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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:
•
Criminal violence•
Accident or suicide
•
or when death is:•
Unattended by a physician
•
Sudden and decedent is in apparently good health•
Suspicious, or occurs in an unusual manner
•
or when death occurs:•
In a correctional facility or in custody
•
the OCME also investigates:•
Case that may present a threat to public health
•
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)
•
New weapons? New injuries? New drugs?•
Emerging Infectious Diseases
•
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
•
Increased mass disaster planning–
$22 million in grant money
•
Molecular genetics
NYC OCME
NYC OCME
Storage of Remains
•
Memorial Park until final resting place•
Interment in WTC memorial
•
Unidentified and unclaimed•
Ease of future access, above ground
NYC OCME
Memorial Park
NYC OCME
RemainsRepository
NYC OCME
Ideal Preservation
•
Odor
•
Minimize DNA degradation
•
Environmentally feasible
NYC OCME
Methods of Preservation
•
Freezing•
Chemical
•
Drying–
Eliminates putrefaction
–
Less degradation of DNA than chemical–
Low humidity, refrigeration unnecessary
–
Natural process
NYC OCME
NYC OCME
NYC OCME
Commitment to Families•
Whatever it takes, for as long as it takes
•
New technology → renewed effort•
Spring 05, pause; Autumn 05, resume
•
Rooftops, sewers, damaged buildings → 15,000 cu yd material → 1,769 fragments
•
22 new identifications•
595 links to previously ID’d; 781 additional from retesting old specimens
NYC OCME
WTC Operational Statistics
•
Reported Missing: 2753 •
Remains Recovered: 21817
•
Victims Identified: 1630 •
Remains Identified: 12901 59%
NYC OCME
NYC OCME
NYC OCME
NYC OCME
WTC related illnesses
•
Pulmonary disease•
Cancer
•
Post Traumatic Stress Disorder•
Fatalities-
? Manner of Death
NYC OCME
Mass Disaster Planning
•
H1N1•
Regional Mass Fatality Planning
•
UVIS•
Training-
incident command, hazardous
materials, regional drills
NYC OCME
Mass Disaster Planning
•
H1N1•
Regional Mass Fatality Planning
•
UVIS•
Training-
incident command, hazardous
materials, regional drills
NYC OCME
•
Dept. of Forensic Biology
•
OCME Admin Offices
•
Molecular Genetics Laboratory
OCME DNA Building
NYC OCME
Cases Sent for Molecular Genetics Testing
•
Sudden death with positive autopsy findingsPulmonary Thromboembolism (PE) (2004)Sickle Cell Disease (S, C, A) (2005)Cardiomyopathies (CM)
-
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
•
Lab standards set by NYS Clinical Laboratory Evaluation Program (CLEP) and CAP
•
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
•
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
•
Question: what is the COD?
NYC OCME
Case 2 -
B07-XXXXX•
26yo HF with Hx of unknown cardiac problem collapsed at home•
No gross or microscopic injury or pathology•
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 3 –
B04-XXXXX
•
Reported healthy, 6 weeks WF, found dead at home co-sleeping with parents
•
Postmortem studies within normal limits, no congenital abnormalities at autopsy
•
COD/MOD: undetermined
•
Question: what is the COD?
NYC OCME
SIDS Definitions•
1969 Seattle definition–
Two parts: unexpected and negative autopsy
•
1989 NICHD definition–
Three parts: <1 yo, negative autopsy, scene, and history
•
2004 San Diego Definition–
Four parts: <1 yo, sleeping, negative autopsy, scene, and history
–
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).
•
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
•
Routine in suspected SIDS cases:–
Scene investigation, sleep position/condition
–
Complete autopsy–
Neuropathology of brain and spinal cord
–
Histology, detailed heart exam–
Toxicology, vitreous glucose, vitreous electrolytes
–
Microbiology (bacterial and viral in CSF & blood)–
Metabolic studies
–
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
•
Brainstem: Neurotransmission (serotonin system): –
Hannah C. Kinney ( Boston Children’s Hospital and Harvard University)
•
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
•
Large genes, multiplex exons
•
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
•
Class 2. Sequence variation is previously unreported and is of the type which is expected to cause the disorder
•
Class 3. Sequence variation is previously unreported and is of the type which may or may not be causative of the disorder
•
Class 4. Sequence variation is previously unreported and is probably not causative of disease
•
Class 5. Sequence variation is previously reported and is a recognized neutral variant
•
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
•
Question: what is the COD?
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•
No gross or microscopic injury or pathology•
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
•
Question: familial SCD? –
LQTKCNQ1 S277L (830 C>T), heterozygote, (Class I)
Her children?
NYC OCME
Case 3 –
B04-XXXXX
•
Reported healthy, 6 weeks WF, found dead at home co-sleeping with parents
•
Postmortem studies within normal limits, no congenital abnormalities at autopsy
•
COD/MOD: undetermined
•
Question: what is the COD?
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
•
Male:Female Ratio? •
Race?
•
Genotype/Phenotype Relationship?
•
Genotype & Mechanism Relationship?
•
Gene/gene, gene/external interactions?
•
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
•
Improve the testing throughput and capacity to test more genes by unbiased whole genome exome analysis using next-generation sequencing technology
-
New genes/biomarkers
•
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
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