from the IRB of record will be sent to the participant within 30 days. Interpreters may serve 
as a witness to the short form consent process per OHRP guidelines; their signature as an interpreter will serve 
as a witness signature.  
 
Pregnant women and fetuses will only be included in this study in the rare circumstances that an associated 
family member is incidentally pregnant. Fetal testing is not a part of this study at this time. 
 
Newborns will be included in this study as well for the purposes of enhancing early detection and diagnosis. It 
is believed that early diagnoses will prevent disease progression and co-morbidities from developing with early 
interventions. As such, permission will only be required from one parent, although both parents’ permission 

 
 
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and participation will be sought. 
 
Employees may be included in this study if they are genetically related to a patient referred to this study. 
Employees will not be specifically recruited to participate in this study. Inclusion of employees will be done 
only for the benefit of the affected patient. Study related information will not be released to the employer. 
Similarly, employment status will not be affected by participation or refusal to participate. Informed consent 
will not be obtained by a direct supervisor of the employee. 
 
For participants less than 18 years of age and participants aged 18 or older who are not able to consent on their 
own behalf, informed consent must be obtained from legally authorized representatives. For those participants 7 
to 17 years of age, the participant must assent if developmentally capable of doing so (cognitive age of 7 years). 
Those for whom consent was provided by a guardian when they were under the age of 18 will be asked to 
consent for continued participation in this study after they become 18 years old. Those who are unable to be 
located or re-consented into the study will be removed from the study, see section 12 for process of 
withdrawing a patient from the study. 
 
Enrollment for all vulnerable populations will follow 45 CFR 46 as outlined in the code and section 12.
11.
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
Identification of Study Participants: 
Investigators will query the RCH NICU, PICU and CVICU census list daily and identify potential candidates 
based on primary diagnosis and symptoms. Alerts may be created in Epic to either generate a list, or 
notifications will be sent of potential candidates based on whether genetic tests or genetic consults were ordered 
on the patient. Potential candidates may be discussed with the clinical team regarding eligibility. Alternatively, 
clinicians, including those from other hospital services, may nominate patients who they feel meet 
inclusion/exclusion criteria.   
Those patients identified through the screening process will have the following data recorded in the 
prescreening log.  
 Identifiable Information: Patient- name, date of birth, medical record number, location in the hospital, 
date of admission. Parents- names, dates of birth if available (or ages), and contact information. 
 Clinical Information: clinical symptoms, positive genetic testing results, list of genetic tests pending, 
sex of patient, date eligible/identified for potential enrollment,  
 Study tracking date: date of enrollment if enrolled, enrollment status. Documentation of interactions 
with the families will be captured- such as contact attempts, parental feedback, and anticipated future 
meetings with families. 
 Other Information: We will also collect demographic information of if available in medical record 
(child’s race and ethnicity and family’s primary language spoken) and reasons for declining this 
research study, if voluntarily given.  
The identifiable data collected from the pre-screening log will be used strictly for study management to avoid 
unnecessary contacting of families. This log is necessary to track referrals, avoid duplications, unnecessary 
contacting of families who have previously declined participation, and to ensure that all eligible referrals are 
approached for the study. All identifying information from the prescreening log will be destroyed at the 
conclusion of the study. These recruitment procedures are considered minimal risk to the potential subjects. 
We request that enrollment rates, demographics, and reasons given for declining enrollment be allowed to be 

 
 
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retained and aggregated for analysis; all data will be de-identified. Published studies of genomic medicine 
report enrollment of only 3% minorities and as low as 6% of all families approached for genomic testing of 
newborns. We wish to collect such information to allow potential future amendments to this protocol should 
minority enrollment lag relative to the demographics of RCH NICU populations. This other data will be de-
identified and aggregated for the purpose of researching reasons families’ reasons for not enrolling in genomic 
research studies, racial or ethnic disparities, and disparities possibly related to the primary language spoken. It 
is anticipated that this data may be used for future presentations and/or publication and the creation or 
modifications of future genomic research studies.  
This latter analysis of potential subjects who decline to participate in research cannot be conducted by other 
methods requiring consent as often these subjects have already indicated they do not wish to participate in 
research at this time. We believe this data will help guide future studies aimed at minimizing disparities and 
better understanding reasons families decline research in general, genomic research, research on newborns, 
and/or research in an intensive care setting. No identifying information will be used and only aggregate data 
will be reported. The rights and welfare of potential subjects should not be negatively affected by this analysis; 
furthermore, the welfare of collective subpopulations may be improved if enrollment disparities can be 
identified and future research undertaken. Therefore, we believe this additional information and analysis is a 
minimal risk to these potential subjects that could not otherwise be conducted. In the event that this additional 
research conducted with a waiver of consent is determined to be harmful or has risks unforeseen at this time, 
such pertinent information will be communicated to the families affected whenever possible by the research 
team either in-person if possible, via a telephone call, or by mail (any letters that will be sent to families will be 
submitted for IRB approval prior to mailing). The research team will make every effort to contact these 
potential subjects based on the most recent contact information recorded in the medical record at the time such 
pertinent information is identified.  
A waiver of consent and a partial waiver of HIPAA authorization is requested for the prescreening process 
stated herein. 
12. INFORMED CONSENT 
Institutional Review Board (IRB) Review and Informed Consent 
This protocol, and any subsequent modifications, will be reviewed and approved by the IRB at UCSD.  
Research activities and protocol changes for other locations will be reviewed and approved by their local IRB. 
Potential subjects will be determined by study personnel by reviewing the daily neonatal intensive care census 
and identifying potential affected candidates. Medical Information Technology (MIT) will also provide a list of 
potential subjects. We request a partial waiver of HIPAA Authorization for this pre-screening review of charts. 
Once general eligibility is determined, the parents or guardians of potential subjects will be approached by 
study staff. Subjects will be approached at the hospital bedside of the affected subject or if parents not directly 
available via phone.  Prior to drawing any blood or performing any other procedures related to this study, the 
permission/assent form or consent form will be reviewed carefully with the participant (and parent) in person or 
by telephone in extenuating circumstances (for example, lives over 50 miles away from hospital, and not able to 
be physically present, currently admitted following delivery of their child, with acknowledged parental rights). 
In the event that the child’s mother is still admitted to another hospital due to the labor and delivery, all efforts 
will be made to include the mother in the consent conversation with the father.  
Telephone consenting would be rare and only utilized in case the custodial parent cannot physically attend the 
visit due to the circumstances mentioned above. It is the intention of the study team to obtain consent from both 
parents in-person whenever possible to facilitate their enrollment and blood collection. It is anticipated that in 

 
 
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rare cases, we will need a mother to enroll and have blood or saliva collected prior to her discharge from the 
birthing hospital. In those extreme cases, we will attempt consent via phone and work with the other hospital to 
collect the sample and return the consent documentation.  
Whenever possible, all efforts will be made to conduct the consent process in-person. Should a participant be 
unable to be consented in-person, telephone consents may be used when appropriate. Telephone consent 
policies will be followed in such circumstances. In the event that a telephone consent be necessary the 
following will happen: 
1) The absent party will be contacted by phone. The research team will explain the research study in 
general and the process required for telephone consent. If the other party does not object, an email 
address or fax number will be obtained to send the consent form electronically. A mailing address may 
be obtained in lieu of the above. A time will be scheduled for a full informed consent when both parties 
will be able to have the consent physically in front of them to sign.  
2) The consent will be sent to the absent party. The absent party will be advised that they are welcome to 
read this document, but they will be asked not to sign the document until the time of the scheduled 
consent. 
3) At the time of the scheduled consent, the research staff will have a witness present to confirm the 
validity of the telephone consent. All study information will be discussed. All questions will be 
answered. Should the consent be in another language, an interpreter will be used whenever necessary. 
The signature of the interpreter may be used in lieu of a separate witness. 
4) Following the explanation of the study, the absent party will be asked to sign and date the document. 
The research staff and witness will also sign and date their copy. 
5) The participant will be asked to return the signed document to the research team, either electronically or 
by mail. The participant will not be considered enrolled until such time as the signed document is 
received.  
6) Copies of both signed documents will be made and returned to the participant. 
7) If necessary, the research team will attempt to arrange for a blood collection or send a saliva collection 
kit to the participant.  
8) The consent will be documented per hospital and IRB policies. 
All questions will be answered and signatures will be obtained by study staff form the parent before procedures 
begin on the child. The PI will ensure the procedures for securing telephone consent are followed. 
Study personnel will obtain informed permission, assent, and consent from eligible participants. All study 
personnel will have completed CITI training. Referring clinicians may be asked to speak with families prior to 
their approach by the research team depending on the family and clinical circumstances. Researchers will contact 
the family either in-person or by telephone if the family is unavailable. Following the informed 
permission/assent/consent process, copies of the signed consents along with the HIPAA authorization will be 
given to the family member. Participants will also be given contact information for study personnel. In the event 
of telephone consent, copies will be mailed or sent electronically (fax or email) per the choice of the participant. 
The signed consent will be scanned into the medical records along with a consent note. Original copies will be 
maintained in a locked file cabinet or secure storage facility. 
All efforts will be made to conduct the consent process at times where emotional distress is minimal. The consent 
process will be done in privacy to the greatest extent possible. Families will be given as much time to consider the 
study and read the consent documents as they deem necessary. Emphasis will be made that their decision not to 
participate will in no way affect their child’s or their own medical care. The consent process will not include any 

 
 
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use of exculpatory language regarding rights or liability. Employees will be notified that participation or refusal to 
participate will in no way affect their employment status.  
Samples and clinical data collection will not be done prior to consent into the study.  
Waiver of Consent for Clinician Participation: 
As a part of this research study, clinicians will be administered a brief questionnaire regarding changes in care as 
a result of this research study’s result. Multiple clinicians may be surveyed for any one subject depending on what 
clinicians and subspecialties were involved in clinical care at the time results were returned. No identifying 
information will be collected about the clinicians. General information such as years of experience and credential 
information will be collected. The remaining data collected will be regarding the child’s clinical care and 
perceived utility of testing.  
The analysis of clinician surveys will include correlating credentials and/or years of experience with perceived 
clinical utility. The rights and welfare of clinicians should not be negatively affected by this analysis. No 
identifying information will be used and only aggregate data will be reported. As each patient may have any 
number of providers caring for the child at the time results are returned, it is not feasible to obtain informed 
consent from each clinician prior to administering the surveys. Similarly, only publicly available data such as 
years of experience and credentials are being collected about the clinician themselves. Therefore, we believe this 
to be a minimal risk to clinicians that could not otherwise be conducted. A waiver of consent is requested for the 
surveying of clinicians as a part of this study. 
In the event that this research conducted with a waiver of consent is determined to be harmful or has risks 
unforeseen at this time, such pertinent information will be communicated to the clinicians whenever possible by 
the research team either in-person if possible, via a telephone call, by mail, or most likely by email (any letters 
that will be sent to families will be submitted for IRB approval prior to mailing. Any emails sent will not show 
identifying information of other participants.). The research team will make every effort to contact clinicians 
based on the employee directory and department records at the time such pertinent information is identified.  
Vulnerable Populations: 
This research is believed to hold the prospect of enhancing the chance of survival of affected individuals with 
minimal risk to participants.  
In accordance with 45 CFR 46 subpart D, pediatric patients will require one parent or legal guardian to provide 
permission for the child to participate. Participants over the age of seven or who show cognitive capabilities to 
assent for this research study will be required to assent for participation. Those participants enrolled under the age 
of 18 will be asked to re-consent after turning 18 years old in order to remain in the study. Those who are not re-
consented after turning 18 years old will be removed from the study, no additional data will be collected, and all 
identifying information will be removed. 
Pregnant women may be included as a part of this study. As fetal testing is not the purpose of this research, the 
fetus would not be a subject of this research. Therefore, we will not seek permission from the father. This study 
will have no role in determining viability or decisions regarding pregnancy termination. 
In accordance with 45 CFR 46 subpart B, as this study is a minimal risk study and may improve morbidity and 
mortality of neonates less than 29 days, permission to enroll will be sought from both parents but only required 

 
 
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from one parent.  
Employees will be notified that participation or refusal to participate will in no way affect their employment 
status. 
Fully translated consents will be made available in Spanish.  A qualified interpreter will be used for all non-
English speaking families. When an interpreter is not available for an in-person consent, a professional phone 
interpreter service may be used. Family members will not serve as interpreters due to the nature of genetic testing. 
Consents will be translated to accommodate the most common foreign language(s), and UCSD approved and 
translated short-forms will be used in lieu of full translations to allow for the inclusion of the most diverse 
population possible. If no short forms are available for the family’s preferred language, consent will be 
obtained through a certified interpreter and documented on the English consent form. In the event a short form 
is used, UCSD informed consent policy will be followed regarding the documentation and consenting process. 
The full consent form will be translated and after approval from the IRB of record will be sent to the participant 
within 30 days. Interpreters may serve as a witness to the short form consent process per OHRP guidelines; 
their signature as an interpreter will serve as a witness signature. 
If the participant is unable to consent for themselves due to either age or cognitive disability, a parent or legally 
authorized representative may sign permission. Assent will be sought when appropriate. See section 30 for 
additional details.  
Post-consent Process: 
Following the informed permission/assent/consent process, copies of the signed consents along with the HIPAA 
authorization will be given to the family member. The study personnel will: 
 Review the Permission/assent/consent form and ensure that is properly completed 
 Provide the participant or legal representative with a copy of the signed form 
 File original signed form securely in the research file 
 Scan a copy of the form into the patient medical record  
 Record that consent was obtained in the medical record  
 Schedule or perform blood collection from the participant, if a sample is not available in the clinical 
laboratory 
 Add the participant to the Master List in the secure Institute’s folder on the internal shared drive and/or 
secure REDCap database. 
If the patient or legal representative refuses to participate in the study: 
 Communicate refusal to relevant study or clinical personnel. 
Original copies will be maintained in a locked file cabinet or secure storage facility.  
Optional Questions: 
The consent document will ask about the use of photographs. Subjects who agree to the use of photographs who 
have clinical features that would aid the scientific community by publishing a photograph of such features will 
have their picture taken. In the event that the subject agrees to the use of photographs, this would be the only 

 
 
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identifying information released for publication. The research team may also request the use of these photographs 
for new technologies to ascertain physical features through the use of programmatic algorithms. The photographs 
themselves would not be shared outside of the research team. The RCHSD policy regarding the use of 
photographs will be followed.  
Withdrawal of consent: 
Participation in this study is completely voluntary. As part of the parental permission/assent/consent process, 
participants are informed that they can withdraw consent at any time, for any reason. If at any time, a patient 
decides to withdraw consent, personnel at the bio bank will take appropriate steps to respect the will of the 
participant and ensure that the participant is able to withdraw without reprisal. 
Follow-up action after receiving a request to withdrawal: 
Upon receipt of request to withdrawal, the study staff will notify the Rady Children’s Clinical Genome Center of 
the subject’s withdrawal. In accordance with this protocol and  the Genomics Institute Biorepository study 
protocol (IRB #160468), the following actions will be taken by both studies:  
1. Ensure that unused blood from the participant is destroyed. Permanently break any link between personal 
identifying information and purified DNA and/or RNA from the participant. Isolated DNA and RNA that has not 
been sequenced will be destroyed in the event of withdrawal of a study subject. 
2. Permanently break any link between personal identifying information and the anonymized records in the 
bioinformatic database by replacing PHI in the Master List with a note that the subject has withdrawn. 
3. Not collect any additional clinical information about the individual from any source. 
4. Only anonymized data may be used for future research after consent has been revoked. 
5. Should a back-up of the inventory database/informatics system ever be restored, then the director should ensure 
that identifying records stored on the discarded samples log (that are relevant to the samples) are again deleted 
from the records. 
6. Shred any hard copies of associated identifying information not required to be maintained for regulatory 
purposes. 
7. Retain the executed consent form and request to withdrawal in a separate, secured file of discontinued subjects 
and redact any identifiers that link the subject to the data (such as subject number). 
8. The Repository Director will certify that identifying links have been broken, that unused and unprocessed 
biological material has been destroyed.  
Proprietary Interest Disclosure/ Moore Clause: 
Consent into this study requires participants to agree to giving blood or tissue specimens, these specimens will 
become the property of the Genomic Institute. Dr. Kingsmore or designee will be responsible for deciding how 
samples and collected data will be used. Dr. Kingsmore and his associates or his successors in these studies will 
keep specimen, DNA, clinical data and/or the information derived from the specimens indefinitely. If as a result 

 
 
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of participation in this study, the study team obtains information that could significantly affect a participant’s 
health and well-being, we will attempt to inform the participant of the existence of this information.  The 
information obtained from this testing will be kept completely confidential to the extent permitted by law. 
The specimens, the DNA they contain, and the clinical data collected may be used in this research and in other 
research, and may be shared with other organizations. In addition, de-identified data will also be shared with 
public databases sponsored by the National Institutes of Health and other agencies, and possibly with future 
scientists that are not known at this time. The specimens could lead to discoveries or inventions that may be of 
value to RCIGM or to other organizations. These discoveries or inventions may have significant commercial 
value. Under state law, participants do not have any right to money or other compensation stemming from 
products that may be developed from the specimens.  
13. ALTERNATIVES TO STUDY PARTICIPATION 
 The alternative to this study is to not participate in this study.
14. POTENTIAL RISKS 
Risks associated with blood draws include pain, anxiety, bleeding, bruising, or possibility of fainting or 
infection.  
 
Slight risk of loss of confidentiality.  
 
Risk of discrimination associated with genetic testing.  
 
Genetic testing may cause anxiety or emotional distress due to feelings of responsibility for carrying genetic 
components passed on to children.  
 
Risk of secondary or incidental findings being determined. 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
Whenever possible, samples for this study will be obtained from clinical samples to minimize risk and invasive 
procedures. All sample collection will be obtained by qualified staff following the hospital guidelines and 
standard precautions.  
 
All study related material will be stored securely. All identifying information will be kept in a separate database 
with access limited to study personnel. All data will be maintained in password protected, secure databases and 
or internal servers with access limited to study personnel and approved investigators.  
 
Information regarding the protections and limitations of the Genetic Information Nondiscrimination Act 
(GINA) will be included in the consent. 
 
Genetic counselors will be a part of the study team and will be available to all participants at all times while 
enrolled in the study to answer questions or concerns related to testing or results. 
 
This study does not intend to report matters of paternity, carrier statuses or other secondary findings. 
 
As the inclusion of pregnant women is for the purpose of improving clinical outcomes for the living affected 
infant, study participation is considered minimal risk. Blood draws and sample collection from the mother may 
be done independently for research or with routine clinical care. 
 
Study auditing and monitoring will be conducted internally. The PI will periodically review the collection, 
storage, and distribution practices associated with this data bank and determine whether changes to enhance 

 
 
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confidentiality and privacy are required. Annual progress reports will be conducted and available to the IRB. 
All protocol deviations will be reported to the PI and the IRB as soon as identified. In the unlikely event of a 
serious adverse event or breach in confidentiality, the event will be reported to the IRB within 48 hours of it 
becoming known to the PI.  
 
External auditing and monitoring by members of the NIH and/or FDA will be conducted per agency request. 
DSMB will monitor study through NIH consortium.  
 
Any employees of the hospital who are eligible to participate will be consented by a study team member who is 
not their direct supervisor and, whenever possible, not a coworker or acquaintance of the staff member. 
Employees will be notified that participation or refusal to participate will in no way affect their employment 
status.  
 
All clinical testing and therapy appropriate to the study participant's care will be continued without disruption 
during the study.  The clinicians are initially blinded to the randomization and will continue all clinical testing 
regardless of whether rapid genomic sequencing is performed.
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND 
MANAGEMENT
Subject Confidentiality-  
Research personnel will identify patients meeting inclusion criteria via daily census review as well as through 
recommendations of clinicians and a list from MIT. Upon enrollment, each medical record will be reviewed by 
research staff and data entered into the research record.  All genomic sequencing and biospecimens will be 
performed and maintained under the Genomic Institute Biorepository protocol (IRB #160468).  
 
All research records and genomic sequencing data will be electronically stored in a password protected database 
accessible only to research personnel.  HIPAA identifiers of all study subjects will be kept in a password 
protected database and will be linked only with a study identification number for this research. All computer entry 
and networking programs will be done using study identification numbers only.  All data will be entered into a 
computer that is password protected. All sequencing data and biospecimens will be stored securely under the 
Genomic Institute Biorepository protocol (Study #160468). Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by IRB, the FDA, the OHRP, the Sponsor, 
or the Sponsor’s designee.  Data will be stored in a locked office of the investigators and maintained for a 
minimum of three years after the completion of the study.  
 
Records to be kept 
Information will be collected on a data collection sheet for each patient participant (Appendix) and stored in a 
password protected relational database. A master linking list will be maintained that links the subject’s medical 
record number with their study number (Appendix). De-identified genomic sequencing data will be stored in a 
password protected relational database. 
 
Secure Storage of Data 
The research record generated will consist of an excel sheet and/or secured REDCap database. Only the data 
points listed will be entered into the data collection sheet (Appendix ). Security measures include: storage of the 
password protected excel sheet on a password protected computer in a restricted access departmental folder 
limited to only listed study personnel and/or in a secured, password protected REDCap database with access 
limited to research study members.  
 
All study related material will be stored securely. Access to research records, pre-screening logs, and the master 

 
 
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list will be limited to study personnel and maintained securely with password protection on a secure internal 
server.  
 
Surveys may be sent via email by REDCap to clinicians and family members. Study information, personal 
identifiers, such as name, MRN, and contact information will be stored in REDCap. The survey functionality of 
REDCap does not allow survey participants access to any other REDCap data or forms. 
 
Participant and clinician survey data will be collected by researchers at RCIGM/RCHSD. The data will be stored 
in a secure, HIPAA compliant, password protected database such as REDCap, within the RCIGM server. The 
IT department from RCIGM will send de-identified data to UCSD to be stored and analyzed on the UCSD 
secured server. 
All samples and data will be stored de-identified in the Genomic Institute Biorepository (IRB #160468).   
 
All transfer of study related information between sites will be done securely without identifying information 
whenever possible.  
 
17. POTENTIAL BENEFITS
Study may or may not have any benefit to participants. Affected participants may receive a diagnosis or 
additional information regarding their medical condition. This information may improve their clinical care and 
outcomes. There will be no direct benefit to participation for unaffected family members except where a 
diagnosis provides information regarding reproductive decisions and future recurrences.
18. RISK/BENEFIT RATIO 
This study does not intend to report secondary findings, non-actionable findings on healthy subjects, nor will it 
affect decisions of pregnancy termination. The direct benefits to the affected participants may improve clinical 
care, morbidity, and mortality. As such, we believe the potential benefits far outweigh the slight risks.
19. EXPENSE TO PARTICIPANT
No expense to participate.
20. COMPENSATION FOR PARTICIPATION
No compensation for participation. 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
All study personnel, unless otherwise indicated, will have completed CITI training. 
Research Team: 
Stephen Kingsmore, MD, DSc 
Principal Investigator. Research scientist and CEO and President 
of Rady Children’s Institute for Genomic Medicine.  Dr. 
Kingsmore has research privileges at RCHSD. 
David Dimmock, MD 
Co-Investigator. Medical Director, Pediatrician, Medical 
Geneticist, Biochemical Geneticist, licensed to practice medicine 
within the state of California.  
Lauge Farnaes, MD 
Co-Investigator. Asst. Medical Director, licensed to practice 
medicine within the state of California and has privileges at 
RCHSD
James Perry, MD 
Scientific Investigator. Cardiologist licensed to practice medicine 
within the state of California. 

 
 
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Joe Gleeson, MD 
Scientific Investigator. Neurologist licensed to practice medicine 
within the state of California.  
Jennifer Freidman, MD 
Scientific Investigator. Neurologist licensed to practice medicine 
within the state of California. 
Julie Ryu, MD 
Scientific Investigator. Pulmonologist licensed to practice 
medicine within the state of California. 
George Chiang, MD 
Scientific Investigator. Urologist licensed to practice medicine 
within the state of California. 
Jeanne Carroll, MD 
Scientific Investigator. Neonatologist licensed to practice medicine 
within the state of California. 
Kristen Wigby, MD 
Sub-Investigator. Genetics Fellow licensed to practice medicine 
within the state of California and has privileges at RCHSD. CITI 
Biomedical Training, HIPAA. 
Erica Sanford Kobayashi, MD 
 
Sub-Investigator. PICU Fellow licensed to practice medicine 
within the state of California and has privileges at RCHSD 
Amelia Lindgren, MD 
Sub-Investigator. Orthopedic Fellow licensed to practice medicine 
within the state of California and has privileges at RCHSD 
Chelsea Gatcliffe, MD 
Sub- Investigator. Pulmonology Fellow licensed to practice 
medicine within the state of California. 
Benjamin Briggs, MD 
Sub-Investigator. Oncology &Hematology Fellow licensed to 
practice medicine within the state of California.
Nathaly Sweeney, MD 
Sub-Investigator. Neonatologist Fellow licensed to practice 
medicine within the state of California and has privileges at 
RCHSD
Serena Galosi, MD 
Sub-Investigator. Intern. Neurologist licensed to practice medicine 
within the state of California 
Shareef Nahas, PhD FACMG 
Co-Investigator. Lab Director and Molecular Geneticist licensed 
(or pending) to practice within the state of California. 
Shimul Chowdhury, PhD, DABMGG 
Co-Investigator. Lab Director and Molecular Geneticist licensed 
(or pending) to practice within the state of California. 
Kasia Ellsworth, PhD 
Co-Investigator. Associate lab director and molecular geneticist 
with license (or pending) to practice within the state of California.
Mari Tokita, MD 
Co-Investigator. Associate lab director and molecular geneticist 
with license (or pending) to practice within the state of California.
Yan Ding, MD, MS, MB, ASCP 
Director of Sequencing Operations not practicing medicine at this 
time. MB, ASCP national licensure is active. 
Luca Van Der Kraan
Clinical Lab Staff licensed to practice in California
Laura Puckett
Clinical Lab Staff licensed to practice in California
Cathy Yamada 
Clinical Lab Staff licensed to practice in California
Zaira Bezares Orin 
Clinical Lab Staff licensed to practice in California
Jennie Le
Clinical Lab Staff licensed to practice in California
Meredith Wright, PhD 
Research staff. Clinical genomics analyst.
Terence Wong, Ph.D. 
Research staff. Clinical genomics analyst.
Kiely James, Ph.D. 
Research staff. Clinical genomics analyst.
Sylvia Breeding 
Quality Assurance 

 
 
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Co-Investigators and Sub-Investigators may consent, collect samples, collect data, analyze data, manage 
regulatory matters, and follow up with participants. Staff includes David Dimmock, Luage Farnaes, Amelia 
Lindgren, Erica Sanford, Nathaly Sweeney, Kristen Wigby, Chelsea Gatcliffe, Benjamin Briggs, Serena Galosi, 
Caryn Rubanovich, Cinnamon Bloss, Julie Cakici, Nanda Ramchander, and  Mathew Bainbridge.  Staff not 
actively licensed in the state of California will not collect samples until they have obtained their licensure.  
Scientific investigators may collect data, analyze data, and follow up with participants. Staff includes Jeanne 
Carroll, George Chiang, Jennifer Friedman, Joseph Gleeson, Julie Ryu, James Perry, and Michelle Clark. 
Research staff and Genetic Counselors may collect data, analyze data, and follow up with participants.  Staff 
includes Kasia Ellsworth, Mari Tokita, Kiely James, Terence Wong, Meredith Wright, Katherine Nguyen, Lisa 
Salz, Kelly Watkins, Jerica Lenberg and Cheyenne Camp. 
Lisa Salz, MS, LCGC 
Genetic counselor. Board certified, licensed to practice within the 
state of California. 
Kelly Watkins, MS, LCGC 
Genetic counselor. Board certified, licensed to practice within the 
state of California. 
Jerica Lenberg, MS, LGCG 
Genetic counselor. Board certified, licensed to practice within the 
state of California. 
Cheyenne Camp, BS
Genetics Intern
Michelle Clark, PhD
Scientific Investigator.  
Matthew Bainbridge, PhD 
Co-Investigator. Research PI at RCIGM
Narayanan Veeraraghavan, PhD
IT & Bioinformatics Director 
Sergey Batalov
Bioinformatics Staff
Ray Hovey
Bioinformatics Staff
Dorjee Tamang 
Bioinformatics Staff
Katherine Nguyen, MPH 
Research Staff  
Caryn Rubanovich, MS 
Sub-Investigator 
Cinnamon Bloss, PhD
Sub-Investigator. Psychologist and Statistical Geneticist.  
Julie Cakici, BA, BSN, RN 
Co-Investigator/Data Analyst with Cinnamon Bloss;
Sara Caylor, BS, BSN, RN
Research Coordinator. Licensed nurse in the state of California. 
Christina Clark, BSN, RN 
Research Coordinator. Licensed nurse in the state of California. 
Mary Gaughran, BSN, RN 
Research Coordinator. Licensed nurse in the state of California.  
Iris Reyes, MPH 
Program Specialist.
Michele Feddock, BS, CCRP 
Program Specialist. 
Maria Ortiz-Arechiga 
Lab Accessioner
Nanda Ramchander, MD 
Co-Investigator
Kee Chan, PhD 
Consultant
 
 
 
 
 
 

 
 
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Molecular Geneticists will review and report clinical results into the medical record. Staff may also collect, 
analyze data, manage regulatory matters and follow up with clinicians and participants. Staff includes Shareef 
Nahas and Shimul Chowdhury.  
Laboratory staff will have access to the master list and EMR to verify participation and consent prior to 
Biorepository Study activities. Staff includes Yan Ding, Sylvia Breeding, Zaira Bezarek Orin, Laura Puckett, 
Luca Van Der Kraan, Jennie Le, Catherine Yamada, and Maria Ortiz-Arechiga . 
Clinical Research Coordinators and Project Managers/Specialists may consent, collect samples, collect data, 
analyze data, manage regulatory matters, and follow up with participants.  Staff includes  Sara Caylor, Christina 
Clark, Mary Gaughran, Michele Feddock, and Iris Reyes. 
Bioinformatics staff will have access to genomic and sample data as well as the entire research record. Staff 
may collect and analyze data. Staff includes: the Genomic Institute’s Bioinformatics Director, Narayanan 
Veeraraghavan, PhD, Serge Batalov,  Raymond Hovey, and Dorjee Tamang. 
Outside investigators: 
Outside collaborators able to request de-identified data for secondary analysis.  
Kee Chan, PhD, will be consulting on the Health Economics Analysis. 
 
 
 

 
 
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22. BIBLIOGRAPHY
1. Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, Soden SE, Cakici JA, Herd SM, 
Twist G, Noll A, Creed M; Alba PM, Carpenter SL, Clements MA, Fischer RT, Hays JA, Kilbride H, 
McDonough RJ, Rosterman JL, Tsai SL, Zellmer L, Farrow EG, Kingsmore SF. Diagnostic and Clinical 
Findings among Critically Ill Infants Receiving Rapid Whole Genome Sequencing for Identification of 
Mendelian Disorders. Lancet Respir Med. 2015 May;3(5):377-87. 
2. Miller NA, Farrow EG, Gibson M, Willig LK, Twist G, Yoo B, Marrs T, Corder S, Krivohlavek L, Walter 
A, Petrikin JE, Saunders CJ, Thiffault I, Soden SE, Smith LD, Dinwiddie DL, Herd S, Cakici JA, Catreux 
S, Ruehle M, Kingsmore SF. A 26-hour system of highly sensitive whole genome sequencing for 
emergency management of genetic diseases. Genome Med. 2015 Sep 30;7(1):100. 
3. Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, Andraws N, Patterson ML, 
Krivohlavek LA, Fellis J, Humphray S, Saffrey P, Kingsbury Z, Weir JC, Betley J, Grocock RJ, Margulies 
EH, Farrow EG, Artman M, Safina NP, Petrikin JE, Hall KP, Kingsmore SF. Rapid whole-genome 
sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012 Oct 
3;4(154):154ra135. 
4. G.J. Downing, A.E. Zuckerman, C. Coon, M.A. Lloyd-Puryear. Enhancing the quality and efficiency of 
newborn screening programs through the use of health information technology. Semin. Perinatol. 34, 156-
62 (2010). 
5. J.D. Lantos, W.L. Meadow. Costs and end-of-life care in the NICU: lessons for the MICU? J. Law Med. 
Ethics 39, 194-200 (2011). 
6. S. F. Kingsmore, D. L. Dinwiddie, N. A. Miller, S. E. Soden, C. J. Saunders,  Adopting orphans: 
Comprehensive genetic testing of Mendelian diseases of childhood by next-generation sequencing. Expert 
Rev. Mol. Diagn. 11, 855-868 (2011). 
7. M. N. Bainbridge, W. Wiszniewski, D. R. Murdock, J. Friedman, C. Gonzaga-Jauregui, I.Newsham, J. G. 
Reid, J. K. Fink, M. B. Morgan, M. C. Gingras, D. M. Muzny, L. D. Hoang, S. Yousaf, J. R. Lupski, R. A. 
Gibbs. Whole-genome sequencing for optimized patient management. Sci. Transl. Med. 3, 87re3 (2011). 
8. S.F. Kingsmore, C.J. Saunders. Deep sequencing of patient genomes for disease diagnosis: When will it 
become routine? Sci. Transl. Med. 3, 87ps23 (2011). 
23. FUNDING SUPPORT FOR THIS STUDY
A 5-year NIH U19 grant entitled Genomic Sequencing and Newborn Screening Disorders 
 
NIH Full Grant Number: 5 U19 HD 77693-3  
Project Title: Newborn Sequencing In Genomic medicine and public HealTh (NSIGHT). 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not applicable, biological samples to be transferred within Rady Children's Hospital San Diego. BMTA for 
sequencing related material transfers regulated through Genomic Institute’s Biorepository (IRB Study 
#160468)
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
Study Modification/Discontinuation 
This study has been reviewed by the FDA and granted non-significant risk (NSR) status. Thus, this study does 
not require an investigational device exemption from the FDA. However, the study may be modified or 
discontinued at any time by the IRB, the Sponsor, the OHRP, or other Government agencies as part of their 
duties to ensure that research subjects are protected.
26. IMPACT ON STAFF
Nursing and clinical lab staff may be involved in sample collection and transfer. 
 
 

 
 
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27. CONFLICT OF INTEREST 
N/A 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES
N/A
29. OTHER APPROVALS/REGULATED MATERIALS 
RCIGM Genomic Biorepository Protocol, IRB# 160468
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY 
ASSESSMENT
Due to the nature of this study, any individual, adult or child, suffering from cognitive or developmental 
disability will be secondary to a suspected underlying genetic disorder. As such, these individuals will have 
been suffering chronically from this disability for which a parent or legal guardian is anticipated to be available 
to provide informed consent. If an individual having chronic compromised cognitive function such that they 
function at delayed levels yet are capable of providing assent, such assent will be sought. The assessment will 
follow the requirements of the UCSD HRPP Decision Making Capacity Guidelines. We do not anticipate acute 
changes in cognitive function, such as would require an acute transfer of decisional capacity.