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 IDSequence TypeNeonatal & Pediatric ICU Enrollment CriteriaPatientsDiagnosis RateClinical UtilityChange 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 disease3557%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.
31246743rWGS4 months-18 years; PICU; Suspected genetic diseases3848%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.
31564432rWGSInfants; disease of unknown etiology; within 96 hours of admission9419%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

Best practices for the interpretation and reporting of clinical whole genome sequencing
Austin-Tse CA, Jobanputra V, Perry DL, Bick D, Taft RJ, Venner E, Gibbs RA, Young T, Barnett S, Belmont JW, Boczek N, Chowdhury S, Ellsworth KA, Guha S, Kulkarni S, Marcou C, Meng L, Murdock DR, Rehman AU, Spiteri E, Thomas-Wilson A, Kearney HM, Rehm HL; Medical Genome Initiative*.

NPJ Genom Med. 2022 Apr 8;7(1):27. doi: 10.1038/s41525-022-00295-z.

ABSTRACT

Whole genome sequencing (WGS) shows promise as a first-tier diagnostic test for patients with rare genetic disorders. However, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading health care and research organizations in the US and Canada, was formed to expand access to high quality clinical WGS by convening experts and publishing best practices. Here, we present best practice recommendations for the interpretation and reporting of clinical diagnostic WGS, including discussion of challenges and emerging approaches that will be critical to harness the full potential of this comprehensive test.

PMID:35395838 | DOI:10.1038/s41525-022-00295-z

Healthcare Professionals’ Attitudes toward Rapid Whole Genome Sequencing in Pediatric Acute Care
Franck LS, Scheurer-Monaghan A, Bupp CP, Fakhoury JD, Hoffmann TJ, Deshpandey M, Arenchild M, Dimmock DP.

Children. 2022; 9(3):357.

Abstract

We aimed to characterize knowledge and attitudes about rapid whole genome sequencing (rWGS) implementation of a broad constituency of healthcare professionals at hospitals participating in a statewide initiative to implement rWGS for hospitalized neonates and children up to 18 years of age meeting clinical criteria for testing. We surveyed 307 healthcare professionals from eight hospitals about their knowledge and attitudes regarding rWGS. We examined survey internal reliability using exploratory factor analysis and associations between respondent characteristics and attitudes toward rWGS with linear regression. We thematically analyzed free-text responses. Views about rWGS implementation in respondents’ own setting and respondents’ personal capability to implement rWGS were generally neutral (M = 3.44 (SD = 0.74); M = 3.30 (SD = 0.85), respectively). Views about the potential for rWGS in clinical practice were overall positive (M = 4.12 (SD = 0.57)). The degree of positivity of attitudes about rWGS was strongly influenced by perceived knowledge, clinical or non-clinical role, concerns about future insurance coverage for rWGS as a first-tier test, and future adverse impact of genomics health information on patients or families. We identified several actionable factors influencing attitudes toward rWGS of pediatric healthcare professionals. Expanded education and ongoing implementation research are needed for the full potential of rWGS in pediatrics to be realized.
https://doi.org/10.3390/children9030357
2022: A pivotal year for diagnosis and treatment of rare genetic diseases
Kingsmore SF

Cold Spring Harb Mol Case Stud. 2022 Feb 25:mcs.a006204. doi: 10.1101/mcs.a006204. Online ahead of print.

ABSTRACT

The start of 2022 is an inflection point in the development of diagnostics and treatments for rare genetic diseases in prenatal, pediatric, and adult individuals; the theme of this special issue. Here I briefly review recent developments in the latter two aspects of rare genetic disease diagnostics and treatments.

PMID:35217563 | DOI:10.1101/mcs.a006204

Retrospective identification of prenatal fetal anomalies associated with diagnostic neonatal genomic sequencing results
Zhang-Rutledge K, Owen M, Sweeney NM, Dimmock D, Kingsmore SF, Laurent LC.

Prenat Diagn. 2022 Feb 9. doi: 10.1002/pd.6111. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine which types of fetal anomalies are associated with postnatal diagnoses of genetic diseases by genomic sequencing and to assess how prenatal genomic sequencing could affect clinical management.

METHOD: This was a secondary analysis of the second Newborn Sequencing in Genomic Medicine and Public Health study that compared fetal imaging results in critically ill infants who had actionable versus negative postnatal genomic sequencing results.

RESULTS: Of 213 infants who received genomic sequencing, 80 had available prenatal ultrasounds. Twenty-one (26%) of these were found to have genetic diseases by genomic sequencing. Fourteen (67%) of the 21 with genetic diseases had suspected anomalies prenatally, compared with 33 (56%) of 59 with negative results. Among fetuses with suspected anomalies, genetic diseases were 4.5 times more common in those with multiple anomalies and 6.7 times more common in those with anomalies of the extremities compared to those with negative results. Had the genetic diseases been diagnosed prenatally, clinical management would have been altered in 13 of 14.

CONCLUSION: Critically ill infants with diagnostic genomic sequencing were more likely to have multiple anomalies and anomalies of the extremities on fetal imaging. Among almost all infants with suspected fetal anomalies and diagnostic genomic sequencing results, prenatal diagnosis would have likely altered clinical management.

PMID:35141907 | DOI:10.1002/pd.6111

Evaluating use of changing technologies for rapid next-generation sequencing in pediatrics
Palmquist R, Jenkins SM, Bentley D, Miller C, Mao R, Meibos B, Bayrak-Toydemir P, Tvrdik T, Nadauld LD, Bleyl SB, Chowdhury S, Ostrander B, Flores-Daboub J, Longo N, Tristani-Firouzi M, Hobbs C, Bonkowsky JL, Brunelli L.

Pediatr Res. 2022 Feb 3. doi: 10.1038/s41390-022-01965-5. Online ahead of print.

ABSTRACT

BACKGROUND: Rapid next-generation sequencing (NGS) offers the potential to shorten the diagnostic process and improve the care of acutely ill children. The goal of this study was to report our findings, including benefits and limitations, of a targeted NGS panel and rapid genome sequencing (rGS) in neonatal and pediatric acute clinical care settings.

METHODS: Retrospective analysis of patient characteristics, diagnostic yields, turnaround time, and changes in management for infants and children receiving either RapSeq, a targeted NGS panel for 4500+ genes, or rGS, at the University of Utah Hospital and Primary Children’s Hospital, from 2015 to 2020.

RESULTS: Over a 5-year period, 142 probands underwent rapid NGS: 66 received RapSeq and 76 rGS. Overall diagnostic yield was 39%. In the majority of diagnostic cases, there were one or more changes in clinical care management. Of note, 7% of diagnoses identified by rGS would not have been identified by RapSeq.

CONCLUSIONS: Our results indicate that rapid NGS impacts acute pediatric care in real-life clinical settings. Although affected by patient selection criteria, diagnostic yields were similar to those from clinical trial settings. Future studies are needed to determine relative advantages, including cost, turnaround time, and benefits for patients, of each approach in specific clinical circumstances.

IMPACT: The use of comprehensive Mendelian gene panels and genome sequencing in the clinical setting allows for early diagnosis of patients in neonatal, pediatric, and cardiac intensive care units and impactful change in management. Diagnoses led to significant changes in management for several patients in lower acuity inpatient units supporting further exploration of the utility of rapid sequencing in these settings. This study reviews the limitations of comparing sequencing platforms in the clinical setting and the variables that should be considered in evaluating diagnostic rates across studies.

PMID:35115709 | DOI:10.1038/s41390-022-01965-5

Cost Efficacy of Rapid Whole Genome Sequencing in the Pediatric Intensive Care Unit 
Sanford Kobayashi Erica, Waldman Bryce, Engorn Branden M., Perofsky Katherine, Allred Erika, Briggs Benjamin, Gatcliffe Chelsea, Ramchandar Nanda, Gold Jeffrey J., Doshi Ami, Ingulli Elizabeth G., Thornburg Courtney D., Benson Wendy, Farnaes Lauge, Chowdhury Shimul, Rego Seema, Hobbs Charlotte, Kingsmore Stephen F., Dimmock David P., Coufal Nicole G.

Front. Pediatr., 24 January 2022. doi: 10.3389/fped.2021.809536.

ABSTRACT

The diagnostic and clinical utility of rapid whole genome sequencing (rWGS) for critically ill children in the intensive care unit (ICU) has been substantiated by multiple studies, but comprehensive cost-effectiveness evaluation of rWGS in the ICU outside of the neonatal age group is lacking. In this study, we examined cost data retrospectively for a cohort of 38 children in a regional pediatric ICU (PICU) who received rWGS. We identified seven of 17 patients who received molecular diagnoses by rWGS and had resultant changes in clinical management with sufficient clarity to permit cost and quality adjusted life years (QALY) modeling. Cost of PICU care was estimated to be reduced by $184,846 and a total of 12.1 QALYs were gained among these seven patients. The total cost of rWGS for patients and families for the entire cohort (38 probands) was $239,400. Thus, the net cost of rWGS was $54,554, representing $4,509 per QALY gained. This quantitative, retrospective examination of healthcare utilization associated with rWGS-informed medicine interventions in the PICU revealed approximately one-third of a QALY gained per patient tested at a cost per QALY that was approximately one-tenth of that typically sought for cost-effective new medical interventions. This evidence suggests that performance of rWGS as a first-tier test in selected PICU children with diseases of unknown etiology is associated with acceptable cost-per-QALY gained.

PMID:35141181 | PMC:PMC8818891 | DOI:10.3389/fped.2021.809536

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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.