Designing Case-control Studies: Decisions About The Controls

The authors quantified, first, the effect of misclassified controls (i.e., individuals who are affected with the disease under study but who are classified as controls) on the ability of a case-control study to detect an association between a disease and a genetic marker, and second, the effect of leaving misclassified controls in the study, as opposed to removing them (thus decreasing sample size). The authors developed an informativeness measure of a study's ability to identify real differences between cases and controls. They then examined this measure's behavior when there are no misclassified controls, when there are misclassified controls, and when there were misclassified controls but they have been removed from the study. The results show that if, for example, 10% of controls are misclassified, the study's informativeness is reduced to approximately 81% of what it would have been in a sample with no misclassified controls, whereas if these misclassified controls are removed from the study, the informativeness is only reduced to about 90%, despite the reduced sample size. If 25% are misclassified, those figures become approximately 56% and 75%, respectively. Thus, leaving the misclassified controls in the control sample is worse than removing them altogether. Finally, the authors illustrate how insufficient power is not necessarily circumvented by having an unlimited number of controls. The formulas provided by the authors enable investigators to make rational decisions about removing misclassified controls or leaving them in

Models of Consent to Return of Incidental Findings in Genomic Research

Genomic research has the capacity to generate a wide array of findings that go beyond the goals of the study—usually referred to as “incidental findings.” The evolving consensus of researchers, participants, and expert panels is that at least some incidental results should be made available to participants. However, there are a number of challenges to discussing these issues with participants and ascertaining their preferences, including the complexity and magnitude of the relevant information. Believing that usual models of informed consent are not likely to be effective in this context, we identify four approaches that investigators and IRBs might consider: traditional consent, staged consent, mandatory return, and outsourcing. Each has advantages and disadvantages compared with the other options, and which one is selected for a given project will depend on a mix of practical and normative considerations that are described in this paper

Informed consent for return of incidental findings in genomic research

Purpose: Researchers face the dilemma of how to obtain consent for return of incidental findings from genomic research. We surveyed and interviewed investigators and study participants, with the goal of providing suggestions for how to shape the consent process. Methods: We performed an online survey of 254 US genetic researchers identified through the NIH RePORTER database, abstracts from the 2011 American Society of Human Genetics meeting, and qualitative semi-structured interviews with 28 genomic researchers and 20 research participants. Results: Most researchers and participants endorsed disclosure of a wide range of information about return of incidental findings, including risks, benefits, impact on family members, data security, and procedures, for return of results in the event of death or incapacity and for recontact. However, most researchers were willing to devote 30 min or less to this process and expressed concerns that disclosed information would overwhelm participants, a concern shared by many participants themselves. Conclusion: There is a disjunction between the views of investigators and participants about the amount of information that should be disclosed and the practical realities of the research setting, including the time available for consent discussions. This strongly suggests the need for innovative approaches to the informed consent process

Research Participants’ Preferences for Hypothetical Secondary Results from Genomic Research

Secondary or incidental results can be identified in genomic research that increasingly uses whole exome/genome sequencing. Understanding research participants’ preferences for secondary results and what influences these decisions is important for patient education, counseling, and consent, and for the development of policies regarding return of secondary results. Two hundred nineteen research participants enrolled in genomic studies were surveyed regarding hypothetical preferences for specific types of secondary results, and these preferences were correlated with demographic information and psychosocial data. The majority of research participants (73%) indicated a preference to learn about all results offered, with no clear pattern regarding which results were not desired by the remaining participants. Participants who reported greater interest in genetic privacy were less likely to indicate a preference to learn all results, as were individuals who self‐identified as Jewish. Although most research participants preferred to receive all secondary results offered, a significant subset preferred to exclude some results, suggesting that an all‐or‐none policy would not be ideal for all participants. The correlations between preferences to receive secondary results, religious identification, and privacy concerns demonstrate the need for culturally sensitive counseling and educational materials accessible to all education levels to allow participants to make the best choices for themselves

Researchers’ views on return of incidental genomic research results: qualitative and quantitative findings

Purpose: Comprehensive genomic analysis including exome and genome sequencing is increasingly being utilized in research studies, leading to the generation of incidental genetic findings. It is unclear how researchers plan to deal with incidental genetic findings. Methods: We conducted a survey of the practices and attitudes of 234 members of the US genetic research community and performed qualitative semistructured interviews with 28 genomic researchers to understand their views and experiences with incidental genetic research findings. Results: We found that 12% of the researchers had returned incidental genetic findings, and an additional 28% planned to do so. A large majority of researchers (95%) believe that incidental findings for highly penetrant disorders with immediate medical implications should be offered to research participants. However, there was no consensus on returning incidental results for other conditions varying in penetrance and medical actionability. Researchers raised concerns that the return of incidental findings would impose significant burdens on research and could potentially have deleterious effects on research participants if not performed well. Researchers identified assistance needed to enable effective, accurate return of incidental findings. Conclusion: The majority of the researchers believe that research participants should have the option to receive at least some incidental genetic research results

Processes and factors involved in decisions regarding return of incidental genomic findings in research

Purpose: Studies have begun exploring whether researchers should return incidental findings in genomic studies, and if so, which findings should be returned; however, how researchers make these decisions—the processes and factors involved—has remained largely unexplored. Methods: We interviewed 28 genomics researchers in-depth about their experiences and views concerning the return of incidental findings. Results: Researchers often struggle with questions concerning which incidental findings to return and how to make those decisions. Multiple factors shape their views, including information about the gene variant (e.g., pathogenicity and disease characteristics), concerns about participants’ well-being and researcher responsibility, and input from external entities. Researchers weigh the evidence, yet they face conflicting pressures, with relevant data frequently being unavailable. Researchers vary in who they believe should decide: participants, principal investigators, institutional review boards, and/or professional organizations. Contextual factors can influence these decisions, including policies governing return of results by institutions and biobanks and the study design. Researchers vary in desires for: guidance from institutions and professional organizations, changes to current institutional processes, and community-wide genetics education. Conclusion: These data, the first to examine the processes by which researchers make decisions regarding the return of genetic incidental findings, highlight several complexities involved and have important implications for future genetics research, policy, and examinations of these issues

Association of Researcher Characteristics with Views on Return of Incidental Findings from Genomic Research

Whole exome/ genome sequencing (WES/WGS) is now commonly used in research and is increasingly used in clinical care to identify the genetic basis of rare and unknown diseases. The management of incidental findings (IFs) generated through these analyses is debated within the research community. To examine how views regarding genomic research IFs are associated with researcher characteristics and experiences, we surveyed genetic professionals and assessed the effect of professional background and experience on their opinions. Researchers who did not have clinical training, provide clinical care to research participants, or have prior experience returning research results were in general more inclined to offer return of IFs than their colleagues with these characteristics. Understanding this will be important to fully appreciate the impact that policies on return of genetic IFs could have on participants, researchers, and genomic research

Genome-Wide Association Study in Obsessive-Compulsive Disorder: Results from the OCGAS

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients, with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1 065 families (containing 1 406 patients with OCD), combined with population-based samples (resulting in a total sample of 5 061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at SNP- and gene-levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13×10−7). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of GWAS signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2, and PTPRD. Analyses at the gene-level revealed association of IQCK and C16orf88 (both P<1×10−6, experiment-wide significant), as well as OFCC1 (P=6.29×10−5). The suggestive findings in this study await replication in larger samples