Regulating Direct-to-Consumer Polygenic Risk Scores.

This Viewpoint discusses the possible harms associated with direct-to-consumer polygenic risk scores and advocates for federal regulation.

Development of a Checklist Tool to Assess the Quality of Skin Lesion Images Acquired by Consumers Using Sequential Mobile Teledermoscopy.

BACKGROUND: Mobile teledermoscopy is an emerging technology that involves imaging and digitally sending dermoscopic images of skin lesions to a clinician for assessment. High-quality, consistent images are required for accurate telediagnoses when monitoring lesions over time. To date there are no tools to assess the quality of sequential images taken by consumers using mobile teledermoscopy. The purpose of this study was to develop a tool to assess the quality of images acquired by consumers. METHODS: Participants imaged skin lesions that they felt were concerning at baseline, 1-, and 2-months. A checklist to assess the quality of consumer sequential imaging of skin lesions was developed based on the International Skin Imaging Collaboration guidelines. A scale was implemented to grade the quality of the images: 0 (low) to 18 (very high). Intra- and inter-reliability of the checklist was assessed using Bland-Altman analysis. Using this checklist, the consistency with which 85 sets of images were scored by 2 evaluators were compared using Kappa statistics. Items with a low Kappa value <0.4 were removed. RESULTS: After reliability testing, 5 of the items were removed due to low Kappa values (<0.4) and the final checklist included 13 items surveying: lesion selection; image orientation; lighting; field of view; focus and depth of view. Participants had a mean age of 41 years (range 19-73), and 67% were female. Most participants (84%, n = 71/85) were able to select and image the correct lesion over time for both the dermoscopic and overview images. Younger participants (<40 years old) scored significantly higher (8.1 ± 2.1) on the imaging checklist compared to older participants (7.1 ± 2.4; p = 0.037). Participants had most difficulty with consistent image orientation. CONCLUSIONS: This checklist could be used as a triage tool to filter images acquired by consumers prior to telediagnosis evaluation, which would improve the efficiency and accuracy of teledermatology and teledermoscopy processes. It may also be used to provide feedback to the consumers to improve image acquisition over time.

Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.

Importance: Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants. Objective: To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing. Design, Setting, and Participants: This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form. Main Outcomes and Measures: Number of pathogenic or likely pathogenic (P/LP) variants identified. Results: This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen. Conclusions and Relevance: Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.

Strategies to Improve the Clinical Outcomes for Direct-to-Consumer Pharmacogenomic Tests.

Direct-to-consumer genetic tests (DTC-GT) have become a bridge between marketing and traditional healthcare services. After earning FDA endorsement for such facilities, several fast-developing companies started to compete in the related area. Pharmacogenomic (PGx) tests have been introduced as potentially one of the main medical services of such companies. Most of the individuals will be interested in finding out about the phenotypic consequences of their genetic variants and molecular risk factors against diverse medicines they take or will take later. Direct-to-consumer pharmacogenomic tests (DTC-PT) is still in its young age, however it is expected to expand rapidly through the industry in the future. The result of PGx tests could be considered as the main road toward the implementation of personalized and precision medicine in the clinic. This narrative critical review study provides a descriptive overview on DTC-GT, then focuses on DTC-PT, and also introduces and suggests the potential approaches for improving the clinical related outcomes of such tests on healthcare systems.

Detection of Tachyarrhythmias in a Large Cohort of Infants Using Direct-to-Consumer Heart Rate Monitoring.

OBJECTIVE: Current estimates of the incidence of tachyarrhythmias in infants rely on clinical documentation and may not reflect the true rate in the general population. Our aim was to describe the epidemiology of tachyarrhythmia detected in a large cohort of infants using direct-to-consumer heart rate (HR) monitoring. STUDY DESIGN: Data were collected from Owlet Smart Sock devices used in infants in the US with birthdates between February 2017 and February 2019. We queried the HR data for episodes of tachyarrhythmia (HR of ≥240 bpm for >60 seconds). RESULTS: The study included 100 949 infants (50.8% male) monitored for more than 200 million total hours. We identified 5070 episodes of tachyarrhythmia in 2508 infants. The cumulative incidence of tachyarrhythmia in our cohort was 2.5% over the first year of life. The median age at the time of the first episode of tachyarrhythmia was 36 days (range, 1-358 days). Tachyarrhythmia was more common in infants with congenital heart disease (4.0% vs 2.4%; P = .015) and in females (2.7% vs 2.0%; P < .001). The median length of an episode was 7.3 minutes (range, 60 seconds to 5.4 hours) and the probability of an episode lasting longer than 45 minutes was 16.8% (95% CI, 15.4%-18.3%). CONCLUSIONS: We found the cumulative incidence of tachyarrhythmia among infants using direct-to-consumer HR monitors to be higher than previously reported in studies relying on clinical diagnosis. This finding may represent previously undetected subclinical disease in young infants, the significance of which remains uncertain. Clinicians should be prepared to discuss these events with parents.

Direct-to-Consumer Genetic Testing: Value and Risk.

Although the explosive growth of direct-to-consumer (DTC) genetic testing has moderated, a substantial number of patients are choosing to undergo genetic testing outside the purview of their regular healthcare providers. Further, many industry leaders have been expanding reports to cover many more genes, as well as partnering with employers and others to expand access. This review addresses continuing concerns about DTC genetic testing quality, psychosocial impact, integration with medical practice, effects on the healthcare system, and privacy, as well as emerging concerns about third-party interpretation services and non-health-related uses such as investigative genetic genealogy. It concludes with an examination of two possible futures for DTC genetic testing: merger with traditional modes of healthcare delivery or continuation as a parallel system for patient-driven generation of health-relevant information. Each possibility is associated with distinctive questions related to value and risk.

Health outcomes and experiences of direct-to-consumer high-intensity screening using both whole-body magnetic resonance imaging and cardiological examination.

BACKGROUND: Alongside a clinical and research setting, whole body magnetic resonance imaging (WB-MRI) is increasingly offered as a direct-to-consumer screening service. Data is needed on the clinical relevance of findings and associated psychological impact of such screening. Therefore, we conducted a prospective follow-up study to provide insight in the effectiveness and psychological impact of direct-to-consumer screening using both WB-MRI and cardiological examination. METHODS AND FINDINGS: The study population consisted of 3603 voluntary, primarily middle-aged participants who underwent commercial WB-MRI and cardiological screening at one of 6 study clinics in Germany or the Netherlands between July 2014 and March 2016. MRI investigation consisted of directed scans of the brain, neck, abdomen and pelvis. Cardiovascular examination included pulmonary function, resting electrocardiogram, transthoracic echocardiogram and a bicycle exercise stress test. Findings were assessed by experienced radiologists and cardiologists. In addition, participants were inquired about several (psychological) domains, including the expectations and consequences of the screening procedure. Out of 3603 individuals, 402 (11.2%) demonstrated abnormal MRI (n = 381) and/or cardiological findings (n = 79) for which they were advised to undergo further consultation <3 months in regular healthcare. In 59.1% of cases of abnormal MRI findings which were consulted, fully completed consultations were available in 87.1%. After consultation, 77.6% of initial MRI outcomes were adopted. In 40.9% of cases of abnormal MRI findings, recommendations for consultation were not adhered to during the study period. 71.1% of adopted MRI-findings required treatment or monitoring, including 19 malignancies. For abnormal cardiological findings, 70.9% of cases were consulted in regular healthcare. Of these, 91.1% had a completed follow-up procedure of which 72.5% of initial findings were adopted and 83.8% of these findings required treatment or monitoring. The most frequently reported psychological consequences of the screening procedure were getting reassurance (72.0%) and insight into one's own health status (83.0%). 5.0% reported to feel insecure about their health and 6.2% worried more about their health as a consequence of screening. Main limitations of the study were considered the telephonic follow-up of referred clients and the heterogeneity of screening equipment and assessment of radiologists and cardiologists. CONCLUSIONS: Direct-to-consumer screening using whole-body MRI and cardiological testing is feasible and effective for the detection of clinically relevant and treatable abnormalities. Psychological harm was not frequently reported in study participants.

[Direct-to-consumer genetic testing: a regulation by the market, or a medical regulation?] / Les tests génétiques en libre accès - Régulation par le marché, ou régulation médicale ?

The direct-to-consumer genetic testing (DTC-GT) market has been developing for about twenty years now, raising various debates, even controversies. But what about the regulation of these so-called "innovative" devices, but whose medical status is ambiguous? A first regulatory aspect is depending on the market itself, since the latter is currently subjected to a strong structuring process. A second regulatory aspect, more classical, is the legal one. While the DTC-GT status has long been unclear on European scale, a new text (a Regulation, not a Directive) is modifying the situation. It encourages regulation "by the market" rather than "by the medical profession", which does not imply that the latter will have no (indirect) impact on the DTC-GT market.

TITLE: Les tests génétiques en libre accès - Régulation par le marché, ou régulation médicale ? ABSTRACT: Le marché des auto-tests génétiques se développe depuis une vingtaine d'années, non sans soulever des débats, voire des controverses. Qu'en est-il de la régulation de ces dispositifs dits « innovants ¼, mais dont le statut médical est ambigu ? Un premier aspect régulatoire vient du marché lui-même, puisqu'il est en cours de forte structuration. Un second aspect régulatoire relève plus classiquement du juridique. Alors que le statut des auto-tests a longtemps manqué de clarté à l'échelle européenne, un nouveau texte (un Règlement, et non une Directive) change la situation. Il encourage une régulation « par le marché ¼, plutôt que « par la profession médicale ¼, ce qui n'implique pas que cette dernière n'aura aucun impact (indirect) sur le marché des auto-tests.

Valuable Genomes: Taxonomy and Archetypes of Business Models in Direct-to-Consumer Genetic Testing.

BACKGROUND: Recent progress in genome data collection and analysis technologies has led to a surge of direct-to-consumer (DTC) genetic testing services. Owing to the clinical value and sensitivity of genomic data, as well as uncertainty and hearsay surrounding business practices of DTC genetic testing service providers, DTC genetic testing has faced significant criticism by researchers and practitioners. Research in this area has centered on ethical and legal implications of providing genetic tests directly to consumers, but we still lack a more profound understanding of how businesses in the DTC genetic testing markets work and provide value to different stakeholders. OBJECTIVE: The aim of this study was to address the lack of knowledge concerning business models of DTC genetic testing services by systematically identifying the salient properties of various DTC genetic testing service business models as well as discerning dominant business models in the market. METHODS: We employed a 3-phased research approach. In phase 1, we set up a database of 277 DTC genetic testing services. In phase 2, we drew on these data as well as conceptual models of DTC genetic testing services and iteratively developed a taxonomy of DTC genetic testing service business models. In phase 3, we used a 2-stage clustering method to cluster the 277 services that we identified during phase 1 and derived 6 dominant archetypes of DTC genetic testing service business models. RESULTS: The contributions of this research are 2-fold. First, we provided a first of its kind, systematically developed taxonomy of DTC genetic testing service business models consisting of 15 dimensions in 4 categories. Each dimension comprises 2 to 5 characteristics and captures relevant aspects of DTC genetic testing service business models. Second, we derived 6 archetypes of DTC genetic testing service business models named as follows: (1) low-cost DTC genomics for enthusiasts, (2) high-privacy DTC genomics for enthusiasts, (3) specific information tests, (4) simple health tests, (5) basic low-value DTC genomics, and (6) comprehensive tests and low data processing. CONCLUSIONS: Our analysis paints a much more complex business landscape in the DTC genetic testing market than previously anticipated. This calls for further research on business models and their effects that underlie DTC genetic testing services and invites specific regulatory interventions to protect consumers and level the playing field.

Personal genomic screening: How best to facilitate preparedness of future clients.

Personal genome screening (PGenS) is increasingly being offered as a screen for future health management, and to identify carrier status pertinent to reproductive decision-making. The aim of this study was therefore to explore the experience of individuals who undertook PGenS through the 2014 Sydney "Understand Your Genome (UYG)" event and a 2015 offer of PGenS by Australian biotechnology company Life Letters (LL). Eligible individuals were invited to participate by their clinical geneticist (UYG), or email from Director of LL. Semi-structured telephone interviews with 17 individuals were audio-recorded, transcribed, de-identified and analyzed by two coders using thematic analysis with an inductive approach. Nine participants had genetic/genomics expertise and eight were well-informed health and business professionals. Individual participant PGenS results included: an autosomal dominant condition not previously clinically identified (n = 1); carrier status for recessive condition(s) (n = 8); a number of disease-causing variants associated with an increased susceptibility to an inherited disorder (n = 7); variants of uncertain significance (n = 5); and a few pharmacogenomically-relevant variants (n = 4). The majority of participants described the importance of pre-test genetic counseling, information and/or consent (n = 12). Some barriers to uptake were identified, including scepticism by GPs (n = 6), colleagues (n = 3), and family members (n = 2), as well as privacy concerns (n = 4). Those without genetic/genomics expertise were mostly motivated to have testing by curiosity or interest in personal health (6/8), one seeking a diagnosis for an inherited medical condition and another for future health management. For many with genetic/genomics experience, the motivation was professional interest (8/9) and/or curiosity (5/9), without concern for personal health risk (4/9). On reflection, despite this initial motivation by the latter, the test result had unanticipated personal impact for some of this group, which changed over time (4/5). Several later recognized this, as health problems developed or family history was interrogated more closely. For all participants, disclosure of results to extended family members was limited. Most participants felt personal and family implications and communication (5/17) and/or expectations (3/17) should be addressed at the pre-test session, including more emphasis on residual risk and changes in interpretation with developing phenotypes. Those without genetics/genomics expertise highlighted the need for easy to understand pre-test information and/or an example report to be provided (7/8). These results are consistent with a need to develop more accessible resources, and more personalized counseling approaches to address expectations, dissemination of results, and preparedness for unexpected findings.

Precision medicine: a call for increased pharmacogenomic education.

Precision medicine is an emerging model of care where providers consider patients' genetic profiles, lifestyles and environments to offer more precise therapy. The potential of precision medicine is boundless as interdisciplinary teams utilize genetic technologies to improve patient outcomes. The integration of precision medicine into healthcare faces many barriers, including a lack of standardization and reimbursement concerns. This article argues that increased pharmacogenetics education and system-wide implementation is necessary to overcome some of these challenges. Extensive expansion of pharmacogenomics education is a step toward producing knowledgeable clinicians who are poised to apply its methodology and champion for patient-centered care.

Direct-to-consumer genetic testing with third party interpretation: beware of spurious results.

Direct-to-consumer (DTC) genetic tests aim to provide insights into issues as varied as ancestry, nutrition, athletic ability and child talent, and some also report on disease risks. DTC companies tend to present their tests as uniformly beneficial, but the quality of the information they provide can be doubtful. Tests often invite people to step between territories, from the consumer in search of 'fun' information to potential patient, and the boundaries between these roles become even murkier when individuals explore the raw data from their DTC tests using third-party interpretation websites. We discuss two composite cases from U.K. genetics centres where patients used third party interpretation services to analyse raw data from DTC genetic tests. They then presented to NHS clinical services requesting interventions based on the disease-associated variants found, only to find that these variants were not actually present: their 'pathogenic results' were spurious. We highlight the risk of false positives (as well as false negatives) from DTC genetic tests, and discuss whether these cases represent the start of a worrying trend, where publicly funded clinicians and clinical scientists increasingly need to spend time and money investigating genetic results of dubious validity.

[Direct-to-consumer genetic tests in the consulting room]. / Direct-to-consumer genetische tests in de spreekkamer.

Rapid developments in genome technology and a growing interest in personalized healthcare have led to a large rise in the range and use of commercial DNA tests, the so-called direct-to-consumer genetic tests (DTC-GT). DTC-GT can be of a non-medical (e.g. for external characteristics) or medical nature; medical tests mostly indicate relative risks of disease e.g. Alzheimer's disease or certain forms of cancer. Low clinical validity and frequently unknown analytical validity of DTC-GT make it difficult to estimate the clinical usefulness of test results. From an ethical perspective, an increase in autonomy and possible health benefits must be weighed against loss of privacy, inadequate provision of information and the risk of misinterpretation of results, over-diagnosis, overtreatment and higher healthcare costs. It is unclear whether providing and implementing DTC-GT require authorisation under Dutch law in the Population Screening Act (Wet op het Bevolkingsonderzoek) or the Special Medical Procedures Act (Wet op BijzondereMedischeVerrichtingen). Clinical utility of DTC-GT can only increase if there is greater clarity on interpretation and scope of the law and regulations, when DTC-GT companies provide better information and guidance for consumers and when there is more focus on DTC-GT in education and training programmes for healthcare professionals.

Genome-wide microRNA analysis of HPV-positive self-samples yields novel triage markers for early detection of cervical cancer.

Offering self-sampling for HPV testing improves the effectiveness of current cervical screening programs by increasing population coverage. Molecular markers directly applicable on self-samples are needed to stratify HPV-positive women at risk of cervical cancer (so-called triage) and to avoid over-referral and overtreatment. Deregulated microRNAs (miRNAs) have been implicated in the development of cervical cancer, and represent potential triage markers. However, it is unknown whether deregulated miRNA expression is reflected in self-samples. Our study is the first to establish genome-wide miRNA profiles in HPV-positive self-samples to identify miRNAs that can predict the presence of CIN3 and cervical cancer in self-samples. Small RNA sequencing (sRNA-Seq) was conducted to determine genome-wide miRNA expression profiles in 74 HPV-positive self-samples of women with and without cervical precancer (CIN3). The optimal miRNA marker panel for CIN3 detection was determined by GRridge, a penalized method on logistic regression. Six miRNAs were validated by qPCR in 191 independent HPV-positive self-samples. Classification of sRNA-Seq data yielded a 9-miRNA marker panel with a combined area under the curve (AUC) of 0.89 for CIN3 detection. Validation by qPCR resulted in a combined AUC of 0.78 for CIN3+ detection. Our study shows that deregulated miRNA expression associated with CIN3 and cervical cancer development can be detected by sRNA-Seq in HPV-positive self-samples. Validation by qPCR indicates that miRNA expression analysis offers a promising novel molecular triage strategy for CIN3 and cervical cancer detection applicable to self-samples.