1 An Introduction to Use, Application, Technology and Coding
Molecular and Genetic Clinical Diagnostics February 16, 2011
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Results For Life: The Value of Laboratory Medicine Message
Laboratory medicine central to medical decisions Laboratory
medicine changes course of diagnosis, treatment, management
Audience Congress, media, thought leaders Tools Briefings, OpEds,
advertising 2
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ACLA Members and Associate Members ACLA Member Sponsors
Associate Members Aculabs Agendia Arista Laboratories ARUP
Laboratories Aureon Laboratories Aurora Diagnostics Axial Biotech
Berkeley Heartlab Biodesix BioReference Laboratories
bioTheranostics CBLPath Clarient Cleveland Clinic Foundation
CorePlus DaVita DCI Laboratory Genomic Health Genoptix GI
Pathology, PLLC Joint Venture Hospital Labs Laboratory Corp of
America Laboratory Partners Machaon Diagnostics Mayo Clinic MEDTOX
Laboratories Meridian Laboratories Myriad Genetics NeoGenomics
Laboratories NMS Labs PathNet Esoteric Lab Inst Pathology
Associates Medical Laboratories Pathology PerkinElmer Genetics
Precision Therapeutics Quest Diagnostics Incorporated RenaLab
RedPath Integrated Pathology Satellite Laboratory Services Solstas
Lab Partners Spectra Laboratories Tethys Bioscience TridentUSA
Health Services Virco Lab XDx Abbott Molecular American Medical
Technologists Aperio Cgate Health HillCo Health LipoScience
McKesson Health Solutions-Adv Diagn. Mgt Roche Siemens Sysmex XIFIN
3
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A revolution in science requires a revolution in thinking What
disease is How to identify and treat disease When it is best to
take action Which individuals are at risk The size of the
population we treat The economics of utilization and health
spending The ability to reduce adverse events, side effects,
inappropriate use 4
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Because we know vastly more about disease 5 Diagnose more
preciselyMore effective treatment Select specific treatment that
best fits disease Avoid adverse drug reaction Improve utilization
Predict risk before symptoms occur Earlier treatment Preventive
action Manage more effectively Better timing Adjustments as disease
changes
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Today The basics of genetic testing The use and value of
genetic testing Personalized medicine Pharmacogenomics Emerging
Technologies Laboratory procedures and coding 6 Presentation
Speakers Vicky Pratt, Ph.D., FACMG, Quest Diagnostics Sherri Bale,
Ph.D., FACMG, GeneDX Kaye Jones, MLS (ASCP), CPC, LabCorp
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7 Presented by Victoria Pratt, Ph.D., FACMG T HE B ASICS OF G
ENETIC T ESTING
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Diagnostic laboratory testing drives health decisions 70% of
healthcare decisions based on diagnostic data Diagnostic data
yields essential information Helps identify trends for public
health Enables physicians to care for individual patients
Facilitates new test development Continuum of diagnostic lab
testing From diagnosis to predictive and personalized medicine
Diagnostic data increasingly is providing actionable insights
physicians can use to improve patient healthcare outcomes 8 One of
the most fundamental basics
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Nucleus DNA bases mRNA DNA Protein Ribosome Cell membrane Gene
Chain of amino acids DNA RNA Protein 9
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Chromosome Cytogenetics Protein Biochemical Genetics DNA
Molecular Genetics Gene Tests: Three Common Methods 10 Mutation
AbsentMutation Present
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Types of Mutations Single nucleotide - traditional Missense
Nonsense (creation of stop codon) Splicing Regulatory sequences
(promoter, 3 end) Deletions/Insertions copy number variants (CNVs)
In frame frameshift Expansions (triplet repeat disorders)
Epigenetic (methylation) Translocations and inversions 11
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Dominant Allele Quiet! Ill speak for both of us! Damaged Allele
Normal Allele Recessive Allele Ill have to be in charge now!
Alleles 12
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12345678 910111213141516 171819202122X Y Human Chromosomes
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Mismatch Insertion Deletion Gene Mutations 14
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General Principles Hereditary disorders can affect multiple
organs Penetrance can be influenced by modifiers: genes +
environment Complexity of mutational spectrum varies 15
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Pancreas CellBone CellBrain Cell Different Genes, Different
Functions 16
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Mutation 2 No Symptoms Mucus Production Gene Normal No Symptoms
Mild Symptoms Severe Symptoms Mutation 1Mutation 3 Gene Changes in
Cystic Fibrosis Gene inheritance is complex 17
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Continuum of Diagnostic Lab Testing 18
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Common genetic disorders Inherited (predictive or diagnostic)
Cystic fibrosis Thrombophilia Hereditary hemochromatosis Fragile X
syndrome Acquired (predictive or diagnostic) Chronic myelogenous
leukemia (CML) Pharmacogenetics (personalized) Cytochrome P450s HLA
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New Assay/Biomarker Progression 20 C LINICAL R ESEARCH T EST T
RANSLATION C LINICAL V ALIDITY C LINICAL U TILITY Biomarker
associated with disease Lab test developed - Analytical validation
Test can predict clinical outcomes Benefits patients Retrospective
clinical trials Prospective clinical trials
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21 Presented by Sherri J Bale, Ph.D., FACMG Victoria Pratt,
Ph.D., FACMG T HE U SE AND V ALUE OF G ENETIC T ESTS FOR P
ATIENTS
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Genetic Tests for Constitutional Mutations Cytogenetic Tests
Molecular Tests 22
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Cytogenetic Test Standard karyotype, used to look for gross
chromosomal anomalies in children with development delays,
congenital anomalies, mental retardation FISH, used to look at 1 or
2 specific chromosomal regions suspected by the physician BAC
arrays, used to look at many (100s) chromosomal regions at once,
using FISH technology CGH array, used to look at MANY (50K-200K)
regions at once, and identify specifically which genes are involved
in the chromosomal anomaly 23
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Child with Multiple Congenital Anomalies and/or Autism 24
Standard karyotypeCGH array - molecular karyotype
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Patient with Tetralogy of Fallot, Suspected 22q11 Deletion 25
FISH test, 2 probes: used in baby found deletion confirmed dx
Provided prognostic info to family. Parents tested by FISH:
Negative Provided information re: risk in future children
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Child with Multiple Anomalies and Autism; No Specific Syndrome
Suspected Karyotype normal CGH array followed Karyotype. Identified
deletion involving end of one arm of chromosome 3 Parents tested by
FISH and dad found to be balanced carrier of the deletion Prenatal
diagnosis by quantitative PCR is now possible for the family.
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Molecular Test PCR, followed by sequencing, for identification
of mutation Used to identify mutation in a patient with inherited
disease Number of times PCR is done and how much sequencing is
required depends on SIZE of gene, MANY UNITS. Once mutation is
identified, testing of parents, sibs, other relatives for ONLY that
mutation, is needed. ONE or ONLY a FEW UNITS. 27
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Molecular diagnosis of Gorlin Syndrome 13 yo child presented to
dentist with a jaw cyst surgery performed but tooth was lost.
Referred to geneticist. Geneticist suspected Gorlin Syndrome
Molecular diagnosis involved PCR and sequencing, 26 units (large
gene). Mutation identified. Prognosis now known: This individual
would develop many skin cancers, more jaw cysts. Regular
surveillance by dermatologist and dentist allowed early
identification, less expensive treatment, and good clinical
outcome: Teeth were saved; Minimal damage to nose, ears, eyes
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Use and Value of Genetic Tests Diagnosis Enables physicians to
properly care for patient Prognosis Appropriate surveillance
leading to early care and intervention Risk Information Is it
inherited? What is the recurrence risk in future pregnancies?
Prenatal/Pre-symptomatic diagnosis Allows informed decision making,
preventive care 29
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Personalized Medicine, Pharmacogenetics 30
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Chronic Myelogenous Leukemia 31 SciencePatient Care Fusion of
BCR/ABL genes FISH, Quantitative PCR to identify Treatable with
Gleevac Better response rates, less toxicity Complete remission in
many patients 5-year survival rate: 69% in 2001, 89% now Some
patients become resistant to Gleevac Mutations in tyrosine kinase
domains (DNA sequencing)
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Clopidogrel (Plavix) 32 SciencePatient Care To inhibit blood
clots in coronary artery disease, peripheral artery disease, and
cerebrovascular disease. Metabolized by cytochrome P450 2C19 to
active form FDA: clopidogrel cannot be taken with Prilosec
(omeprazole) and Nexium (esomeprazole) Inhibitors of 2C19
Prevention of vascular ischemic events in patients with symptomatic
artherosclerosis Also used, along with aspirin, for preventing
thrombosis after placement of intracoronary stent
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33 Presented by Victoria Pratt, Ph.D., FACMG E MERGING T
ECHNOLOGIES AND T ESTING
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The genome is complex High throughput DNA sequencing microRNAs
Copy Number Variants (CNVs) Epigenetics methylation Proteomics Up
and down regulation Disease-specific patterns 34
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New high throughput DNA (NextGen) sequencing methods Reduced
the cost Increased sequencing capacity 454 (Roche) Solexa
(Illumina) SOLiD (ABI) 35
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MicroRNAs (miRNA) Single-stranded RNA molecules 21-23 nt
Transcribed from non-coding DNA Regulate gene expression Cancer May
enable classification of cancers (CUP = cancer of unknown primary)
Determine therapy 36
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Copy Number Variants (CNVs) (Variome) Large deletions or
duplications of DNA Usually cannot be detected by DNA sequencing
Newer technologies aCGH Impacts Autism Alzheimer disease Parkinson
disease susceptibility to HIV-1 some forms of color blindness
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Epigenetics Changes in chromatin structure (how DNA is
packaged) or alters gene activity without changing the DNA DNA
methylation Modification of histones Position effects Cancer and
imprinting disorders 38
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Chances of Developing Breast Cancer by Age 65 Normal BRCA1
Altered BRCA1 0 1 2 3 4 5 6 7 8 Genetic tests find mutations, not
disease 39 With BRCA 1 Gene Without BRCA 1 Gene
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40 Presented by Kaye Jones, MLS(ASCP), CPC L ABORATORY P
ROCEDURES AND C ODING
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Objective To improve your understanding of current molecular
diagnostic CPT coding 41
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Molecular Codes CPT codes 83890-83914 represent steps performed
during molecular diagnostic procedures CPT codes are assigned based
on the different steps and the number of times each type of step is
performed. Example: 83898 Amplification x3 83896 Nucleic acid
probe, each x25 42
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Molecular Codes Different molecular methods may be used for the
same analyte Those methods may vary among different laboratories.
Therefore, different labs may code their tests differently 43
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Molecular Codes No clear written guidelines for how to assign
units of service Example: When a Cystic Fibrosis procedure for 23
mutations is performed by two different labs One lab bills for 23
probes (1 per mutation). The other lab bills for 46 probes (2 per
mutation because you need a normal and a mutant probe for each in
order to interpret the assay). 44
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Molecular Codes All industry stakeholders recognize the issues
surrounding the assignment and billing of molecular diagnostic
procedures A number of organizations and entities are engaged in a
collaborative process to review and address coding issues in an
effort to increase transparency 45
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Cytogenetics This is another area where CPT codes are assigned
based on the procedural steps performed. Routine chromosome
analysis typically requires three steps to complete the procedure.
88230 Tissue culture 88262 Karyotyping 88291 Interpretation and
report with a picture of the actual chromosomes 46
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Cytogenetics Cytogenetic FISH is often necessary to diagnose
constitutional defects Cytogenetic FISH may also be a stand alone
order necessary to evaluate leukemias such as CML and MM Units of
service are determined by the number of FISH probes and specific
procedures needed to evaluate the cells 47
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Molecular Diagnostics and Cytogenetics Think of newer CGH
procedure as a combination of molecular diagnostic procedural steps
needed to prepare the patients sample, and the cytogenetic CGH chip
analysis There is much confusion within the industry regarding how
to assign CPT codes to CGH procedures 48
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Molecular Diagnostics and Cytogenetics Array CPTs 88384-88386
are in the Surgical Pathology section of CPT. These codes are
global codes with Technical and Professional components, only
represent the work needed for the array chip and I&R sample
preparation is coded with molecular diagnostic codes only
appropriate for when a physician/pathologist performs the I&R
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Molecular and Cytogenetic Codes In summary: Molecular
procedures are coded based on the procedural steps Units of service
are determined by the number of times each step is performed
Different procedures may exist for the same analyte, which makes
the CPT coding different Lack of standardized coding guidelines add
to the complexities of how to assign CPTs 50
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Thank you For more information, contact: David Mongillo, Vice
President for Policy and Medical Affairs American Clinical
Laboratory Association [email protected] 202-637-9466
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