Transcript Slide 1

Whole Genome Sequencing
and Incidental Findings in
Clinical Laboratory Settings
Mark E. Sobel, MD, PhD
Executive Officer, Intersociety Council for Pathology Information
Executive Officer, American Society for Investigative Pathology
Executive Officer Emeritus, Association for Molecular Pathology
[email protected]
Eighth Meeting of the CEER Investigators, NHGRI
October 16, 2012
Definitions and Acronyms
• Whole Genome Sequencing (WGS)
• Whole Genome Analysis (WGA)
• Next-generation Sequencing (NGS)
• Whole Exome Sequencing (WES)
Incidental Findings
An incidental finding is a finding concerning an individual
in the course of conducting research that has potential
health or reproductive importance and is discovered in
the course of conducting research, but is beyond the aims
of the study and is not anticipated in the research
protocol.
Susan M. Wolf, et al. (2012). Genetics in Medicine, 12: 361-384.
What about incidental findings that occur in the
course of clinical testing? Especially WGS!
CLIA ‘88
Clinical Laboratory Improvement Amendment
The following analytical characteristics must be documented:
•Accuracy
•Precision
•Analytical sensitivity
•Analytical specificity
•Reportable range
•Reference intervals (normal values)
•Any other performance characteristic required for test
performance
Test Validity
 Is the test accurate?
 False positives?
 False negatives?
Clinical Validity – does it test for the stated disease
or syndrome?
Clinical Utility
• Is there a treatment?
• Does it help select treatment
• Are there preventive measures that can be taken?
CLIA ‘88
Upon a patient’s request, the laboratory may
provide access to completed test reports that,
using the laboratory’s authentication process,
can be identified as belonging to the patient.
Proposed Rule
42 CFR Part 493
September 14, 2011
Centers for Medicare & Medicaid Services
(CMS)
According to the HIT Policy Committee, CLIA regulations are
perceived by some stakeholders as imposing barriers to the
exchange of health information.
While individuals can obtain test results through the ordering
provider, the advent of certain health reform concepts (e.g.,
individualized medicine and an individual’s active involvement
in his or her own health care) may be best served by revisiting
the CLIA limitations on the disclosure of laboratory test results.
Proposed Rule
42 CFR Part 493
Retain the existing provisions that provide for release of test
reports to authorized persons….
Amend the Health Insurance Portability and Accountability Act
of 1996 (HIPAA) Privacy Rule to provide individuals the right to
receive their test reports directly from laboratories by
removing the exceptions for CLIA-certified laboratories and
CLIA-exempt laboratories.
Clinical Diagnostic Genome Sequencing
The introduction of high-throughput,
next-generation sequencing (NGS) in 2005
heralded a critical and transformative step
in the history of DNA sequencing.
This report of the Whole Genome Analysis group of the Association for Molecular Pathology
illuminates the opportunities and challenges associated with clinical diagnostic genome
sequencing. With the reality of clinical application of next-generation sequencing, technical aspects
of molecular testing can be accomplished at greater speed and with higher volume, while much
information is obtained. Although this testing is a next logical step for molecular pathology
laboratories, the potential impact on the diagnostic process and clinical correlations is
extraordinary and clinical interpretation will be challenging. We review the rapidly evolving
technologies; provide application examples; discuss aspects of clinical utility, ethics, and consent;
and address the analytic, postanalytic, and professional implications. (J Mol Diagn 2012,
14:525540; http://dx.doi.org/10.1016/j.jmoldx.2012.04.006)
NGS Platforms
Although the NGS platforms differ in design
and specific chemistries, they are
fundamentally related by a paradigm in which
sequencing of spatially separated, clonally
amplified DNA templates or single DNA
molecules is performed in a massively parallel
manner.
NGS Technology
All NGS technologies offer the ability to
simultaneously sequence thousands to
millions of relatively short nucleic acid
sequences in parallel. They can provide
orders of magnitude more information, at
competitive costs, when large regions of
the genome are sequenced.
Advantages of NGS Technology
Individual sequencing assays based on
capillary electrophoresis tend to be:
•Expensive
•Laborious
•Less comprehensive, necessitating serial geneby-gene testing to identify causative
mutation(s)
Informed Consent and Ethical Considerations
The capacity to perform large-scale sequencing on the human
genome presents unique challenges regarding the provision of
informed consent, particularly in deciding on the level of detail that
needs to be shared.
No specific guidance exists, and each institution offering such
testing is deriving its own policies.
With genome testing by NGS, the perceived and real potential risks
are magnified compared with genetic tests that target only one
gene at a time.
Bioinformatics Requirements
Major computations performed with NGS data:
•Data assembly with base calling at the level of
individual reads
•Alignment of the assembled sequence to a
reference sequence
•Variant calling
Variant Calling
•Different computational analyses devoted to
SNPs, small indels, structural variants or large
indels, copy number variants
•Generation of an unprecedented amount of
medical data that result in special informatics
needs and require tools for data management,
storage, analysis, and archiving
•Manage the large data set without error and
to ensure proper quality and documentation.
Electronic Health Record
Reporting of NGS test results raises several
issues:
•Ordering of the test
•Receiving a document that summarizes the
clinical interpretation
•Storage of the interpretation
Presidential Commission
for the Study of Bioethical Issues
Washington, DC
October 2012
http://www.bioethics.gov
Basic Ethical Principles
Ideal of respect for persons
•Public beneficence
•Responsible stewardship
•Intellectual freedom and responsibility
•Democratic deliberation
•Justice and fairness
Recommendations
Recommendation 1.1
Funders of WGS research, managers of research,
clinical, and commercial databases, and policy makers
should maintain or establish clear policies defining
acceptable access to and permissible uses of WGS
data. These policies should promote opportunities for
models of data sharing by individuals who want to
share their WGS data with clinicians, researchers, or
others.
Recommendations
Recommendation 1.2
Federal and state governments should ensure a
consistent floor of privacy protections covering WGS
data regardless of how they were obtained. These
policies should protect individual privacy by
prohibiting unauthorized WGS without the consent of
the individual from whom the sample came.
Recommendations
Recommendation 2.1
Funders of WGS research, managers of research,
clinical, and commercial databases, and policy makers
should ensure the security of WGS data.
Recommendation 2.2
Funders of WGS research, managers of research,
clinical, and commercial databases, and policy makers
must outline to donors or suppliers of specimens
acceptable access to and permissible use of
identifiable WGS data.
Recommendations
Recommendation 2.3
Relevant federal agencies should continue to invest in
initiatives to ensure that third-party entrustment of
WGS data, particularly when these data are
interpreted to generate health-related information,
complies with relevant regulatory schemes such as
HIPAA and other data privacy and security
requirements. Best practices for keeping data secure
should be shared across the industry to create a solid
foundation of knowledge upon which to maximize
public trust.
Recommendations
Recommendation 3.1
Researchers and clinicians should evaluate and adopt
robust and workable consent processes that allow
research participants, patients, and others to
understand who has access to their WGS and other
data generated…., and to know how these data might
be used in the future. Consent processes should
ascertain participant or patient preferences at the
time the samples are obtained.
Recommendations
Recommendation 3.2
The federal OHRP or a designated central organizing federal
agency should establish clear and consistent guidelines for
informed consent forms for research conducted by those under
the purview of the Common Rule that involves WGS. Informed
consent forms should:
•Briefly describe WGS and WGA
•State how the data will be used in the present study, and state, to the
extent feasible, how the data might be used in the future
•Explain the extent to which the individual will have control over future data
use
•Define benefits, potential risks, and state that their might be unknown
future risks
•State what data and information might be returned to the individual
Recommendations
Recommendation 3.3
Researchers, clinicians, and commercial WGS entities
must make individuals aware that incidental findings
are likely to be discovered in the course of WGS. The
consent process should convey whether these findings
will be communicated, the scope of communicated
findings, and to whom the findings will be
communicated.
Recommendations
Recommendation 3.4
Funders of WGS research should support studies to
evaluate proposed frameworks for offering return of
incidental findings and other research results derived
from WGS. Funders should also investigate the related
preferences and expectations of the individuals
contributing samples and data to genomic research
and undergoing WGS in clinical care, research, or
commercial contexts.
Recommendations
Recommendation 4.1
Funders of WGS research, relevant clinical entities,
and the commercial sector should facilitate explicit
exchange of information between genomic
researchers and clinicians, while maintaining robust
data protection safeguards, so that WGS and health
data can be shared to advance genomic medicine.
Recommendations
Recommendation 4.2
Policy makers should promote opportunities for the
public to benefit from WGS research. Further, policy
makers and the research community should promote
opportunities for the exploration of alternative
models of the relationship between researchers and
research participants, including participatory models
that promote collaborative relationships.
Recommendations
Recommendation 5
The federal government should facilitate access to the
numerous scientific advances generated through its
investments in WGS to the broadest group of persons
possible to ensure that all persons who could benefit
from these developments have the opportunity to do
so.