Rapid Precision Medicine

Our research and clinical work is focused on accelerating and optimizing the whole genome sequencing process to offer testing, analysis and interpretation of life-threatening genetic variations for newborns and children enrolled in one of our multi-center clinical studies.

Our primary focus has been on babies and children hospitalized in neonatal, pediatric or cardiovascular intensive care. In other cases, our studies focus on ending the diagnostic odyssey for stable pediatric patients who have been living with a rare disease, the cause of which has not been identified.

Change in Clinical Management to Improve Outcomes

Providing a rapid diagnosis is particularly important in cases where early intervention with a highly specific treatment, can prevent severe disability or death. Historically, testing for genetic disorders has been a lengthy, difficult process that rarely provided actionable data in time to change the patient’s medical management. Both positive (molecular diagnosis) and negative findings from rapid Whole Genome Sequencing™ (rWGS®) can inform optimal treatment of patients and also facilitate accurate, evidence-based discussions with the families of critically ill children in intensive care unit (ICU) settings.

Building the Evidence Base for rWGS

RCIGM research has contributed to 9 of 20 clinical trials demonstrating the utility of genome wide sequencing in children in intensive care settings.

The published evidence supporting the clinical utility of rapid Whole Genome Sequencing™ (rWGS®) and rapid whole exome sequencing (rWES) has increased rapidly.

PubMed ID
Sequence Type
Neonatal & Pediatric ICU Enrollment CriteriaPatients
Diagnosis Rate
Clinical Utility
Change in Outcome
Indicates RCIGM publicationrWGS = rapid WGS | urWGS = ultra-rapid Whole Genome Sequencing | rWES = rapid Whole Exome Sequencing
23035047urWGS NICU infants with suspected genetic disease475%n.d.n.d.
25937001rWGS
<4 mo of age; suspected actionable genetic disease
3557%31%29%
28973083rWES<100 days of life; Suspected genetic disease6351%37%19%
29449963rWGS<4 mo of age; Suspected genetic disease3241%31%n.d.
29644095rWGSinfants; Suspected genetic disease4243%31%26%
29543227rWESAcutely ill children with suspected genetic diseases4053%30%8%
30049826rWGSChildren; PICU and Cardiovascular ICU2442%13%n.d.
31246743rWGS
4 months-18 years; PICU; Suspected genetic diseases
3848%39%8%
30847515rWGSSuspected genetic disease19521%13%n.d.
31019026urWGS Infants; Suspected genetic disease743%43%n.d.
31780822rWES<4 mo of age; ICU; hypotonia, seizures, metabolic, multiple congenital anomalies5054%48%n.d.
32411386rWESNICU & PICU; complex13048%23%n.d.
32553838rWES<6 months; ICU; suspected genetic disease4652%52%n.d.
32221475rWESPICU; < 6 years; new metabolic/neurologic disease1050%30%n.d.
32336750rWESInfants; ICU; Genetic consult36827%22%n.d.
32573669urWES NICU and PICU; Genetic counsult10851%44%n.d.
32668698rWESICU infants; Severe or progressive conditions1872%n.d.n.d.
31564432rWGS
Infants; disease of unknown etiology; within 96 hours of admission
9419%24%10%
rWES9520%20%18%
urWGS2446%63%25%
Baby BearurWGSMediCal Infants; <1 week of admission17843%31%n.d.
Baby ManateeurWGSInpatient children; 90% in ICUs5040%38%n.d.

Timely Dissemination

When we return genetic test results, we make experts available to assist the doctors caring for a child to find the most up to date information on the disorder.

RCIGM Related Publications

Perspectives of Pediatric Providers Regarding Clinical Use of Pharmacogenetics
Avello K, Bell M, Stein Q, Bares V, Landsverk M, Salyakina D, McCafferty-Fernandez J, Kingsmore S, Bedrick A, Bhojwani D, Hoyme HE.
S D Med. 2021 Jul;74(7):294-301. ABSTRACT INTRODUCTION: A major goal of the current personalized medicine era is to utilize pharmacogenetics (PGx) in order to influence how medications and therapies are prescribed by providers. However, disparities for prescribing medications between adults and children exist. Research has shown that children are not just small adults and there are different challenges for pediatric providers in regards to ordering and interpreting PGx tests. The goal of this study was to obtain an initial understanding of current pharmacogenetic testing by pediatric providers, as well as determine perceived barriers. METHODS: We distributed an online survey to pediatric providers at six different institutions across the U.S. RESULTS: Of the 252 respondents who completed the survey, 24 percent reported previously ordering PGx tests, however, over 90 percent of respondents reported they would feel more comfortable ordering and interpreting results with the assistance of a pharmacist, geneticist, genetic counselor or PGx expert. Additionally, participants identified specific barriers towards the utilization of PGx testing, as well as suggested solutions to overcome these barriers, including increasing provider education regarding testing, collaboration through a multidisciplinary team approach and established PGx programs. CONCLUSION: As the pharmacogenetic field continues to demonstrate clinical utility in the pediatric population, it will be important to continuously identify and address barriers that exist for providers to allow for more successful implementation of PGx in the pediatric setting, as well as enhance patient care. PMID:34449988
Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children's hospitals demonstrates improved clinical outcomes and reduced costs of care
Dimmock D, Caylor S, Waldman B, Benson W, Ashburner C, Carmichael JL, Carroll J, Cham E, Chowdhury S, Cleary J, D'Harlingue A, Doshi A, Ellsworth K, Galarreta CI, Hobbs C, Houtchens K, Hunt J, Joe P, Joseph M, Kaplan RH, Kingsmore SF, Knight J, Kochhar A, Kronick RG, Limon J, Martin M, Rauen KA, Schwarz A, Shankar SP, Spicer R, Rojas MA, Vargas-Shiraishi O, Wigby K, Zadeh N, Farnaes L. 
Am J Hum Genet. 2021 May 29:S0002-9297(21)00192-0. doi: 10.1016/j.ajhg.2021.05.008. Online ahead of print. ABSTRACT Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear. PMID:34089648 | DOI:10.1016/j.ajhg.2021.05.008
An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm
Dimmock DP, Clark MM, Gaughran M, Cakici JA, Caylor SA, Clarke C, Feddock M, Chowdhury S, Salz L, Cheung C, Bird LM, Hobbs C, Wigby K, Farnaes L, Bloss CS, Kingsmore SF; RCIGM Investigators.
Am J Hum Genet. 2020 Nov 5;107(5):942-952. doi: 10.1016/j.ajhg.2020.10.003. ABSTRACT The second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study was a randomized, controlled trial of rapid whole-genome sequencing (rWGS) or rapid whole-exome sequencing (rWES) in infants with diseases of unknown etiology in intensive care units (ICUs). Gravely ill infants were not randomized and received ultra-rapid whole-genome sequencing (urWGS). Herein we report results of clinician surveys of the clinical utility of rapid genomic sequencing (RGS). The primary end-point-clinician perception that RGS was useful- was met for 154 (77%) of 201 infants. Both positive and negative tests were rated as having clinical utility (42 of 45 [93%] and 112 of 156 [72%], respectively). Physicians reported that RGS changed clinical management in 57 (28%) infants, particularly in those receiving urWGS (p = 0.0001) and positive tests (p < 0.00001). Outcomes of 32 (15%) infants were perceived to be changed by RGS. Positive tests changed outcomes more frequently than negative tests (p < 0.00001). In logistic regression models, the likelihood that RGS was perceived as useful increased 6.7-fold when associated with changes in management (95% CI 1.8-43.3). Changes in management were 10.1-fold more likely when results were positive (95% CI 4.7-22.4) and turnaround time was shorter (odds ratio 0.92, 95% CI 0.85-0.99). RGS seldom led to clinician-perceived confusion or distress among families (6 of 207 [3%]). In summary, clinicians perceived high clinical utility and low likelihood of harm with first-tier RGS of infants in ICUs with diseases of unknown etiology. RGS was perceived as beneficial irrespective of whether results were positive or negative. PMID:33157007 | PMC:PMC7675004 | DOI:10.1016/j.ajhg.2020.10.003
Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas
Li H, Byers HM, Diaz-Kuan A, Vos MB, Hall PL, Tortorelli S, Singh R, Wallenstein MB, Allain M, Dimmock DP, Farrell RM, McCandless S, Gambello MJ.
Mol Genet Metab. 2018 Apr;123(4):428-432. doi: 10.1016/j.ymgme.2018.02.016. Epub 2018 Feb 27. ABSTRACT Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI. PMID:29510902 | DOI:10.1016/j.ymgme.2018.02.016

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Robert Wechler-Reva

PHD, Neuro-Oncology Program Director

Noted scientist Robert Wechsler-Reya, PhD, is also a professor and researcher at the Sanford Burnham Prebys Medical Discovery Institute (SBP) where he is focused on investigating the genes and nervous system signaling pathways that contribute to medulloblastoma, the most common malignant brain tumor in children.