the future of forensics - chicago...

The Future of Forensics

OFFICE OF CHIEF MEDICAL EXAMINERTHE CITY OF NEW YORK

Barbara Sampson, M.D.-Ph.D.

First Deputy Chief Medical Examiner

NYC OCME

Mission NYC OCMEResponsible for investigating deaths resulting from:

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Criminal violence•

Accident or suicide

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or when death is:•

Unattended by a physician

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Sudden and decedent is in apparently good health•

Suspicious, or occurs in an unusual manner

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or when death occurs:•

In a correctional facility or in custody

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the OCME also investigates:•

Case that may present a threat to public health

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Applications to perform cremation

NYC OCME

ManhattanHQ Facility

OCME DNABuilding26th Street

BronxFacility

Staten IslandFacility

BrooklynFacility

QueensFacility

NYC OCME

NYC OCME Headquarter

NYC OCME

NYC OCME

NYC OCME

What’s new?•

DNA identification (CSI)

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New weapons? New injuries? New drugs?•

Emerging Infectious Diseases

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Arch Pathol

Lab Med. 2010 Feb;134(2):235-43.Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections.New York City Office of Chief Medical Examiner and Department of

Forensic Medicine, New York University School of Medicine

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Increased mass disaster planning–

$22 million in grant money

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Molecular genetics

NYC OCME

NYC OCME

Storage of Remains

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Memorial Park until final resting place•

Interment in WTC memorial

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Unidentified and unclaimed•

Ease of future access, above ground

NYC OCME

Memorial Park

NYC OCME

RemainsRepository

NYC OCME

Ideal Preservation

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Odor

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Minimize DNA degradation

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Environmentally feasible

NYC OCME

Methods of Preservation

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Freezing•

Chemical

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Drying–

Eliminates putrefaction

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Less degradation of DNA than chemical–

Low humidity, refrigeration unnecessary

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Natural process

NYC OCME

NYC OCME

Commitment to Families•

Whatever it takes, for as long as it takes

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New technology → renewed effort•

Spring 05, pause; Autumn 05, resume

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Rooftops, sewers, damaged buildings → 15,000 cu yd material → 1,769 fragments

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22 new identifications•

595 links to previously ID’d; 781 additional from retesting old specimens

NYC OCME

WTC Operational Statistics

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Reported Missing: 2753 •

Remains Recovered: 21817

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Victims Identified: 1630 •

Remains Identified: 12901 59%

NYC OCME

NYC OCME

WTC related illnesses

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Pulmonary disease•

Cancer

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Post Traumatic Stress Disorder•

Fatalities-

? Manner of Death

NYC OCME

Mass Disaster Planning

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H1N1•

Regional Mass Fatality Planning

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UVIS•

Training-

incident command, hazardous

materials, regional drills

NYC OCME

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Dept. of Forensic Biology

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OCME Admin Offices

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Molecular Genetics Laboratory

OCME DNA Building

NYC OCME

Cases Sent for Molecular Genetics Testing

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Sudden death with positive autopsy findingsPulmonary Thromboembolism (PE) (2004)Sickle Cell Disease (S, C, A) (2005)Cardiomyopathies (CM)

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Dilated, Hypertrophic, ARVC•

Sudden death with no positive autopsy findings

Sudden Infant Death Syndrome (SIDS) (2008)Sudden Unexplained Death Syndrome (SUDS)(2008)

NYC OCME

Molecular Genetics Cases Received

(2003-2011)

NYC OCME

2011 Molecular Genetics Case Statistics

Purposes # CasesTurn‐Around‐Time

(average, days)

Requested for PE testing 220 25

Requested for Sickle testing 34 23Requested for Channelopathy

testing 51 32

CAP Proficiency samples 30 ‐

Storage 176 ‐

Total 511 ‐

NYC OCME

Laboratory Standards and Accreditation

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Lab standards set by NYS Clinical Laboratory Evaluation Program (CLEP) and CAP

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College of American Pathologists (CAP) 2011

NYC OCME

Molecular Genetic Testing for SIDS/SUDS

NYC OCME

Case 1 –

K08-XXXXX•

16yo BF, complained of abdominal pain, went to lie down. Found unresponsive about 1 hr later by mother, EMS unable to resuscitate

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No gross or microscopic injury or pathology•

Her surviving sister has since been diagnosed with long QT syndrome. The sister's results are: KCNQ1 R518X heterozygote and KCNH2 R835Q heterozygote

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Question: what is the COD?

NYC OCME

Case 2 -

B07-XXXXX•

26yo HF with Hx of unknown cardiac problem collapsed at home•


COD: Acute intoxication due to combined effects of cocaine and ethanol; MOD: Accident

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A year later…

“The patient was diagnosed as having long QT based on a routine ECG that was followed up by cardiologists here in the Bronx but before she could be adequately worked up she passed away…

Both of her parents died of unknown causes at age 35…There are 3 young children at risk we are seeing at our clinic…”

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Question: familial SCD?

NYC OCME

Case 3 –

B04-XXXXX

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Reported healthy, 6 weeks WF, found dead at home co-sleeping with parents

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Postmortem studies within normal limits, no congenital abnormalities at autopsy

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COD/MOD: undetermined

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NYC OCME

SIDS Definitions•

1969 Seattle definition–

Two parts: unexpected and negative autopsy

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1989 NICHD definition–

Three parts: <1 yo, negative autopsy, scene, and history

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2004 San Diego Definition–

Four parts: <1 yo, sleeping, negative autopsy, scene, and history

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Stratified for research

SUDS: over one year of age. Peak age is 20-40 years.

NYC OCME

Prevalence/Epidemiology•

SIDS remains the number one cause of death for the infants from one month to one year of age (2,500 SIDS cases /yr in US).

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Peak time of occurrence: 2-5 months•

Higher incidence

- Blacks- male infants- colder months- preterm/LBW infants- maternal smoking during pregnancy- lower socioeconomic status

National Vital Statistics Report, Vol.57(2), 2008

NYC OCME

SIDS work-up in NYC-OCME•

SIDS as a diagnosis of exclusion requires the most extensive work-up

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Routine in suspected SIDS cases:–

Scene investigation, sleep position/condition

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Complete autopsy–

Neuropathology of brain and spinal cord

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Histology, detailed heart exam–

Toxicology, vitreous glucose, vitreous electrolytes

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Microbiology (bacterial and viral in CSF & blood)–

Metabolic studies

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Molecular Genetics Testing since October, 2008

NYC OCME

Triple-risk Model in SIDS

Bedding/bed sharingHypo/hyperthermiaCO/CO2.Prone sleeping position

Genetic factors

NYC OCME

Two Mainstream Ideas

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Brainstem: Neurotransmission (serotonin system): –

Hannah C. Kinney ( Boston Children’s Hospital and Harvard University)

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Heart: Cardiac arrhythmia–

Peter John Schwartz (Italy)–

Michael Ackerman (Mayo Clinics)–

JefferyTowbin (Texas Children's Hospital)–

G. Michael Vincent (University of Utah School of Medicine)–

Mark Keating (Harvard Medical School)

NYC OCME

Medullary 5-HT Pathology in SIDS

JAMA, November 1, 2006—Vol 296, No. 17 JAMA, February 03, 2010—Vol 303, No. 5

NYC OCME

ECG Evidence of Long QT in SIDS34,442 newborns34 deaths24 SIDS

NYC OCME

Molecular Evidence of LQT in SIDS

S941N

SCN5A: a Sodium channel

NYC OCME

Prevalence of Cardiac Arrhythmia Syndromes in SIDS

~10-15%

NYC OCME

P Q S T

R

http://en.wikipedia.org/wiki/Cardiac_action_potential

Ventricular action potential

Sodium channelSCN5A

Ica. Iks. CACNA1C, KCNQ1,KCNE1

Ica. Iks. Ikr. KCNH2,KCNE2Ik1

Ik1 KCNJ2

Keating M. and Sanguinetti M. Cell Vol.104, 569-580, 2001

SCN5A

NYC OCME

David Tester and Michael Ackerman. Annu.Rev.Med.2009.60:15.1-15.16

Genes for Cardiac Arrhythmia Syndromes

NYC OCME

NYC OCME Arrhythmia Panel

Gene Exon TestedKCNQ1 All 16 exonsKCNH2 All 15 exonsSCN5A Exons 12 to 28KCNE1 all 1 exon KCNE2 all 1 exon

RyR 2Exons 8, 14, 15, 44-47, 49, 88-93,

95-97, 100-105

NYC OCME

Technical Challenges

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Large genes, multiplex exons

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No common mutationsGene KCNQ1 KCNH2 SCN5A KCNE1 KCNE2 RyR2

mutation 246 291 173 30 11 71

NYC OCME

Test Method –

PCR Direct Sequencing

PCR

MG-training lecture

Bi-direction Sequencing

NYC OCME

Interpretation Challenges•

Class 1. Sequence variation is previously reported and is a recognized cause of the disorder

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Class 2. Sequence variation is previously unreported and is of the type which is expected to cause the disorder

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Class 3. Sequence variation is previously unreported and is of the type which may or may not be causative of the disorder

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Class 4. Sequence variation is previously unreported and is probably not causative of disease

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Class 5. Sequence variation is previously reported and is a recognized neutral variant

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Class 6. Sequence variation is not known or expected to be causative of disease, but is found to be associated with a clinical presentation

ACMG Sequence Variant Interpretation Guidelines

NYC OCME

Case 1 –

K08-XXXXX•

16yo BF, complained of abdominal pain, went to lie down. Found unresponsive about 1 hr later by mother, EMS unable to resuscitate

•

No gross or microscopic evidence of injury or natural disease.

•

Her surviving sister has now been diagnosed with long QT syndrome. The sister's results are: KCNQ1 R518X heterozygote and KCNH2 R835Q heterozygote

•


NYC OCME

Case 1 –

K08-XXXXX•

Question: what is the COD? – LQT

KCNQ1 R518X (1552 C>T), homozygote (class I)

KCNH2 R835Q (2504 G>A)Heterozygote, (Class III)

NYC OCME

Case 2 -

B07-XXXXX•

26yo HF with Hx of unknown cardiac problem collapsed at home•


COD: Acute intoxication due to combined effects of cocaine and ethanol; MOD: Accident

•

A year later…

“The patient was diagnosed as having long QT

based on a routine ECG that was followed up by cardiologists here in the Bronx but before she could be adequately worked up she passed away…

Both of her parents died of unknown causes at age 35…There are 3 young children at risk we are seeing at our clinic…”

•

Question: familial SCD?

NYC OCME

Case 2 -

B07-XXXXX

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Question: familial SCD? –

LQTKCNQ1 S277L (830 C>T), heterozygote, (Class I)

Her children?

NYC OCME

Case 3 –

B04-XXXXX

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Reported healthy, 6 weeks WF, found dead at home co-sleeping with parents

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Postmortem studies within normal limits, no congenital abnormalities at autopsy

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COD/MOD: undetermined

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NYC OCME

Case 3 –

B04-00928

Question: what is the COD? –

Possible CPVTRyR2 G4471R (13411 G>A), heterozygote, (Class III)

NYC OCME

Data Analysis Algorithm of 323 Cases Tested

OFFICE OF CHIEF MEDICAL EXAMINER

THE CITY OF

NEW

YORK

323 Cases Tested

263 casesUndetermined COD

60 casesContributory COD

139 casesUndetermined, <1y

124 casesUndetermined, >1y

NYC OCME

139 Undetermined (<1y)Sex Ethnicity Total

Female Black 35HISPANIC 8WHITE 6Asian 3white/his 2Hispanic/Black 2Black/Indian 1black/his 1white/black 1

Female Total 59Male Black 48

HISPANIC 17WHITE 4Asian 3Black/ White 1Black/ West

Indian 1Indian/ White 1white/his 1white/black 1Black/Hispanic 1Asian/his 1black/his 1

Male Total 80F:M 0.74Grand Total 139

Gene Class 1 Class II Class III SCN5A 7 1 6

kCNH2 ‐ ‐ 1

KCNQ1 ‐ ‐ 3

RyR2 ‐ ‐ 1

4 (F), 3 (M) 1 (F) 3 (F), 8 (M)

DemographicsSignificance of molecular testing –

Class I, II, and III

NYC OCME

124 Undetermined (>1y)Age Group Sex Ethnicity Total

1‐5y Female White 2BLACK 2Asian 1

Male White 2BLACK 2

Hispanic 2F:M 0.833

6‐18y Female BLACK 6Asian 1

Male BLACK 6

Hispanic 3White 1

F:M 0.7>18y Female White 16

BLACK 12Asian 5

Hispanic 3

Male Hispanic 23BLACK 14White 12Asian 10

White/hispanic 1F:M 0.6

Grand Total 124

Class 1 Class II Class III

KCNQ1 2 ‐ 1

KCNH2 2 1 1

SCN5A 6 ‐ 4

KCNE1 1 ‐ ‐

KCNE2 1 ‐ ‐

RyR2 1 ‐ 2

age groups 1 (6‐18y); 12 (>18y) 1 (>18y)2 (1‐5y), 1 (6‐

18y), 5 (>18y)

F, M 5 (F), 8 (M) 1(F) 4 (F), 4 (M)

Significance of molecular testing –

Class I, II, and III

NYC OCME

60 Cases with other Possible CODAge group Sex Ethnicity Total

<1 y Female Black 2Hispanic 2

Male Hispanic 2White 1

F:M 1.331-5y Female Black 1

White 3F:M -

6-18y Female Black 1Male Black 4

Hispanic 1F:M 0.2

>18y Female Black 1Asian 2Black 6

Hispanic 4White 6

Male Asian 4Black 10

Hispanic 2White 7

White/Black 1F:M 0.79

Grand Total 60

3 cases class I, 2 cases class III-Benefit to family member treatment-Cocaine and ion channel def-Cardiac hypertrophy and ion channel def.

Contributory COD by System

NYC OCME

Challenges•

Time/labor costly

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Male:Female Ratio? •

Race?

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Genotype/Phenotype Relationship?

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Genotype & Mechanism Relationship?

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Gene/gene, gene/external interactions?

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80% unknown?

NYC OCME

Future Sudden Unexplained Death Study•

>52 Genes May play roles in SUD:Category # Genes

Cardiac Channelopathies

Long QT Syndromes, Brugada Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Short QT Syndrome,

Ventricular fibrillation, Wolff-Parkinson-White Syndrome, Sick Sinus Syndrome, Cardiac

Conduction Defect, Progressive Familial Heart Block, Type Ib, Atrial fibrillation and sudden

Death

>20 genes

CardiomyopathiesHypertrophic Cardiomyopathy (HCM), Dilated

Cardiomyopathy (DCM), Heart-Hand Syndrome, Arrhythmogenic Right Ventricular

Cardiomyopathy (ARVC), Left Ventricular Noncompaction Cardiomyopathy (LVNC);

Emery-Dreifuss Muscular Dystrophy

>20 genes

Central Neural System

Sudden Explained Death in Epilepsy, Rett Syndrome (with long QT phenotype), Central

Hypoventilation Syndrome>2 genes

Whole-Genome-Association Hits

Cardiac genes, Transcription Factors, Cell Cycle genes, Neural gene >10 genes

High Throughput (up to 1.5-2 Gb)Cheaper Faster

NYC OCME

SIDS/SUDS Current & Future•

Collaboration of the functional analysis and family follow-

up with Albert Einstein College of Medicine

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Improve the testing throughput and capacity to test more genes by unbiased whole genome exome analysis using next-generation sequencing technology

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New genes/biomarkers

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Offer services to other medical examiner offices

NYC OCME

Yingying Tang

Sung Yon Um Ph.D.

Dawei Wang Ph. D. Krunal Shah, M.S.

Lucy Eng, M. S. Bo Zhou Ph.D.

Molecular Genetics Laboratory Staff

Current

Past•

Eric Bieschke•

St. Jean Judy•

Adrianna Kim•

Stacy Saint-Marie•

Stephanie Pack•

Maribel Sansone•

Donald Siegel•

Interns

NYC OCME

the future of forensics - chicago...

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