Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization.

Over 100 million research participants around the world have had research array-based genotyping (GT) or genome sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to confirm and return pathogenic and likely pathogenic variants (PLPVs) in 59 genes. Variant verification prior to participant recontact revealed that GT falsely identified PLPVs in 44.9% of samples, and GT failed to identify 72.0% of PLPVs detected in a subset of samples that were also sequenced. GT and GS detected verified PLPVs in 1% and 2.5% of the cohort, respectively. Of 256 participants who were alerted that they carried actionable PLPVs, 37.5% actively or passively declined further disclosure. 76.3% of those carrying PLPVs were unaware that they were carrying the variant, and over half of those met published professional criteria for genetic testing but had never been tested. This gRoR protocol cost approximately $129,000 USD per year in laboratory testing and research staff support, representing $14 per participant whose DNA was analyzed or $3,224 per participant in whom a PLPV was confirmed and disclosed. These data provide logistical details around gRoR that could help other investigators planning to return genomic results.

Patient and public preferences for being recontacted with updated genomic results: a mixed methods study.

Variants of uncertain significance (VUS) are frequently reclassified but recontacting patients with updated results poses significant resource challenges. We aimed to characterize public and patient preferences for being recontacted with updated results. A discrete choice experiment (DCE) was administered to representative samples of the Canadian public and cancer patients. DCE attributes were uncertainty, cost, recontact modality, choice of results, and actionability. DCE data were analyzed using a mixed logit model and by calculating willingness to pay (WTP) for types of recontact. Qualitative interviews exploring recontact preferences were analyzed thematically. DCE response rate was 60% (n = 1003, 50% cancer patient participants). 31 participants were interviewed (11 cancer patients). Interviews revealed that participants expected to be recontacted. Quantitatively, preferences for how to be recontacted varied based on certainty of results. For certain results, WTP was highest for being recontacted by a doctor with updates ($1075, 95% CI: $845, $1305) and for contacting a doctor to request updates ($1038, 95% CI: $820, $1256). For VUS results, WTP was highest for an online database ($1735, 95% CI: $1224, $2247) and for contacting a doctor ($1705, 95% CI: $1102, $2307). Qualitative data revealed that preferences for provider-mediated recontact were influenced by trust in healthcare providers. Preferences for a database were influenced by lack of trust in providers and desire for control. Patients and public participants support an online database (e.g. patient portal) to recontact for VUS, improving feasibility, and provider-mediated recontact for certain results, consistent with usual care.

Cost and efficacy comparison of prenatal recall and reflex DNA screening for trisomy 21, 18 and 13.

OBJECTIVE: To compare costs and efficacy of reflex and recall prenatal DNA screening for trisomy 21, 18 and 13 (affected pregnancies). In both methods women have Combined test markers measured. With recall screening, women with a high Combined test risk are recalled for counselling and offered a DNA blood test or invasive diagnostic testing. With reflex screening, a DNA analysis is automatically performed on plasma collected when blood was collected for measurement of the Combined test markers. METHODS: Published data were used to estimate, for each method, using various unit costs and risk cut-offs, the cost per woman screened, cost per affected pregnancy diagnosed, and for a given number of women screened, numbers of affected pregnancies diagnosed, unaffected pregnancies with positive results, and women with unaffected pregnancies having invasive diagnostic testing. RESULTS: Cost per woman screened is lower with reflex v recall screening: £37 v £38, and £11,043 v £11,178 per affected pregnancy diagnosed (DNA £250, Combined test markers risk cut-off 1 in 150). Reflex screening results in similar numbers of affected pregnancies diagnosed, with 100-fold fewer false-positives and 20-fold fewer women with unaffected pregnancies having invasive diagnostic testing. CONCLUSIONS: Reflex DNA screening is less expensive, more cost-effective, and safer than recall screening.

Feedback of Individual Genetic Results to Research Participants: Is It Feasible in Europe?

BACKGROUND: There is growing consensus that individual genetic research results that are scientifically robust, analytically valid, and clinically actionable should be offered to research participants. However, the general practice in European research projects is that results are usually not provided to research participants for many reasons. This article reports on the views of European experts and scholars who are members of the European COST Action CHIP ME IS1303 (Citizen's Health through public-private Initiatives: Public health, Market and Ethical perspectives) regarding challenges to the feedback of individual genetic results to research participants in Europe and potential strategies to address these challenges. MATERIALS AND METHODS: A consultation of the COST Action members was conducted through an email survey and a workshop. The results from the consultation were analyzed following a conventional content analysis approach. RESULTS: Legal frameworks, professional guidelines, and financial, organizational, and human resources to support the feedback of results are largely missing in Europe. Necessary steps to facilitate the feedback process include clarifying legal requirements to the feedback of results, developing harmonized European best practices, promoting interdisciplinary and cross-institutional collaboration, designing educational programs and cost-efficient IT-based platforms, involving research ethics committees, and documenting the health benefits and risks of the feedback process. CONCLUSIONS: Coordinated efforts at pan-European level are needed to enable equitable, scientifically sound, and socially robust feedback of results to research participants.

Recontact in clinical practice: a survey of clinical genetics services in the United Kingdom.

PURPOSE: To ascertain whether and how recontacting occurs in the United Kingdom. METHOD: A Web-based survey was administered online between October 2014 and July 2015. A link to the survey was circulated via an e-mail invitation to the clinical leads of the United Kingdom's 23 clinical genetics services, with follow-up with senior clinical genetics staff. RESULTS: The majority of UK services reported that they recontact patients and their family members. However, recontacting generally occurs in an ad hoc fashion when an unplanned event causes clinicians to review a file (a "trigger"). There are no standardized recontacting practices in the United Kingdom. More than half of the services were unsure whether formalized recontacting systems should be implemented. Some suggested greater patient involvement in the process of recontacting. CONCLUSION: This research suggests that a thorough evaluation of the efficacy and sustainability of potential recontacting systems within the National Health Service would be necessary before deciding whether and how to implement such a service or to create guidelines on best-practice models.Genet Med 18 9, 876-881.

An update to returning genetic research results to individuals: perspectives of the industry pharmacogenomics working group.

The ease with which genotyping technologies generate tremendous amounts of data on research participants has been well chronicled, a feat that continues to become both faster and cheaper to perform. In parallel to these advances come additional ethical considerations and debates, one of which centers on providing individual research results and incidental findings back to research participants taking part in genetic research efforts. In 2006 the Industry Pharmacogenomics Working Group (I-PWG) offered some 'Points-to-Consider' on this topic within the context of the drug development process from those who are affiliated to pharmaceutical companies. Today many of these points remain applicable to the discussion but will be expanded upon in this updated viewpoint from the I-PWG. The exploratory nature of pharmacogenomic work in the pharmaceutical industry is discussed to provide context for why these results typically are not best suited for return. Operational challenges unique to this industry which cause barriers to returning this information are also explained.

Can head and neck cancer patients be discharged after three years?

BACKGROUND: Follow-up surveillance of head and neck cancer patients varies throughout the UK. The heterogeneity of these patients limits the applicability of a standardised protocol. Improvements in our understanding of the natural history of the disease may assist in the tailoring of resources to patients. METHOD: Prospective data collected at the Cumberland Infirmary over a 13-year period were analysed, primarily focusing upon recurrence rates and time to recurrence. RESULTS: In keeping with other studies, recurrence of head and neck squamous cell carcinoma was found to be maximal within the first three years of treatment, regardless of subsite. CONCLUSION: Hospital-based surveillance may be safely discontinued after three years for some patients. Laryngeal carcinoma may require further surveillance due to possible delayed recurrence of a second primary formation. Emphasis must be placed on patient education, accessibility to head and neck services, and the existence of a robust system to facilitate urgent referrals.

[Counter-transference in eating disorder treatment:a systematic review]. / [Le contre-transfert dans le traitement des troubles alimentaires : recension systématique des écrits.]

OBJECTIVE: To identify counter-transference occurrences and causes in therapists treating patients with eating disorders, and to present suggested solutions to overcome counter-transference's negative aspects and to enhance treatment quality. METHOD: Using the major health science and psychology databases, we have identified studies dealing with counter-transference in eating disorder treatment. RESULTS: Many counter-transference occurrences are identified. It seems that therapists often feel negative affects while treating patients with eating disorders. Counter transference seems to be affected by factors related to both the disorder and to the patient and therapist. Further, negative counter-transference can lead to consequences interfering with proper conduct of treatment. The main solutions identified to deal with counter-transference are supervision, consulting with colleagues, and teamwork. CONCLUSIONS: Many factors involved in counter-transference seem hardly modifiable;hence it is important to implement efficient solutions allowing overcoming its negative aspects. Moreover, few empirical studies have focused on counter-transference in eating disorder treatment. That research field is highly pertinent but very rarely exploited, and it deserves the scientific community's attention.

The duty to follow up.

Case histories are based on actual medical negligence claims, however certain facts have been omitted or changed by the author to ensure the anonymity of the parties involved. Many general practitioners are concerned that the law places all of the responsibility for follow up on to the GP and ask: 'What is the patient's responsibility'? This article explores the duty of GPs and patients to follow up tests and results.

Privacy issues in second stage genomics.

Research that identifies genes useful in the prevention and treatment of disease will require access to biologic samples and medical records protected by traditional notions of privacy and confidentiality. Resolving conflicts between privacy and genomic research will require articulating the ethical rules that should govern such practices and then implementing those rules in the national, regional, or local health systems in which the data of interest exists. As consensus develops about the ethical rules that should govern such research, attention will shift to the practical and political problems of installing and implementing those rules in the agencies and institutions where such research will occur.

Participant protection with the use of records: ethical issues and recommendations.

This article explores the ethical concerns and protections that may be required when individually identifiable data originally collected solely for clinical or administrative purposes are used in research or evaluation. It asks the following broad question with respect to the interim policy developed by the Substance Abuse and Mental Health Services Administration (SAMHSA) to protect the rights and welfare of participants in its programs: For those programs and projects not classified as research, are the protections and system for review adequate? Background information on SAMHSA's interim policy is provided, along with issues and questions related to the use of clinical and administrative records in research and evaluation. The article concludes with recommendations for modifying the existing participant protection guidelines, based on the preceding discussion of issues and questions.