Studies have begun exploring whether researchers should return incidental findings in genomic studies, and if so, which findings should be returned; however, how researchers make these decisions— the processes and factors involved—has remained largely unexplored.
We interviewed 28 genomics researchers in-depth about their experiences and views concerning the return of incidental findings.
Researchers often struggle with questions concerning which incidental findings to return and how to make those decisions. Multiple factors shape their views, including information about the gene variant (e.g., pathogenicity and disease characteristics), concerns about participants’ well-being and researcher responsibility, and input from external entities. Researchers weigh the evidence, yet they face conflicting pressures, with relevant data frequently being unavailable. Researchers vary in who they believe should decide: participants, principal investigators, institutional review boards, and/or professional organizations. Contextual factors can influence these decisions, including policies governing return of results by institutions and biobanks and the study design. Researchers vary in desires for: guidance from institutions and professional organizations, changes to current institutional processes, and community- wide genetics education.
These data, the first to examine the processes by which researchers make decisions regarding the return of genetic incidental findings, highlight several complexities involved and have important implications for future genetics research, policy, and examinations of these issues.
benefits and risks; decision making; genome sequencing; incidental findings; return of results
Although patients with neurofibromatosis are predisposed to multiple nerve sheath tumors that can develop anywhere in the body and cause significant morbidity (e.g., hearing loss; pain), little research has examined emotional correlates of neurofibromatosis. The purpose of this study was to examine emotional functioning among adult patients with neurofibromatosis.
A total of 248 patients with neurofibromatosis (neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis) who received care at a specialized clinic completed validated measures to assess symptoms of depression and anxiety, level of perceived stress, and self-esteem.
Patients with neurofibromatosis reported significantly more symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem as compared with general population norms. No significant differences were found among patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis, and emotional functioning was not significantly associated with disease severity. However, increased symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem were associated with a higher frequency of self-reported medical visits in the past year (P values ≤0.05).
Neurofibromatosis appears to be associated with reduced emotional functioning. Although further research is needed, these findings suggest a role for a multidisciplinary treatment approach to address emotional distress among adult patients with neurofibromatosis.
emotional function; neurofibromatosis 1; neurofibromatosis 2; schwannomatosis; tumor suppressor syndromes
The design of electronic health records (EHR) to translate genomic medicine into clinical care is crucial to successful introduction of new genomic services, yet there are few published guides to implementation.
The design, implemented features, and evolution of a locally developed EHR that supports a large pharmacogenomics program at a tertiary care academic medical center was tracked over a 4-year development period.
Developers and program staff created EHR mechanisms for ordering a pharmacogenomics panel in advance of clinical need (preemptive genotyping) and in response to a specific drug indication. Genetic data from panel-based genotyping were sequestered from the EHR until drug-gene interactions (DGIs) met evidentiary standards and deemed clinically actionable. A service to translate genotype to predicted drug response phenotype populated a summary of DGIs, triggered inpatient and outpatient clinical decision support, updated laboratory records, and created gene results within online personal health records.
The design of a locally developed EHR supporting pharmacogenomics has generalizable utility. The challenge of representing genomic data in a comprehensible and clinically actionable format is discussed along with reflection on the scalability of the model to larger sets of genomic data.
To characterize cognition in individuals with germline PTEN mutations (N=23) as well as in PTEN mutation-negative individuals with classic Cowden Syndrome or Bannayan-Riley-Ruvalcaba Syndrome (N=2).
Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. Chi-square analyses compared these classifications to expected proportions in normal control samples.
The mean IQ was in the average range, and there was a wide range of intellectual functioning (extremely low to very superior). However, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall suggesting a pattern of frontal lobe dysfunction in a large subset of participants.
This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous association with intellectual disability, mean IQ was average, and there was a broad range of intellectual abilities. Specific evidence of frontal lobe dysfunction may have implications for treatment compliance and cancer surveillance and warrants further investigation.
PTEN; PTEN Hamartoma Tumor Syndromes; Cowden Syndrome; Bannayan-Riley-Ruvalcaba Syndrome; Cognition; Neuropsychology
Enzyme replacement therapy with rhGAA (Myozyme®) has lead to improved survival, which is largely attributable to improvements in cardiomyopathy and skeletal muscle function. However, crossreactive immunologic material-negative patients have a poor clinical response to enzyme replacement therapy secondary to high sustained antibody titers. Furthermore, although the majority of crossreactive immunologic material-positive patients tolerize or experience a downtrend in anti-rhGAA antibody titers, antibody response is variable with some crossreactive immunologic material-positive infants also mounting high sustained antibody titers.
We retrospectively analyzed 34 infants with Pompe disease: 11 crossreactive immunologic material-negative patients, nine high-titer crossreactive immunologic material-positive patients, and 14 low-titer crossreactive immunologic material-positive patients. Clinical outcome measures were overall survival, ventilator-free survival, left ventricular mass index, Alberta Infant Motor Scale score, and urine Glc4 levels.
Clinical outcomes in the high-titer crossreactive immunologic material-positive group were poor across all areas evaluated relative to the low-titer crossreactive immunologic material-positive group. For the crossreactive immunologic material-negative and high-titer crossreactive immunologic material-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly.
Our data indicate that, irrespective of crossreactive immunologic material status, patients with infantile Pompe disease with high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. With the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical.
Pompe disease; enzyme replacement therapy (ERT); crossreactive immunologic material (CRIM); CRIM negative (CN); high sustained antibody titers (HSAT); high-titer CRIM-positive (HTCP); low-titer CRIM-positive (LTCP); therapeutic proteins
There is uncertainty about when personalized medicine tests provide economic value. We assessed evidence on the economic value of personalized medicine tests and gaps in the evidence base.
We created a unique evidence base by linking data on published cost–utility analyses from the Tufts Cost-Effectiveness Analysis Registry with data measuring test characteristics and reflecting where value analyses may be most needed: (i) tests currently available or in advanced development, (ii) tests for drugs with Food and Drug Administration labels with genetic information, (iii) tests with demonstrated or likely clinical utility, (iv) tests for conditions with high mortality, and (v) tests for conditions with high expenditures.
We identified 59 cost–utility analyses studies that examined personalized medicine tests (1998–2011). A majority (72%) of the cost/quality-adjusted life year ratios indicate that testing provides better health although at higher cost, with almost half of the ratios falling below $50,000 per quality-adjusted life year gained. One-fifth of the results indicate that tests may save money.
Many personalized medicine tests have been found to be relatively cost-effective, although fewer have been found to be cost saving, and many available or emerging medicine tests have not been evaluated. More evidence on value will be needed to inform decision making and assessment of genomic priorities.
cost-effectiveness; economic value; ethical/legal/social implications (ELSI); genetic tests; personalized medicine
Genome-scale clinical sequencing is being adopted more broadly in medical practice. The National Institutes of Health developed the Clinical Sequencing Exploratory Research (CSER) program to guide implementation and dissemination of best practices for the integration of sequencing into clinical care. This study describes and compares the state of the art of incorporating whole-exome and whole-genome sequencing results into the electronic health record, including approaches to decision support across the six current CSER sites.
The CSER Medical Record Working Group collaboratively developed and completed an in-depth survey to assess the communication of genome-scale data into the electronic health record. We summarized commonalities and divergent approaches.
Despite common sequencing platform (Illumina) adoptions, there is a great diversity of approaches to annotation tools and workflow, as well as to report generation. At all sites, reports are human-readable structured documents available as passive decision support in the electronic health record. Active decision support is in early implementation at two sites.
The parallel efforts across CSER sites in the creation of systems for report generation and integration of reports into the electronic health record, as well as the lack of standardized approaches to interfacing with variant databases to create active clinical decision support, create opportunities for cross-site and vendor collaborations.
clinical decision support; clinical sequencing; decision support rules; electronic health record; electronic medical record; next-generation sequencing
Enzyme replacement therapy with alglucosidase alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors.
Inclusion criteria included ventilator-free status and age ≤6 months at treatment initiation, and survival to age ≥5 years. Clinical outcome measures included invasive ventilator-free survival and parameters for cardiac, pulmonary, musculoskeletal, gross motor and ambulatory status; growth; speech, hearing, and swallowing; and gastrointestinal and nutritional status.
Eleven of 17 patients met study criteria. All were cross-reactive immunologic material-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range: 5.4 to 12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux disease, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers.
Long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings.
acid maltase deficiency; enzyme replacement therapy; glycogen storage disease type II; neuromuscular diseases; Pompe disease
Most discussions of researchers’ duties to return incidental findings or research results to research participants or repository contributors fail to provide an adequate theoretical grounding for such duties. Returning findings is a positive duty, a duty to help somebody. Typically, such duties are specified narrowly such that helping is only a duty when it poses little or no risk or burden to the helper and does not interfere with her legitimate aims. Under current budgetary and personnel constraints, and with currently available information technology, routine return of individual findings from research using repository materials would constitute a substantial burden on the scientific enterprise and would seriously frustrate the aims of both scientists and specimen/data contributors. In most cases, researchers’ limited duties to help repository contributors probably can be fulfilled by some action less demanding than returning individual findings. Furthermore, the duty-to-return issue should be analyzed as a conflict between (possibly) helping some contributors now and (possibly) helping a greater number of people who would benefit in the future from the knowledge produced by research.
biobank; duties; genomics; research ethics; supererogation
The aim of this study was to determine the frequency with which medical geneticists discuss the psychiatric manifestations of 22q11.2 deletion syndrome (22q11DS) with families in relation to the frequency with which they discuss the other manifestations of the syndrome and to explore relationships between discussion of these features and stigma toward psychiatric disorders.
We surveyed medical geneticists in the United States and Canada regarding the frequency with which they discuss various features of 22q11DS with families in the context of four clinical scenarios in which only the age of the patient at diagnosis differed. Respondents also completed a 20-item validated psychometric measure of stigma towards psychiatric disorders.
308/546 medical geneticists completed the survey (56% response rate). Psychiatric disorders were discussed significantly less often than other features of 22q11DS (p<0.0001), but psychiatric disorders were discussed significantly more often when the patient was ≥ 13 years old (p<0.0001), than when the patient was younger. Geneticists who discussed psychiatric disorders the least had significantly higher levels of stigma towards psychiatric disorders (p=0.007).
Psychiatric risks are less often discussed with families during childhood. Education for physicians to help reduce stigma towards psychiatric disorders (which may impede discussion of psychiatric disorders) may warrant exploration in this population.
PMID: 23579435 CAMSID: cams3095
22q11.2 deletion syndrome; medical geneticists; psychiatric disorders; stigma; mental illness
As genomic and exomic testing expands in both the research and clinical arenas, determining whether, how, and which incidental findings to return to the ordering clinician and patient becomes increasingly important. Although opinion is varied on what should be returned to consenting patients or research participants, most experts agree that return of medically actionable results should be considered. There is insufficient evidence to fully inform evidence-based clinical practice guidelines regarding return of results from genome-scale sequencing, and thus generation of such evidence is imperative, given the rapidity with which genome-scale diagnostic tests are being incorporated into clinical care. We present an overview of the approaches to incidental findings by members of the Clinical Sequencing Exploratory Research network, funded by the National Human Genome Research Institute, to generate discussion of these approaches by the clinical genomics community. We also report specific lists of “medically actionable” genes that have been generated by a subset of investigators in order to explore what types of findings have been included or excluded in various contexts. A discussion of the general principles regarding reporting of novel variants, challenging cases (genes for which consensus was difficult to achieve across Clinical Sequencing Exploratory Research network sites), solicitation of preferences from participants regarding return of incidental findings, and the timing and context of return of incidental findings are provided.
actionability; actionable genes; clinical sequencing; genomic medicine; incidental findings
To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development.
evidence-based medicine/methods; evidence-based medicine/standards; genetics; genomics/methods; genomics/standards; medical/methods
To determine the specific components of family history and personal characteristics related to disease perceptions about breast, colon, and ovarian cancers.
Baseline, cross-sectional data on 2,505 healthy women aged 35–65 years enrolled from 41 primary care practices in the cluster-randomized Family Healthware™ Impact Trial, assessed for detailed family history and perceived risk, perceived severity, worry, and perceived control over getting six common diseases including breast, colon, and ovarian cancers.
Participants provided family history information on 41,841 total relatives. We found evidence of underreporting of paternal family history and lower perceived breast cancer risk with cancer in the paternal versus maternal lineage. We observed cancer-specific perceived risks and worry for individual family history elements and also found novel “spillover” effects where a family history of one cancer was associated with altered disease perceptions of another. Having a mother with early-onset breast or ovarian cancer was strongly associated with perceived risk of breast cancer. Age, parenthood, and affected lineage were associated with disease perceptions and ran counter to empiric risks.
Understanding patients' formulation of risk for multiple diseases is important for public health initiatives that seek to inform risk appraisal, influence disease perceptions, or match preventive interventions to existing risk perceptions.
family history; health knowledge; attitudes; practice; neoplasms; risk assessment; risk perception
Studies have found that people are interested in receiving their individual research results (IRRs) in exchange for participating in genetic studies. However, it is unclear whether the public understands the nature and limitations of these results and whether they would want information with little or no clinical utility.
We conducted 10 focus groups in three U.S. cities to examine the types of results they would want to learn, the perceived value of results with little or no clinical utility, and how individuals might prioritize the value of different types of IRRs.
Nearly all focus group participants said they would want at least some IRRs returned. Priority was placed on results that are well understood. Less important to participants were magnitude of the risk conferred and actionability of the result. In addition to wanting results that will help treat or prevent disease, participants identified other potential clinical and personal reasons for wanting IRRs. Many believed the study had an obligation to return IRRs and that the study should trade off sample size to meet the perceived obligation of returning results. Although most people would prefer to receive as much information as possible, many were willing to accept the return of a limited set of results in exchange for their participation.
Members of the public understood the nuances and limitations that are likely to apply to most IRRs. Researchers and others deciding the value of returning a given result should not base their decision on actionability of the information alone. Rather, they should consider broadening their definition of clinical utility to include the possible personal utility of information.
individual; results; research; genetic; IRR
The inclusion of genomic data in the electronic health record raises important ethical, legal, and social issues. In this article, we highlight these challenges and discuss potential solutions. We provide a brief background on the current state of electronic health records in the context of genomic medicine, discuss the importance of equitable access to genome-enabled electronic health records, and consider the potential use of electronic health records for improving genomic literacy in patients and providers. We highlight the importance of privacy, access, and security, and of determining which genomic information is included in the electronic health record. Finally, we discuss the challenges of reporting incidental findings, storing and reinterpreting genomic data, and nondocumentation and duty to warn family members at potential genetic risk.
clinical decision support, electronic health records; ethical, legal, and social implications; genomics; personalized medicine
Integrating genomic information into clinical care and the electronic health record can facilitate personalized medicine through genetically guided clinical decision support. Stakeholder involvement is critical to the success of these implementation efforts. Prior work on implementation of clinical information systems provides broad guidance to inform effective engagement strategies. We add to this evidence-based recommendations that are specific to issues at the intersection of genomics and the electronic health record. We describe stakeholder engagement strategies employed by the Electronic Medical Records and Genomics Network, a national consortium of US research institutions funded by the National Human Genome Research Institute to develop, disseminate, and apply approaches that combine genomic and electronic health record data. Through select examples drawn from sites of the Electronic Medical Records and Genomics Network, we illustrate a continuum of engagement strategies to inform genomic integration into commercial and homegrown electronic health records across a range of health-care settings. We frame engagement as activities to consult, involve, and partner with key stakeholder groups throughout specific phases of health information technology implementation. Our aim is to provide insights into engagement strategies to guide genomic integration based on our unique network experiences and lessons learned within the broader context of implementation research in biomedical informatics. On the basis of our collective experience, we describe key stakeholder practices, challenges, and considerations for successful genomic integration to support personalized medicine.
electronic health records; genomics; health information technology; personalized medicine; stakeholder engagement; translational medical research
We sought to estimate age-specific risk of Parkinson disease in relatives of patients with Gaucher disease, who are obligate carriers of GBA mutations and who were not ascertained by family history of Parkinson disease.
A validated family history of Parkinson disease questionnaire was administered to 119 patients with Gaucher disease who were evaluated at the Mount Sinai School of Medicine from 2009 to 2012; the ages of their parents, siblings, and children, history of Parkinson disease, age at onset of Parkinson disease, and ethnic background were obtained. Kaplan–Meier survival curves were used to estimate age-specific Parkinson disease penetrance among parents of patients with Gaucher disease, who are obligatory GBA mutation carriers.
Two participants with Gaucher disease were affected by Parkinson disease (5.4% of those who were 60 years or older). Of the 224 informative parents of patients with Gaucher disease, 11 had Parkinson disease (4.9%). Among the parents (obligatory carriers), cumulative risk of Parkinson disease by ages 65 and 85 was estimated to be 2.2% ±2.1% and 10.9% ±7.2%, respectively.
We provide useful age-specific estimates of Parkinson disease penetrance in patients with Gaucher disease and GBA heterozygous carriers for genetic counseling. Although GBA mutations may increase the risk for PD, the vast majority of patients with Gaucher disease and heterozygotes may not develop the disease. Further studies are needed to identify what modifies the risk of Parkinson disease in GBA mutation carriers.
family history; Gaucher disease; GBA mutations; glucocerebrosidase; Parkinson disease; risk
Clinical whole exome and whole genome sequencing will result in a broad range of incidental findings (IFs), but clinicians’ obligations to identify and disclose such findings are a matter of debate. We sought legal cases that could offer insights into clinicians’ legal liability.
We searched for cases in which IFs were related to the cause of action, using the search engines WestLaw, WestLaw Next, Lexis, and Lexis Advance.
We found no case law related to IFs from genetic testing, but identified eight cases involving IFs in medical imaging. These cases suggest that clinicians may face liability for failing to disclose IFs that would have offered an opportunity for interventions to improve health outcome, if (1) under the applicable standard of care, they fail to identify or appreciate the significance of the IF; or 2) they negligently fail to notify other clinicians and/or the patient of the identified IF. Other cases support liability for failure to refer appropriately to a clinician with greater expertise.
Clinicians may face liability if they fail to disclose incidental information that could inform interventions to improve health outcome; information lacking clinical actionability is likely to have less import.
Genomic microarrays can detect copy number variants not detectable by conventional cytogenetics. This technology is diffusing rapidly into prenatal settings even though the clinical implications of many copy number variants are currently unknown. We conducted a qualitative pilot study to explore the experiences of women receiving abnormal results from prenatal microarray testing performed in a research setting.
Participants were a subset of women participating in a multicenter prospective study “Prenatal Cytogenetic Diagnosis by Array-based Copy Number Analysis”. Telephone interviews were conducted with 23 women receiving abnormal prenatal microarray results.
We found that five key elements dominated the experiences of women who had received abnormal prenatal microarray results: an offer too good to pass up, blindsided by the results, uncertainty and unquantifiable risks, need for support, and toxic knowledge.
As prenatal microarray testing is increasingly utilized, uncertain findings will be common resulting in greater need for careful pre and post test counseling, and more education of, and resources for providers so they can adequately support the women who are undergoing testing.
prenatal diagnosis; microarray testing; qualitative research; genetic counseling
Health care has become increasingly information intensive. The advent of genomic data, integrated into patient care, significantly accelerates the complexity and amount of clinical data. Translational research in the present day increasingly embraces new biomedical discovery in this data-intensive world, thus entering the domain of “big data.” The Electronic Medical Records and Genomics consortium has taught us many lessons, while simultaneously advances in commodity computing methods enable the academic community to affordably manage and process big data. Although great promise can emerge from the adoption of big data methods and philosophy, the heterogeneity and complexity of clinical data, in particular, pose additional challenges for big data inferencing and clinical application. However, the ultimate comparability and consistency of heterogeneous clinical information sources can be enhanced by existing and emerging data standards, which promise to bring order to clinical data chaos. Meaningful Use data standards in particular have already simplified the task of identifying clinical phenotyping patterns in electronic health records.
clinical data representation; big data; genomics; health information technology standards
General practitioners (GPs) are increasingly expected to deliver genetics services in daily patient care. Education in primary care genetics is considered suboptimal and in urgent need of revision and innovation. The aim of this study was to prioritize topics for genetics education for general practice.
A Delphi consensus procedure consisting of three rounds was conducted. A purposively selected heterogeneous panel (n = 18) of experts, comprising six practicing GPs who were also engaged in research, five GP trainers, four clinical genetics professionals, and three representatives of patient organizations, participated. Educational needs regarding genetics in general practice in terms of knowledge, skills, and attitudes were rated and ranked in a top-10 list.
The entire panel completed all three rounds. Kendall's coefficient of concordance indicated significant agreement regarding the top 10 genetic education needs (P < 0.001). “Recognizing signals that are potentially indicative of a hereditary component of a disease” was rated highest, followed by “Evaluating indications for referral to a clinical genetics centre” and “Knowledge of the possibilities and limitations of genetic tests.”
The priorities resulting from this study can inform the development of educational modules, including input for case-based education, to improve GP performance in genetic patient care.
Delphi technique; general practice; genetics; health education; primary health care
Recent recommendations by the American College of Medical Genetics and Genomics (ACMG) for reporting incidental findings present novel ethical and legal issues. This article expresses no views on the ethical aspects of these recommendations and focuses strictly on liability risks and how to minimize them. The recommendations place labs and clinicians in a new liability environment that exposes them to intentional tort lawsuits as well to traditional suits for negligence. Intentional tort suits are especially troubling because of their potential to inflict ruinous personal financial losses on individual clinicians and laboratory personnel. This article surveys this new liability landscape and describes analytical approaches for minimizing tort liabilities. To a considerable degree, liability risks can be controlled by structuring activities in ways that make future lawsuits nonviable before the suits ever arise. Proactive liability analysis is an effective tool for minimizing tort liabilities in connection with the testing and reporting activities that the ACMG recommends.
genetic testing; incidental findings; intentional torts; legal defenses; medical malpractice; negligence; return of results
The promise of personalized genomics for common complex diseases depends, in part, on the ability to predict genetic risks on the basis of single nucleotide polymorphisms. We examined and compared the methods of three companies (23andMe, deCODEme, and Navigenics) that have offered direct-to-consumer personal genome testing.
We simulated genotype data for 100,000 individuals on the basis of published genotype frequencies and predicted disease risks using the methods of the companies. Predictive ability for six diseases was assessed by the AUC.
AUC values differed among the diseases and among the companies. The highest values of the AUC were observed for age related macular degeneration, celiac disease, and Crohn disease. The largest difference among the companies was found for celiac disease: the AUC was 0.73 for 23andMe and 0.82 for deCODEme. Predicted risks differed substantially among the companies as a result of differences in the sets of single nucleotide polymorphisms selected and the average population risks selected by the companies, and in the formulas used for the calculation of risks.
Future efforts to design predictive models for the genomics of common complex diseases may benefit from understanding the strengths and limitations of the predictive algorithms designed by these early companies.
Turner syndrome (TS) is a developmental disorder caused by partial or complete monosomy for the X chromosome in 1:2500 females. We hypothesized that single nucleotide polymorphism (SNP) array genotyping can provide superior resolution in comparison to metaphase karyotype analysis to facilitate genotype-phenotype correlations.
We genotyped 187 TS patients with 733,000 SNP marker arrays. All cases met diagnostic criteria for TS based on karyotypes (60%) or characteristic physical features. SNP array results confirmed the diagnosis of TS in 100% of cases.
We identified a single X chromosome (45,X) in 113 cases. In 58 additional cases (31%), other mosaic cell lines were present including isochromosomes (16%), rings (5%) and Xp deletions (8%). The remaining cases were mosaic for monosomy X and normal male or female cell lines. Array-based models of X chromosome structure were compatible with karyotypes in 104 of 116 comparable cases (90%). We found that SNP array data did not detect X;autosome translocations (3 cases), but did identify 2 derivative Y chromosomes and 13 large copy number variants that were not detected by karyotyping.
Our data is the first systematic comparison between the two methods and supports the utility of SNP array genotyping to address clinical and research questions in TS.
Turner Syndrome; Array; sex chromosomes; Karyotype; Cytogenetics; diagnosis