Genetic Testing or Analysis

IRB Member Fact Sheet--Version Date: 11/30/2008

Human Subjects Protocols involving Genetic Testing or Analysis
The following guidelines have been adopted to facilitate review of research involving genetic testing or collection of information that has genetic implications (e.g., pedigree publication, construction of family histories) and intended to assist both IRBs and research teams. The chapter on Human Genetic Research in the IRB Guidebook produced by the Office for Human Research Protections and the National Bioethics Advisory Commission’s report,  Research involving human biological materials: ethical issues and policy guidance,  Vol. 1, served as the primary bases for these guidelines and is an additional source of guidance.

Genetic research involves the analysis of any of the following: DNA, RNA, chromosomes, proteins, or certain metabolites which might act as or identify markers associated with a known or suspected predisposition to disease or behavior.  Usually genetic research involves the collection of human biological material such as blood, skin or other tissues, nail clippings or hair.  Genetic research also may include the construction of pedigrees (maps of the distribution of a particular trait or condition among related individuals) or family medical histories.   Although gene transfer, sometimes known as gene therapy, is another form of genetic research, these studies are not covered in this document.  Please see the Gene Transfer Guidance.

Information Researchers are Required to Provide the IRB for Review
Regardless of whether the research involves a genetic component, UW-Madison IRBs are required to assess whether research studies meet the criteria for IRB approval outlined under the Common Rule and, if applicable, FDA regulations. 

In order for research studies to be approved, the IRB must ensure that the research study meets the criteria specified under the federal regulations for IRB approval (45 CFR 46.111).  These criteria are outlined below and followed by a description of how IRBs and research teams can ensure these are met for genetic research.

  • Risks to subjects are minimized
    • The primary risks to subjects participating in genetic research are psychosocial.  The application should identify these risks and explain how they will be minimized, especially in terms of the privacy and confidentiality protections in place.  It is critical for research teams to identify the nature of the risks to subjects that are known at this point.  A discussion of the risks of genetic research is below.
    • Risks to subjects can be reduced significantly by:
      • De-identifying samples before tests are conducted or the results as soon as possible after the testing is complete
      • Not disclosing results to subjects or their representatives
      • Limiting the number of individuals who have access to identifiable results
      • Not placing the results or consent documents in the participants’ medical record
      • If samples are identifiable, obtaining a Certificate of Confidentiality (see below)
      • Avoiding storage of samples for unspecified future testing
  • Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result
    • Generally genetic analyses in the research context should be considered to present more than minimal risk to subjects.  Thus, research teams must provide a clear rationale to the IRB for the scientific and social benefit of the analyses to be performed and outline adequate protections against the psychosocial risks presented by the research.
  • Selection of subjects is equitable
    • Research teams should explain their choice of subject population.  When vulnerable populations will be enrolled, why it is critical to conduct genetic research on these individuals.
  • Informed consent will be sought from each prospective subject or the subject's legally authorized representative (unless the research qualifies for a waiver of informed consent or documentation of informed consent)
    • The informed consent document and process should include specific descriptions of the genetic component of the study and the risks of the genetic analyses.  See Appendix 1 for specific consent form language recommendations.  With some exceptions, informed consent or documentation of informed consent cannot be waived for research involving genetic testing.
  • There are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data
    • As noted above, privacy and confidentiality protections are key to help minimize risks to subjects.  It is critical for research teams to clarify who has access to identifiable subject data and whether the results of the analyses will be released to participants or others (e.g., physicians, parents).
    • It is important for research teams and IRBs to be aware that genetic analyses not only have implications of the relatives of the individuals undergoing testing but for a group they may be identified with, such as a racial/ethnic group.
    • Generally, a Certificate of Confidentiality should be obtained to provide adequate protection of subjects, especially when socially sensitive conditions or traits are studied or the tests could have adverse consequences for subjects’ financial standing, insurability, or employability should the results be disclosed outside the research team.  Certificates of Confidentiality are issued by the National Institutes of Health (NIH) and other federal agencies to protect identifiable research information from forced disclosure. They allow the investigator and others who have access to research records to refuse to disclose identifying information on research participants in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level.
    • In addition, de-identifying samples and data before genetic testing or soon after genetic testing is performed can help protect confidentiality and minimize risks to subjects.  It is noteworthy that the question as to whether genetic material can truly be de-identified is currently under national debate.
  • IRBs also must ensure additional safeguards are in place when some or all of the subjects are likely to be vulnerable to coercion or undue influence (e.g., children, prisoners, mentally disabled persons, or economically or educationally disadvantaged persons).
    • As for any research, the least vulnerable population is expected to bear its burdens.  If a research team wishes to include a vulnerable population in a genetic research study specific justification is generally needed.  Frequently research teams propose to involve children in genetic studies.  Inclusion of children raises issues about the federal regulations under which the research can be approved, the assent process, disclosure of results, and the potential for re-consenting should the child achieve adult status during the conduct of the study.   Please see the following article that succinctly and cogently outlines issues related to the enrollment of children in genetic research – Burke & Diekma (2006).  Ethical Issues Arising from the Participation of Children in Genetic Research. Journal of Pediatrics, pp. S34-38.
Identification and Assessment of Genetic Research Risks
The risks to research participants from genetic research generally are not the risks from the procedures used to extract the biological sample or the genetic information from the biological sample.  Instead, the risks relate to the potential social, psychological, and economic impact if information from genetic testing or the creation of a pedigree is shared with the research subjects or others. 

Genetic research poses special challenges for IRBs because it is often difficult to assess the nature and degree of risks posed by it and how to minimize these risks, especially as techniques improve to allow easy analysis of a wide range of genes and our knowledge of the function of genes increases. This has been complicated by the requirement that genotyping information derived any NIH-funded genome-wide association studies must be submitted to a federal database (dbGAP) so that it can be shared with other researchers. It is unclear whether these data will be available to law enforcement agencies or others unrelated to research interests. Thus, assurances cannot be confidently made about the identfiability of genetic information submitted to dbGaP. .  Consent processes and documents should be clear about these risks, and should state that all the risks of genetic research are not known at this time.

Identification of Risks
When research teams are preparing applications to the IRB, they should keep in mind what the risks of genetic research are and address proactively in their submissions how these will be minimized.  The risks of genetic research include:
  • Personal stigmatization, discrimination or labeling if it is found that the individual and/or family members have a particular condition or trait
  • Potential loss of or difficulty in obtaining employment or insurance either because of what the test results show with respect to the genetics of the tested individual or the genetics of an identified group with which the individual is associated because of a medical condition, ethnicity or social standing
  • Group stigmatization, discrimination or labeling resulting from genetic inferences associated with certain medical conditions or certain ethnic or social groups
  • Unexpected discovery of mispaternity
If the research team plans on disclosing information to individuals, additional risks include:
  • Emotional trauma, anxiety and confusion to tested individual and/or family members from learning genetic information about self or family.
  • A misunderstanding of the information from a genetic test or pedigree adversely affecting reproductive or other important life decisions.
  • Changes in familial relationships as result of genetic research.
Determining Level of Risk
Generally research studies involving genetic testing or the construction of pedigrees cannot be classified as minimal risk studies.  Consequently, initial review of such research cannot be reviewed under expedited procedures. 

It can be especially challenging for IRBs to determine what category genetic research can be approved under when it involves children.  The federal regulations outline 4 categories under which research involving children can be approved.  One category, research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children, can only be approved by the Secretary of the Department of Health and Human Services.  Otherwise, the research must be able to meet one of the following categories:
  1. Research not involving greater than minimal risk
  2. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects
  3. Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition
    • NOTE: Under this category, the risk must represent a minor increase over minimal risk; the intervention or procedure must present experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; and the intervention or procedure must be likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition.
When a protocol involves genetic testing, the IRB will consider the following factors in determining the level of risk presented by the research:
  • Identifiability of the samples – maintenance of identifiable samples tends to pose greater risk to subjects. “Coded” is not synonymous with “unidentifiable,” since the individual with the key to the code can connect the sample or data with a research participant. Even samples without codes may be identifiable if they can be linked with another identifiable sample.
  • Release of test results – if individual or family members will be told of test results the research tends to present more than minimal risk to subjects.
  • Storage of samples - samples that are identifiable and stored for unspecified use present the most problematic situation because it is difficult for the IRB, let alone the participant, to know all of the risks encumbered by the future uses and the risks associated with them.  Subjects should be informed when results will be submitted to the federal genetic database (dbGAP) now required for NIH-funded genome-wide association studies. 
  • Inclusion of a vulnerable population - non-therapeutic genetic testing on children, prisoners, or individuals with impaired decision-making capacity would be expected to present more than minimal risk to these individuals.
  • Nature of informed consent - genetic testing on identifiable samples without obtaining informed consent for this purpose may not be approvable by an IRB under the federal regulations outlining the conditions under which informed consent can be waived.
  • Condition/trait under study – if testing is done on the genetic basis of a condition already known to be exhibited by the participant (e.g., lung cancer), the risks to the subject may be lessened.  Pharmacogenetic research, for example, which involves the identification of genes involved in the response to a drug or drugs of interest for a particular patient population tends to present lower risk to subjects because these subjects already have been identified with the particular condition (e.g., cancer) of interest and therefore generally do not face additional risks.
  • Potential for linkage among the genes such that a condition or trait not under study could be discovered - testing of a broad range of genes that is then correlated with detailed medical histories tends to be viewed as presenting more than minimal risk to subjects.  For example, APOE was originally found to be related to cardiovascular disease, but subsequently was discovered to have an association with the development of Alzheimer’s disease. 
Disclosure of the Results of Genetic Analyses
Disclosure of results from tests that have not been validated are unlikely to be approved by the IRB.  Whether the results of genetic analyses should be provided to the individuals undergoing the testing should be considered carefully because of the psychosocial risks of associated with disclosure, including confusion, emotional upset, damage to family relationships, or adverse effects on self image.  When the tests conducted in the research study have been validated and are available outside of the study, the IRB would not require the disclosure of results to subjects or their representatives unless the tests are part of their clinical care.  If results will be shared with subjects or others, the research team should describe the following in the application:
  • How subjects would benefit from the release of the results.  Potential benefits depend on whether the information may lead to an intervention that can help mitigate a condition or disease and if a treatment or course of action is readily available to the individual.
  • How predictive the tests are of the condition, disease, or trait.
  • Whether the testing is available outside of the research context.
  • The safeguards (e.g., genetic counseling) in place to help ensure these results are contextualized properly for the subject and they have resource available to them should distress or anxiety occur.
  • The expertise of the personnel responsible for educating and counseling subjects regarding the risks and benefits of the study.
  • If results are to be disclosed, what the qualifications are of key personnel in interpreting results, responding to questions, and providing counseling for psychosocial complications of disclosure.
  • Who is conducting the tests and where they will be conducted.  Even if the tests themselves have been validated, the qualifications of the researchers conducting these tests and the qualifications of the laboratory performing the tests should be considered as they may affect the validity of the test results.
  • Whether information will be placed in a medical record.
IRBs and research teams should keep in mind that some subjects or their representatives may not wish to receive results and should ensure that the consent form allows participants to indicate their choice regarding disclosure.

Genetic testing may be done to with the intent to confirm a diagnosis.  Researchers and IRBs need to consider the consequences should a diagnosis not be confirmed.  If subjects or their representatives will be informed if their diagnosis is not confirmed, the research team should have procedures in place to handle this finding, such as genetic counseling, and disclose this possibility in the consent form.  If the researcher does not plan to disclose failure to confirm a diagnosis to subjects or their representatives, the researcher will need to describe how this information will be handled and whether it will be apparent to subjects (e.g., if a confirmation of diagnosis is needed to determine subjects’ eligibility for a research study will they wonder if this has occurred if they are ineligible to participate).

Implications for Family Members
Genetic family studies pose special issues because of the relationship between the individuals and the fact that the research has implications beyond the individual undergoing the genetic testing.  IRBs must determine when individuals other than those being tested become research subjects.  As the OHRP IRB Guidebook notes, in making this decision IRB should consider whether the information about others provided by a subject is also available to the investigator through public sources (e.g., family names and addresses) and other personal information that is not available through public sources (e.g., information about medical conditions or adoptions).  IRBs also should make certain measures are in place for family-based research that help ensure individuals are not pressured to recruit other family members for the research or confidential information is not shared amongst family members without explicit consent. 

Pedigree Research
Publication of pedigrees may result in the identification of individuals to family members and others.  Research teams and IRBs must consider what measures should be in place to protect subject confidentiality and what level of informed consent is required prior to publication.  Please see the following article that succinctly and cogently outlines issues related to recruitment for familial research – Beskow LM, Botkin JR, Daly M, Juengst ET, Lehmann LS, et al (2004). Ethical issues in identifying and recruiting participants for familial genetic research. American Journal of Medical Genetics, 130A, pp. 424-31.


William W. Lowrance and Francis S. Collins. Identifiability in Genomic Research.

NIH Factsheet: Genome - Wide Association Studies (GWAS) Policy

NIH Policy and Guidance on Genome-Wide Association Studies (GWAS).

GenomeWide Association Studies (GWAS). NIH Points to Consider
NIH Points to Consider for IRBs and Institutions in their Review of Data Submission Plans for Institutional Certifications under NIH’s Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS)

Keywords:genes, pedigree, family history, DNA, RNA, chromosomes, deidentified, genetics, GWAS   Doc ID:19770
Owner:Monica E.Group:Health Sciences IRBs
Created:2011-08-16 11:29 CSTUpdated:2017-11-27 12:48 CST
Sites:Health Sciences IRBs
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