Implementing Inpatient Precision Medicine

Stephen Kingsmore MD DSc

skingsmore@rchsd.org

Radygenomics.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 Children’s 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 infant’s 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

Hirschprung’s 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 Children’s 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

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 Children’s Institute for

Genomic Medicine • NICHD• NHGRI• NIDDK• Illumina

The children are waiting….