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  • Implementing Inpatient Precision Medicine

    Stephen Kingsmore MD DSc

    skingsmore@rchsd.org

    Radygenomics.org

    mailto:skingsmore@rchsd.org

  • Conflicts of Interest

    None

  • Learning Objectives

    Understand principles of genomic medicine

    Understand status of clinical whole genome sequencing

    Be able to ascertain inpatients who may benefit from whole genome sequencing

    Comprehend the evidence base for rapid WGS in ill infants

  • 2 month old male admitted for jaundice x 1 month and

    poor weight gain

    Pregnancy/birth: uneventful

    Negative family history

    Birth weight 2.9kg (14%ile)

    Rady Childrens Hospital Baby 6026, Sunday

  • 15% of US newborns admitted to a NICU or PICU

  • Children with

    Severe Chronic

    Illness

    High Risk

    Children

    Healthy

    Children

    % Cost % Children

    76%

    14%

    10%

    10%

    20%

    70%

    NICU, PICU, CVICUNeuro-oncologyInpatients

    Why start here?

  • Weight 3.9kg (0.05%ile).

    Head circumference 3%ile, length 1%ile

    Jaundiced

    High pitched continuous murmur left chest

    III/VI low pitched harsh systolic murmur LUSB

    No hepatosplenomegaly

    Physical Examination

  • Labs: AST 241, ALT 188, GGT 562, total bilirubin 10.6, direct bilirubin 5.1, ammonia 27 (L)

    Abdominal ultrasound: normal

    Liver Biopsy: giant cell hepatitis

    Hepatobiliary HIDA scan: non-excreting

    Tests negative for infection, alpha-1 antitrypsin deficiency, thyroid disease

    Chest X-Ray, echocardiogram, CT scan heart:

    Patent ductus arteriousus

    Hypoplastic branch pulmonary arteries,

    Patent foramen ovale

    Aberrant right subclavian artery

    Tests

  • Genomics: the study of all of your DNA letters

  • We are fearfully and wonderfully made. Psalm 139

    Each of My 37 Trillion Cells Contains2 Genomes of 3.2 Billion DNA Letters

  • Molecular Diagnosis: ID the cause of a genetic disease in a patient

  • Leading cause of NICU and PICU

    death

    Genetic diseases in infants often look atypical

    Conventional molecular testingtoo slow to guideNICU and PICU care

    Timely Diagnosis of 8,000 Genetic

    Diseases in NICUs and PICUs

    Unique Requirements for Diagnosis of Genetic Diseases in Neonatal, Pediatric and Cardiovascular ICU

  • The conventional model in medicine does not work well in rare diseases or precision therapies

    Clinical diagnosis Empiric Treatment

    Molecular diagnosis Precision Therapy

    Situation today:

    Misdiagnosis & mistreatment

    Delayed diagnosis & empiric treatment

  • Tuesday

    Tachypnea, acidosis: Transferred to PICU

    Clinical diagnosis: biliary atresia

    Incidence 1 in 10,000

    Empiric treatment: Kasai procedure

    Prognosis worsens with time to surgery

  • 2:30PM Consent, blood sample from mum, dad & baby

  • Implementing Inpatient Precision Medicine

  • Computer readable digest of infants medical record

  • Phenomizer or Phenolyzer

  • Isolate DNA and prepare it for sequencing

  • Rapid genome sequencing

  • Genome Analysis and Interpretation

  • Infant with liver disease

  • Infant with liver disease

  • Infant with liver disease

  • Infant with liver disease

  • Infant with liver disease

  • Infant with liver disease

  • 43 Hours Later: Molecular Diagnosis

    0

    10

    20

    30

    40

    50

    60

    9 10 11 12 13 14Chromosome 20

    Gen

    om

    e se

    qu

    ence

    co

    vera

    ge

    Position 10,471,400

    Position 13,459,331

    JAG1: Alagille Syndrome Gene

    Jaundice, bile duct paucity on liver biopsy; congenital heart disease, primarily involving

    pulmonary arteries

  • Kasai hepatoportoenterostomy for biliary atresia

    Friday 11AM

  • Pediatr Gastroenterol Hepatol Nutr. 2015 18:175-9.

    5% of infants with Alagille syndrome are diagnosed clinically asbiliary atresia and undergo Kasai operation.Among 15 children with Alagille syndrome, mortality was 60%among the Kasai group, and 10% in the non-Kasai group .Liver transplantation was performed in 100% of the Kasai group,and 20% of the non-Kasai group.

    Precision Medicine: 50% Reduction in Likelihood of Death

  • Rady NICU Infant 6041

    2 day old female with seizures since 16 hours after delivery

    Normal pregnancy, delivery Electroencephalogram: tonic & myoclonic

    seizures, background burst suppression Head circumference 5th %ile

    Physical exam normal Brain MRI normal Infection, metabolic tests normal Standard anti-epileptics ineffective:

    Phenobarbital then Levetiracetam then Topiramate

  • Molecular Diagnosis in 68 hours

    Ohtahara syndrome

    de novo KCNQ2 c.875T>C; p.Leu292Pro Gene Name DNA Change Protein Change

    Precision Medicine: carbamazepine, phenytoin

    Seizures controlled child discharged (18 days after admission) in time for family Christmas

  • Previous Ohtahara diagnosis in same NICU one year earlier (pre-WGS)

    59 day hospital stay; diagnosis after discharge

    Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder

    Pisano et al. Epilepsia 2015 56:685-91.

  • Randomized Controlled Trial

  • Faster Time to Diagnosis

  • Case Series

    Less than 1 year old

    Inpatient July 2016 February 2017

    Presentation that may be caused by a single gene disorder or clinical course not following typical pattern

    Without known genetic diagnosis

  • Enrollment by Location

    SourceEnrolled

    Families

    NICU 24

    CVICU 3

    PICU 3

    Gastro 9

    Neurology 2

    Hematology 1

    42

  • Less than 1 year of age and inpatient:

    42

    Diagnosis:18

    Non-Diagnostic:24

    43%

  • Diagnostic Utility of Whole Genome and Exome Sequencing

    NICU rWGS

    NICU rWGS

  • Less than 1 year of age and inpatient:

    42

    Diagnosis:18

    Non-Diagnostic:24

    No change in care: 6 cases

  • Presentations of cases with diagnosis but no change in care

    Presentation Causative Gene

    Cholestasis SERPINA1

    Seizure-like/spasm activity. Cluster of infantile spasms SCN1A

    Apnea, cyanosis, posturing, abnormal EEGTetrasomy for 15q1.2q13.1

    Cardiomegaly, heart block, prolonged QT interval, respiratory failure POLR1C

    Myelomeningocele, congenital hydrocephalus CELSR1

    Preterm pulmonary atresia with intact ventricular septum with sinusoids, poor weight gain, feeding intolerance, recurrent pneumonia

    ACTG2

  • Less than 1 year of age and inpatient:

    42

    Diagnosis:18

    Change in management: 12

    Non-Diagnostic:24

    No change in care: 6 cases

    Unable to model concrete cost changes:

    6

    67%

  • Clinical Utility of Whole Genome and Exome Sequencing

    NICU rWGS

    NICU rWGS

  • Presentation Etiology Outcome

    Infantile Spasms, hypertonia, esotropia, poor weight

    gainGABRA1 Appropriate seizure medication

    Hydrops fetalis, cardiomyopathy TPM1

    LSD and arythmogenic

    cardiomyopathy excluded

    proceeded with heart transplant

    Complex partial epilepsy PCDH19

    Switched to targeted therapy

    and referred for research

    protocol

    IUGR, Compex cardiac disease, vertebral

    segmentation defect, GU anomaliesPHEX

    Medication started to prevent

    rickets

    Hirschprungs disease, congenital ileal stenosis RETComprehensive surgical

    approach

    Pulmonary atresia, osteopenia, frequent unexplained

    fevers. NF1

    Pre-emptive management of

    extra cardiac disease

    Congenital hyperinsulinemia, bilateral ventricular

    hypertrophy & left ventricular outflow tract obstructionABCC8 Targeted surgery, preventing DM

    Presentations of cases with diagnosis & change in care

  • Less than 1 year of age and inpatient:

    42

    Diagnosis:18

    Change in management: 12

    Change in management possible

    to model: 5

    Prospective Change in care: 4

    Retrospective care model: 2

    Non-Diagnostic:24

    No change in care: 6 cases

    Unable to model concrete cost changes:

    6

  • Cost savings from care avoided as a result of WGS

    Case Cost avoided Cost saving

    NPC1Avoided biopsies and one hospitalization, started

    precision medicine$54,000

    ARID1B Multiple unnecessary surgeries, ECMO etc. $1,410,000

    KCNQ2 Shortened hospital stay, avoided neurologic damage $129,000

    ARID1B Avoided prolonged hospitalization for IV antibiotics $269,000

    JAG1 Kasai surgery avoided $36,000

    NEB Muscle biopsy avoided $10,000

  • Overview of program impact and cost savings

    Description Value

    Number of NICU discharges at Rady Childrens Hospital during the sample

    period369

    Number of babies enrolled for rapid trio WGS 42

    Cost of rapid trio WGS ($604,000)

    Number of babies with a different course of treatment after diagnosis, and

    identifiable cost savings5

    Savings for babies who received a different course of treatment after

    diagnosis$1,883,000

    Net savings $1,279,000

  • Conclusions

    49% of 125 NICU/PICU infants received diagnoses by rapid WGS

    Rapid WGS returned results faster than standard tests

    39% of 93 NICU/PICU infants had a change in care as a result of rapid WGS

    Cost savings $30,450 per family tested

  • The most significant breakthrough in healthcare in the past 40 years

    GENOME SEQUENCING

  • GOINGBIG

    FOR

    THE

    LITTLE

    ONES

  • Improved outcomesEmpowered families

    Cost effectiveness

    NovaSeq

    Mum DadBaby

  • Newborn Sequencing In GenomicMedicine and Public Health

    http://upload.wikimedia.org/wikipedia/commons/2/23/US-NIH-NICHD-2008Logo.svg

  • The LORD is my creativity, Psalm 27

    Josh Petrikin Laurel Willig

    Carol Saunders John Lantos

    Neil Miller Emily Farrow

    Todd Laird Joe Gleeson, MD, PhD Julie Cakici Ray Veeraraghavan,

    PhD Jennifer Azares Vanessa Wertheim, PhD Shareef Nahas, PhD

    David Dimmock, MD Julie Reinke Yan Ding, MD Michelle Clark, PhD Wendy Benson Matt Bainbrindge, PhD Sergei Batalov, PhD Shimul Chowdhury PhD

    Patrick Mulrooney Olivia Simonides Daeheon "Danny" Oh Catherine Yamada Jennifer Silhavy, Matthew Bainbridge,

    PhD Lisa Salz

    Lance Prince, MD, PhD Farhad Imam, MD, PhD Nicole Coufman, MD,

    PhD Julie Ryu, MD George Chiang, MD James Perry, MD

    Jenni Friedman, MD Tina Chambers, PhD Jeff Neul, MD, PhD Lauge Farnaes, MD, PhD Gail Knight, MD Nathaly Sweeney, MD Cynthia Kuelbs, MD

    Lynn Byrd, MD Amber Hildreth, DO Jonathan Sebat, PhD Albert Oriol Cyndi Kuelbs, MD Bruce Barshop, MD

    Kevin Hall, PhD James Richardson Kyle Farh, MD Susan Tousi Ryan Taft, PhD

    Severine Catreux Mike Ruehle

    Support: Rady Childrens Institute for

    Genomic Medicine NICHD NHGRI NIDDK Illumina

  • The children are waiting.

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