Diagnostic and Clinical Utility of Rapid Genome Sequencing · Diagnostic and Clinical Utility of ... Adam Walter . John Lesko . Emily Farrow PhD CGC . Margaret Gibson . Kyle Harris

© The Children's Mercy Hospital, 2014. 11/14

In Acutely Ill Infants in a Level IV NICU

Laurel Willig, MD, MS

Diagnostic and Clinical Utility of Rapid Genome Sequencing


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Disclosures

Laurel Willig, MD has documented no financial relationships to disclose or conflicts of interest to resolve.


For disorders currently screened for in newborns, how can genomic sequencing replicate or augment known newborn screening results?

What knowledge about conditions not currently screened for in newborns could genomic sequencing of newborns provide?

What additional clinical information could be learned from genomic sequencing relevant to the clinical care of newborns?

Must address one or more of the following:

A. B. C.

NSIGHT U19


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Components

Component 1: Data Acquisition and Analysis

Component 2: Clinical research to advance understanding of specific disorders identifiable in the newborn period using DNA technology

Component 3: Ethical, legal and social implications of genomic sequencing in newborns


Members of the NSIGHT Program

• Robert Green, M.D., and Alan Beggs, Ph.D. Brigham and Women’s Hospital, Boston, MA NICU and healthy newborns, 240 exomes, data sharing, return of results

• Stephen Kingsmore, MB, ChB, BAO, DSc, FRCPath Children’s Mercy Hospital, Kansas City, MO NICU, 1000 patients, return of results

• Robert Nussbaum, M.D. (Jennifer Puck, M.D.) University of California, San Francisco, CA NBS, exome sequencing, return of results

• Cynthia Powell, M.D., M.S., and Jonathan Berg, M.D., Ph.D. University of North Carolina at Chapel Hill, NC NBS, 400 exomes, return of result options


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50-hour STAT-Seq

• Identify patient who may benefit • Parental consent, blood sample

4.5 h • Sonication/Library Prep • Clinical finding entry: SSAGA

25.5h • HiSeq 2500 2x100bp x 140Gbp

17h • Secondary analysis: GSNAP, GATK • Tertiary analysis: RUNES

0.5+h • VIKING-assisted interpretation • Provisional report


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Rapid Whole Genome Testing

Initial proof of concept was on 7 proband parent trios

Cost: ~$6000 per genome

Saunders et al. Sci Transl Med 4; 154ra135 2012


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STATseq Application


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Level II – IV NICU Admissions

•14.4% of newborns

•2% Level IV

•49.1% were preterm •Average hospital stay = 13.2 days •Average hospital charge = $76,000 •Overall mortality in the CMH NICU was 4% (23 deaths in 563 neonates of gestational age >36 weeks admitted in 2013)


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Monogenic (Mendelian) Diseases

in Infants • Affect 4-8% of children and

are leading cause of infant death

• 5,400 known disease genes, and 20 more are discovered each month


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Infant Genetic Disease Diagnostic Complexity

Early in disease progression = incomplete symptoms Early in development

– Stereotyped adaptation to challenges to homeostasis Genocopies/genetic heterogeneity

– Several genes cause same “disease” Poorly defined clinical heterogeneity Phenocopies Early diagnosis = optimal outcome, prevention of

unplanned recurrence

Eligible infants N=49

Excluded infants N=14 Reasons: Age >4 months; patient

deceased at the time of enrollment; patient enrolled at outside institution

STATseq diagnosis N=20 of 35 (57%)

No STATseq diagnosis N=15 of 35 (43%)

Target condition present N=20

Target condition absent

N=0

Target condition present

N=1

Target condition absent N=14

STATseq (Index Test)

N=35

Results: November 2011 – October 2014

57% molecular diagnosis rate in STATseq group, 9% diagnostic rate using standard testing


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Multisystem Congenital Anomalies

26%

Neurologic 20%

Cardiac/Heterotaxy 14%

Hydrops/Pleural Effusion

11%

Metabolic (inc. Hypoglycemia)

11%

Renal 3%

Arthrogryposis 6%

Respiratory 3%

Hepatic 3%

Dermatologic 3%

Phenotypic Distribution of Patients


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65% of WGS diagnoses were associated with De Novo mutations

De Novo 65%

Somatic 5%

Germline 30%


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Important Time Points

Time Points Days (Range)

Age at enrollment 26

Median time from enrollment to variant analysis 5 (3-153)

Median time to clinically confirmed diagnosis 9 (5-912)

Average age at death 46 (16-100)


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Mortality

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 20 40 60 80 100 120

Prop

ortio

n Su

rviv

ing

Days of Life

Molecular Diagnosis

No Molecular Diagnosis 57% of patients

receiving a diagnosis died versus 14% in those without a genetic diagnosis


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Acute Clinical Impact

Clinical utility in 65%

Palliative care initiated in 33%

Other types of changes: medication, dietary, consults, imaging, genetic counseling, procedure performed

Diagnosis led to a positive clinical change in 20%


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Framework

- Largest case series published to date

- Relatively quick diagnostic rate

- Huge selection bias - Unblinded with no set standard

testing - Survey data for clinical impact - No long term follow up with families

Strengths Weaknesses

Take home points - High diagnostic rate - High 120 day mortality rate - Reported affect on clinical management


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6th Grade Perspective


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Clinical Study Aims

Examine risks and benefits of rapid genomic sequencing in the NICU population.

Does STAT-Seq change the clinical care of newborns in the NICU?

– 28-day definitive diagnostic yield of STAT-Seq vs. standard testing

– Time to definitive diagnosis of WGS vs. standard tests

– Physician perception of change in clinical management in WGS-Dx vs. standard tests

– Surrogate measures of objective change in clinical management in WGS-Dx vs. standard tests


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Social and Ethical Study Aims

Describe: – clinicians’ and parents’ perceptions of value of STAT-seq in ill

neonates

– the quality of communication of STAT-seq results

– expectations for STAT-seq in the context of clinical outcome data collected under Component 2

Is STAT-Seq viewed as beneficial, harmful, or immaterial – What factors influence these perceptions

How do these perceptions change pretest to post-test and at 12 month follow up


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Initial Study Visit Plan

Consent/Initial Visit

Genome Consult/Consent

Blinded randomization

Blood draw

Refusal Assessment

Pretest Questionnaires

Parent Questionnaires

Clinician Questionnaires

Return of Results to Clinician

Phone conference or

care conference with neonatal attending to

discuss results/treatment

decisions

Return of Results to

Family

Patient care team to return findings

to families. Genome care

team present if requested.

72 Hours Post Test Results

Parent Questionnaires

Clinician Questionnaires

12 Months Post Results

Patient questionnaires

and medical follow up


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Support: Children’s Mercy Hospital

Marion Merrell Dow Foundation William T. Kemper Foundation Pat &Gil Clements Foundation

Claire Giannini Foundation Black & Veatch

NICHD NHGRI NIDDK

Illumina

Stephen F. Kingsmore MB ChB BAO DSc FRCPath

Nhu Bui Jack Curran Elena Repnikova PhD

FACMG Carol Saunders PhD FACMG Isabelle Thiffault PhD Lee Zellmer CGC Sultan Habeebu MD FACMG Angela Newton Adam Walter John Lesko Emily Farrow PhD CGC Margaret Gibson Kyle Harris Lisa Krivohlavek Melanie Patterson

Suzanne Herd Julie Cakici RN Josh Petrikin MD Laurie Smith MD PhD Sarah Soden MD Erin Guest MD Shane Corder Tyler Hullinger Neil Miller Aaron Noll Greyson Twist Byunggil Yoo

Thank You Questions

Documents

Diagnostic and Clinical Utility of Rapid Genome Sequencing · Diagnostic and Clinical Utility of ... Adam Walter . John Lesko . Emily Farrow PhD CGC . Margaret Gibson . Kyle Harris