Sarah K. Savage

Disclosing pathogenic genetic variants to research participants: Quantifying an emerging ethical responsibility

There is an emerging consensus that when investigators obtain genomic data from research participants, they may incur an ethical responsibility to inform at-risk individuals about clinically significant variants discovered during the course of their research. With whole-exome sequencing becoming commonplace and the falling costs of full-genome sequencing, there will be an increasingly large number of variants identified in research participants that may be of sufficient clinical relevance to share. An explicit approach to triaging and communicating these results has yet to be developed, and even the magnitude of the task is uncertain. To develop an estimate of the number of variants that might qualify for disclosure, we apply recently published recommendations for the return of results to a defined and representative set of variants and then extrapolate these estimates to genome scale. We find that the total number of variants meeting the threshold for recommended disclosure ranges from 3955-12,579 (3.79%-12.06%, 95% CI) in the most conservative estimate to 6998-17,189 (6.69%-16.48%, 95% CI) in an estimate including variants with variable disease expressivity. Additionally, if the growth rate from the previous 4 yr continues, we estimate that the total number of disease-associated variants will grow 37% over the next 4 yr.

The beliefs, motivations, and expectations of parents who have enrolled their children in a genetic biorepository

Purpose:Little is known about parental attitudes toward return of individual research results (IRRs) in pediatric genomic research. The aim of this study was to understand the views of the parents who enrolled their children in a genomic repository in which IRRs will be returned.Methods:We conducted focus groups with parents of children with developmental disorders enrolled in the Gene Partnership (GP), a genomic research repository that offers to return IRRs, to learn about their understanding of the GP, motivations for enrolling their children, and expectations regarding the return of IRRs.Results:Parents hoped to receive IRRs that would help them better understand their children’s condition(s). They understood that this outcome was unlikely, but hoped that their children’s participation in the GP would contribute to scientific knowledge. Most parents wanted to receive all IRRs about their child, even for diseases that were severe and untreatable, citing reasons of personal utility. Parents preferred electronic delivery of the results and wanted to designate their preferences regarding what information they would receive.Conclusion:It is important for researchers to understand participant expectations in enrolling in a research repository that offers to disclose children’s IRRs in order to effectively communicate the implications to parents during the consenting process.Genet Med 2012:14(3):330–337

The Development of a Preference-Setting Model for the Return of Individual Genomic Research Results

Understanding participants’ preferences for the return of individual research results (IRR) in genomic research may allow for the implementation of more beneficial result disclosure methods. We tested four preference-setting models through cognitive interviews of parents to explore how parents conceptualize the process of setting preferences and which disease characteristics they believe to be most important when deciding what results to receive on their child. Severity and preventability of a condition were highly influential in decision making and certain groups of research results were anticipated by participants to have negative psychological effects. These findings informed the development of an educational tool and preference-setting model that can be scaled for use in the return of IRR from large biobank studies.

Participant Satisfaction With a Preference-Setting Tool for the Return of Individual Research Results in Pediatric Genomic Research.

The perceived benefit of return of individual research results (IRRs) in accordance to participants’ preferences in genomic biobank research is unclear. We developed an online preference-setting tool for return of IRRs based on the preventability and severity of a condition, which included an opt-out option for IRRs for mental illness, developmental disorders, childhood-onset degenerative conditions, and adult-onset conditions. Parents of patients <18 years of age at Boston Children’s Hospital were randomized to the hypothetical scenario that their child was enrolled in one of four biobanks with different policies for IRRs to receive (a) “None,” (b) “All,” (c) “Binary”—choice to receive all or none, and (d) “Granular”—use the preference-setting tool to choose categories of IRRs. Parents were given a hypothetical IRRs report for their child. The survey was sent to 11,391 parents and completed by 2,718. The Granular group was the most satisfied with the process, biobank, and hypothetical IRRs received. The None group was least satisfied and least likely to agree that the biobank was beneficial (p < .001). The response to the statement that the biobank was harmful was not different between groups. Our data suggest that the ability to designate preferences leads to greater satisfaction and may increase biobank participation.

Preferences for the return of individual results from research on pediatric biobank samples

Discussions about disclosing individual genetic research results include calls to consider participants’ preferences. In this study, parents of Boston Children’s Hospital patients set preferences for disclosure based on disease preventability and severity, and could exclude mental health, developmental, childhood degenerative, and adult-onset disorders. Participants reviewed hypothetical reports and reset preferences, if desired. Among 661 participants who initially wanted all results (64%), 1% reset preferences. Among 336 participants who initially excluded at least one category (36%), 38% reset preferences. Participants who reset preferences added 0.9 categories, on average; and their mean satisfaction on 0 to 10 scales increased from 4.7 to 7.2 (p < .001). Only 2% reduced the number of categories they wanted disclosed. Findings demonstrate the benefits of providing examples of preference options and the tendency of participants to want results disclosed. Findings also suggest that preference-setting models that do not provide specific examples of results could underestimate participants’ desires for information.

Integration of a standardized pharmacogenomic platform for clinical decision support at Boston Children's Hospital

The Clinical Pharmacogenomics Service (CPS) at Boston Childrens Hospital (BCH) was established to use genomic information to make pediatric medications safer. Nearly one-quarter of outpatients are prescribed one or more drugs with genetic information in the FDA label [1]. However, there are still important barriers that must be overcome for routine pharmacogenomic (PGx) clinical use: (1) identification of clinically significant variants, (2) knowledge of variant genotype prior to prescribing medication, and (3) integration with current electronic health record (EHR) systems. To tackle these challenges at BCH, the CPS decided to standardize thiopurine S-methyltransferase (TPMT) testing hospital-wide. TPMT is best known for its role in the catalyzing the S-methylation of the thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. Approximately 13% of Caucasians and African Americans are heterozygous and have reduced TPMT activity, while approximately 0.3% are completely deficient. Defects in the TPMT gene can lead to decreased methylation and excessive levels of the toxic thioguanine nucleotides, particularly with azathioprine and 6-mercaptopurine, and are at risk for bone marrow suppression. Although the FDA drug label recommends testing for TPMT deficiency prior to dosing and the PharmGKB CPIC group published a guideline [2] with a recommended dosing strategy and interpretation, testing is not universal because these guidelines are difficult to translate into a clinical decision support (CDS) system and integrate with the EHRs. We developed models and specifications to execute PGx CDS rules based on a patients genotype. Rules are modeled at four levels of abstraction: (1) unstructured (narrative), (2) semi-structured, (3) structured, and (4) executable. As genomic sequencing becomes routine, standardized methods to interpret the data and make clinical decisions are paramount. In conjunction with the BCH DNA Diagnostic Laboratory, we streamlined the TPMT testing process to fit into the usual clinical routine (including ordering, testing in-house and return of results to the clinician). We consolidated all genetic sequencing testing into a single clinical workflow (blood to report) that is run, analyzed and interpreted in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory using the codified CDS rules. The interpretation reports are generated automatically directly from the genotype calls and then manually reviewed for accuracy. Once cleared by the laboratory director, the reports are uploaded into the EHR (Cerner). Specialty flow sheets enable providers to easily view the allele status and interpretation report. We intend to expand the PGx platform to include additional drug/gene pairs.

Enhancing Autonomy in Biobank Decisions: Too Much of a Good Thing?:

The opportunity to receive individual research results (IRRs) in accordance with personal preferences may incentivize biobank participation and maximize perceived benefit. This trial investigated the relationship between parents’ preferences and intent to participate (ITP) in biobank research utilizing their child’s genetic information. We randomized parents of pediatric patients to four hypothetical biobanks, one of which employed a preference-setting model for return of results regarding their child. ITP was highest among those desiring all types of IRRs (93.3%) and decreased as participants became increasingly selective with their preferences (p < .0001). We demonstrated that most parents would participate in a biobank that allows for preference setting; however, those who set preferences to receive a narrower set of IRRs are less likely to participate.

Family Health History Reporting is Sensitive to Small Changes in Wording

Purpose:Family health history is often collected through single-item queries that ask patients whether their family members are affected by certain conditions. The specific wording of these queries may influence what individuals report.Methods:Parents of Boston Children’s Hospital patients were invited to participate in a Web-based survey about the return of individual genomic research results regarding their children. Participants reported whether 11 types of medical conditions affected them or their family. Randomization determined whether participants were specifically instructed to consider their extended family.Results:Family health history was reported by 2,901 participants. Those asked to consider their extended family were more likely to report a positive family history for 8 of 11 medical conditions. The largest differences were observed for cancer (65.1 vs. 45.7%; P < 0.001), cardiovascular conditions (72.5 vs. 56.0%; P < 0.001), and endocrine/hormonal conditions (50.9 vs. 36.7%; P < 0.001).Conclusions:Small alterations to the way family health history queries are worded can substantially change patient responses. Clinicians and researchers need to be sensitive about patients’ tendencies to omit extended family from health history reporting unless specifically asked to consider them.Genet Med 18 12, 1308–1311.