Direct-to-consumer raw genetic data and third-party interpretation services: more burden than bargain?

Moscarello, Tia; Murray, Brittney; Reuter, Chloe; Demo, Erin

doi:10.1038/s41436-018-0097-2

Cited by 68 publications

(72 citation statements)

References 4 publications

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“…Customers can download their data and seek an interpretation using third party services. 9 These usually work by cross referencing the data against freely available genetic databases and constructing a report based on interpretations in these databases (which may not be up to date). 10 They may report variants and disease risks that were not reported or referred to by the original DTC genetic test company, and might repurpose raw data from tests designed to answer other questions, such as ancestry, to try to provide health information.…”

Section: What Health Information Do Dtc Genetic Tests Provide?mentioning

confidence: 99%

Direct-to-Consumer Genetic Testing

Gill

Obley²,

Prasad

2018

JAMA

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What you need to know • Finding a "health risk" via direct-to-consumer (DTC) genetic testing often does not mean that a patient will go on to develop the health problem in question • DTC genetic tests might report false positives (artefacts) • "Reassuring" results from DTC genetic tests might be false negatives • Make sure you are confident in the provenance and interpretation of a genetic result before you base any clinical decisions on it • If your patient meets criteria for referral to clinical genetics, refer regardless of the results of their DTC genetic test Direct-to-consumer (DTC) genetic tests are sold online and in shops as a way to "find out what your DNA says." 1 2 Testing kits typically contain instructions and equipment for collecting a saliva sample, which customers post to the DTC company for analysis. Some DTC genetic tests promise insights into ancestry or disease risks; others claim to provide information on personality, athletic ability, and child talent. However, interpretation of genetic data is complex and context dependent, and DTC genetic tests may produce false positive and false negative results. Anyone concerned about a result from a DTC genetic test might turn to their general practitioner (GP) or other primary healthcare provider for advice. This practice pointer aims to help clinicians in this scenario and explains what sort of health information is provided by these tests, their limitations, and how clinicians can respond to common questions about them.

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Section: What Health Information Do Dtc Genetic Tests Provide?mentioning

confidence: 99%

Direct-to-Consumer Genetic Testing

Gill

Obley²,

Prasad

2018

JAMA

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“…Many DTC companies use these additional quality control methods, supplemented by validation of important variants using DNA sequencing, to improve the accuracy of variants they advertise and report directly to consumers. However, most DTC companies (including those focused on ancestry or other non-medical traits) also allow customers to download and analyse their raw data, which will often include many thousands of additional rare variants assayed on the SNP-chip that have not undergone stringent quality control and are therefore much more likely to be false positives [15]. A recent study found that 89% of consumers of DTC genetic tests download their raw data and 94% of those use at least one thirdparty interpretation service to analyse the results [31].…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, consumers of DTC tests are increasingly being screened for numerous rare single gene disorders and are potentially receiving medically-actionable results, which they often take to healthcare professionals for advice [12] ( Figure 2). False positive results for rare clinically-actionable variants detected by DTC SNP-chips have been described in practice guidance [13], several case reports [14,15] and two small case series [16,17]. However, there is no published systematic evaluation of the accuracy of SNP-chips for assaying rare genetic variants.…”

Section: Introductionmentioning

confidence: 99%

Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing

Weedon

Jackson

Harrison

et al. 2019

Preprint

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Objectives:To determine the analytical validity of SNP-chips for genotyping very rare genetic variants.Design: Retrospective study using data from two publicly available resources, the UK Biobank and the Personal Genome Project. Setting:Research biobanks and direct-to-consumer genetic testing in the UK and USA.Participants: 49,908 individuals recruited to UK Biobank, and 21 individuals who purchased consumer genetic tests and shared their data online via the Personal Genomes Project. Main outcome measures:We assessed the analytical validity of genotypes from SNP-chips (index test) with sequencing data (reference standard). We evaluated the genotyping accuracy of the SNPchips and split the results by variant frequency. We went on to select rare pathogenic variants in the BRCA1 and BRCA2 genes as an exemplar for detailed analysis of clinically-actionable variants in UK Biobank, and assessed BRCA-related cancers (breast, ovarian, prostate and pancreatic) in participants using cancer registry data.Results: SNP-chip genotype accuracy is high overall; sensitivity, specificity and precision are all >99% for 108,574 common variants directly genotyped by the UK Biobank SNP-chips. However, the likelihood of a true positive result reduces dramatically with decreasing variant frequency; for variants with a frequency <0.001% in UK Biobank the precision is very low and only 16% of 4,711 variants from the SNP-chips confirm with sequencing data. Results are similar for SNP-chip data from the Personal Genomes Project, and 20/21 individuals have at least one rare pathogenic variant that has been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, the overall performance metrics of the SNP-chips in UK Biobank are sensitivity 34.6%, specificity 98.3% and precision 4.2%. Rates of BRCA-related cancers in individuals in UK Biobank with a positive SNP-chip result are similar to age-matched controls (OR 1.28, P=0.07, 95% CI: 0.98 to 1.67), while sequencepositive individuals have a significantly increased risk (OR 3.73, P=3.5x10 -12 , 95% CI: 2.57 to 5.40).Conclusion: SNP-chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

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“…Genomic medicine is now being incorporated more into numerous areas of clinical practice, and there is an increasing number of people using genetic testing results in direct-toconsumer (DTC) models. There are parallels between this case and recent publications of the analytical errors in DTC genetic testing and the resulting interpretation and clinical use of erroneous genetic data (Moscarello et al 2018;Tandy-Connor et al 2018). This raises concern about genetic testing accuracy, variant calls and classifications, and clinical application and use of erroneous genetic data.…”

Section: Discussionmentioning

confidence: 72%

All Along the Watchtower: a Case of Long QT Syndrome Misdiagnosis Secondary to Genetic Testing Misinterpretation

Helm

Ayers

Kean

2018

Journal of Genetic Counseling

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Clinical genetics services continue to expand into diverse medical specialties. An ever-increasing number of non-genetics providers are independently ordering genetic tests, interpreting results, and at times, making diagnoses leading to patient care recommendations. Non-genetics healthcare providers can help increase patient access to these services, but a potential pitfall occurs when these providers either do not have adequate expertise with genetic variant interpretation or do not have access to multi-disciplinary teams including genetic counselors or clinical geneticists for advanced review. In the cardiology setting, variant misinterpretation can lead to misattribution of disease risk, unnecessary treatments or management, and potentially adverse psychosocial and financial effects. To address this, case reports and series are needed to highlight variant misinterpretation and misdiagnoses, including discussion of possible solutions and best practices for avoidance. This report details a child previously diagnosed with long QT syndrome type 4 by chromosomal microarray who was then subsequently managed for this disease by cardiac providers with insufficient expertise to critically review and question the genetic testing results. The patient was eventually referred to a pediatric electrophysiology team as part of a larger multidisciplinary cardiovascular genetics program, composed of specialist genetic counselors, cardiologists, and clinical geneticists. Advanced review and clinical evaluation raised concern about the initial genetic testing result and diagnosis. Complementary testing with a different modality to confirm or disconfirm the chromosome microarray result was performed, providing evidence that the original result reflected analytic error in the laboratory as well as interpretive error by the clinical geneticist and that the patient was misdiagnosed, and treated over the course of years, for long QT syndrome. This case shows the value of multidisciplinary teams caring for patients with inherited cardiovascular diseases.

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Direct-to-consumer raw genetic data and third-party interpretation services: more burden than bargain?

Cited by 68 publications

References 4 publications

Direct-to-Consumer Genetic Testing

Direct-to-Consumer Genetic Testing

Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing

All Along the Watchtower: a Case of Long QT Syndrome Misdiagnosis Secondary to Genetic Testing Misinterpretation

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