Societal preferences for the return of incidental findings from clinical genomic sequencing: a discrete-choice experiment

Background:An important challenge with the application of next-generation sequencing technology is the possibility of uncovering incidental genomic findings. A paucity of evidence on personal utility for incidental findings has hindered clinical guidelines. Our objective was to estimate personal utility for complex information derived from incidental genomic findings.Methods:We used a discrete-choice experiment to evaluate participants’ personal utility for the following attributes: disease penetrance, disease treatability, disease severity, carrier status and cost. Study participants were drawn from the Canadian public. We analyzed the data with a mixed logit model.Results:In total, 1200 participants completed our questionnaire (available in English and French). Participants valued receiving information about high-penetrance disorders but expressed disutility for receiving information on low-penetrance disorders. The average willingness to pay was $445 (95% confidence interval [CI] $322–$567) to receive incidental findings in a scenario where clinicians returned information about high-penetrance, medically treatable disorders, but only 66% of participants (95% CI 63%–71%) indicated that they would choose to receive information in that scenario. On average, participants placed an important value ($725, 95% CI $600–$850) on having a choice about what type of findings they would receive, including receipt of information about high-penetrance, treatable disorders or receipt of information about high-penetrance disorders with or without available treatment. The predicted uptake of that scenario was 76% (95% CI 72%–79%).Interpretation:Most participants valued receiving incidental findings, but personal utility depended on the type of finding, and not all participants wanted to receive incidental results, regardless of the potential health implications. These results indicate that to maximize benefit, participant-level preferences should inform the decision about whether to return incidental findings.Clinical genomic sequencing technologies are on the verge of allowing individualized care at reasonable cost.¹ Patients and their families will soon receive information from clinical sequencing that has implications for clinical care, including information on consequences related to disease prognosis, treatment response or hereditary risk for disease.² Clinical sequencing can also generate incidental findings, which are clinically relevant genetic variants for disorders unrelated to the reason for ordering the genetic testing. The decision of whether to provide information about incidental findings is complex because such results will have varying clinical validity (whether the genetic variant causes the disorder) and utility (whether effective medical treatment is available for the disorder).^3,4 For example, although effective medical treatment may be available for some validated incidental findings, other incidental findings may not be validated as causing the disorder, and still others will be validated but not associated with effective treatment options.To address in part the challenges surrounding the return of incidental findings, the American College of Medical Genetics and Genomics published recommendations for reporting incidental findings from clinical sequencing.⁵ The statement lists a minimum of 56 genes that laboratories should examine, with results reported to patients through the managing physician. This list includes genes with high-penetrance mutations (i.e., a high proportion of individuals with the mutation will exhibit clinical symptoms) validated to be associated with disorders for which medical interventions are available.The original version of this statement did not “favour offering the patient a preference” for which results would be returned. The reasoning was that clinicians have a duty to prevent potential harm by telling patients about incidental findings. The working group that developed the recommendations further stated that it is impractical to provide the level of genetic counselling required for informed preference on all potential disorders.⁵ As such, the working group recommended that clinicians discuss with patients the possibility of receiving incidental findings from the list. It was argued that patient autonomy is preserved because patients can decline clinical sequencing if they prefer to not receive information about incidental findings.⁵ However, this rationale has been subject to debate because of its “all-or-none” nature, whereby patients must agree to receive information about incidental findings or clinical sequencing is not provided.^6–9 In April 2014, in response to the ongoing debate, the statement was amended to include an “opt-out” option for patients who do not want to receive information about incidental findings.¹⁰Notwithstanding the ethical debate, there is a lack of quantitative, preference-based economic evidence for the return of incidental genomic findings.⁸ It has been argued⁸ that this gap in evidence hindered development of the working group’s recommendation statement. More generally, evidence on preferences for the return of incidental findings is crucial for health policy, for health systems planning and for informing future lists that may include “many more genes.”⁸ We aimed to generate evidence on the personal utility that study participants from the Canadian public ascribe to the return of incidental genomic findings in the clinical setting. We chose participants from the general public because the public is the largest stakeholder in Canada’s publicly funded health care system.     

Complement receptor 1 gene variants are associated with erythrocyte sedimentation rate

The erythrocyte sedimentation rate (ESR), a commonly performed test of the acute phase response, is the rate at which erythrocytes sediment in vitro in 1 hr. The molecular basis of erythrocyte sedimentation is unknown. To identify genetic variants associated with ESR, we carried out a genome-wide association study of 7607 patients in the Electronic Medical Records and Genomics (eMERGE) network. The discovery cohort consisted of 1979 individuals from the Mayo Clinic, and the replication cohort consisted of 5628 individuals from the remaining four eMERGE sites. A nonsynonymous SNP, rs6691117 (Val→IIe), in the complement receptor 1 gene (CR1) was associated with ESR (discovery cohort p = 7 × 10(-12), replication cohort p = 3 × 10(-14), combined cohort p = 9 × 10(-24)). We imputed 61 SNPs in CR1, and a "possibly damaging" SNP (rs2274567, His→Arg) in linkage disequilibrium (r(2) = 0.74) with rs6691117 was also associated with ESR (discovery p = 5 × 10(-11), replication p = 7 × 10(-17), and combined cohort p = 2 × 10(-25)). The two nonsynonymous SNPs in CR1 are near the C3b/C4b binding site, suggesting a possible mechanism by which the variants may influence ESR. In conclusion, genetic variation in CR1, which encodes a protein that clears complement-tagged inflammatory particles from the circulation, influences interindividual variation in ESR, highlighting an association between the innate immunity pathway and erythrocyte interactions.     

Dietary cholesterol increases paraoxonase 1 enzyme activity

HDL-associated paraoxonase 1 (PON1) activity has been consistently associated with cardiovascular and other diseases. Vitamins C and E intake have previously been positively associated with PON1 in a subset of the Carotid Lesion Epidemiology and Risk (CLEAR) cohort. The goal of this study was to replicate these findings and determine whether other nutrient intake affected PON1 activity. To predict nutrient and mineral intake values, 1,402 subjects completed a standardized food frequency survey of their dietary habits over the past year. Stepwise regression was used to evaluate dietary and covariate effects on PON1 arylesterase activity. Five dietary components, cholesterol (P < 2.0 × 10⁻¹⁶), alcohol (P = 8.51 × 10⁻⁸), vitamin C (P = 7.97 × 10⁻⁵), iron (P = 0.0026), and folic acid (0.037) were independently predictive of PON1 activity. Dietary cholesterol was positively associated and predicted 5.5% of PON1 activity, second in variance explained. This study presents a novel finding of dietary cholesterol, iron, and folic acid predicting PON1 activity in humans and confirms prior reported associations, including that with vitamin C. Identifying and understanding environmental factors that affect PON1 activity is necessary to understand its role and that of HDL in human disease.     

Linkage and association analyses identify a candidate region for apoB level on chromosome 4q32.3 in FCHL families

Familial combined hyperlipidemia (FCHL) is a complex trait leading to cardiovascular disease (CVD) risk. Elevated levels and size of apolipoprotein B (apoB) and low-density lipoprotein (LDL) are associated with FCHL, which is genetically heterogeneous and is likely caused by rare variants. We carried out a linkage-based genome scan of four large FCHL pedigrees for apoB level that is independent of LDL: apoB level that is adjusted for LDL level and size. Follow-up included SNP genotyping in the region with the strongest evidence of linkage. Several regions with the evidence of linkage in individual pedigrees support the rare variant model. Evidence of linkage was strongest on chromosome 4q, with multipoint analysis in one pedigree giving LOD = 3.1 with a parametric model, and a log Bayes Factor = 1.5 from a Bayesian oligogenic approach. Of the 293 SNPs spanning the implicated region on 4q, rs6829588 completely explained the evidence of linkage. This SNP accounted for 39% of the apoB phenotypic variance, with heterozygotes for this SNP having a trait value that was ~30% higher than that of the high-frequency homozygote, thus identifying and considerably refining a strong candidate region. These results illustrate the advantage of using large pedigrees in the search for rare variants: reduced genetic heterogeneity within single pedigrees coupled with the large number of individuals segregating otherwise-rare single variants leads to high power to implicate such variants.     

Psychiatry-important advances in clinical medicine: heterogeneity of dementia

The Scientific Board of the California Medical Association presents the following inventory of items of progress in psychiatry. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, research workers or scholars to stay abreast of these items of progress in psychiatry that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another.The items of progress listed below were selected by the Advisory Panel to the Section on Psychiatry of the California Medical Association and the summaries were prepared under its direction.     

Chromosomes in old age: A six year longitudinal study

Summary A new variant of ₁-antitrypsin has been detected with the aid of isoelectric fucosing on polyacrylamide slab gels. In contrast with many other variants this new ₁-antitrypsin allele is found in 10–15% of the phenotypes examined. The electrophoretic properties of the new ₁-antitrypsin variant in isofocusing polyacrylamide gels differ only silightly from the most common ₁-antitrypsin allele M. On the basis of its electroforetic behaviour we propose the term M_N to indicate this new protease inhibitor variant. The isofocusing technique employed, provides an easy to handle, very reproducible method for determining the ₁-antitrypsin phenotype and can be employed for large scale screening.     

Fluorogen-activating single-chain antibodies for imaging cell surface proteins

Imaging of live cells has been revolutionized by genetically encoded fluorescent probes, most famously green and other fluorescent proteins, but also peptide tags that bind exogenous fluorophores. We report here the development of protein reporters that generate fluorescence from otherwise dark molecules (fluorogens). Eight unique fluorogen activating proteins (FAPs) have been isolated by screening a library of human single-chain antibodies (scFvs) using derivatives of thiazole orange and malachite green. When displayed on yeast or mammalian cell surfaces, these FAPs bind fluorogens with nanomolar affinity, increasing green or red fluorescence thousands-fold to brightness levels typical of fluorescent proteins. Spectral variation can be generated by combining different FAPs and fluorogen derivatives. Visualization of FAPs on the cell surface or within the secretory apparatus of mammalian cells can be achieved by choosing membrane permeant or impermeant fluorogens. The FAP technique is extensible to a wide variety of nonfluorescent dyes.