Case Report: Direct Access Genetic Testing and A False-Positive Result For Long QT Syndrome.

We report the case of a woman who pursued direct access genetic testing and then presented with concerns regarding a positive test result for Long-QT syndrome. Although the result ultimately proved to be a false positive, this case illustrates that costs associated with follow-up of direct access genetic testing results can be non-trivial for both the patient and for health care systems. Here we raise policy questions regarding the appropriate distribution of these costs. We also discuss the possibility that, when confronted by a direct access genetic test result that reports high risk for one or more actionable diseases, a family physician might feel compelled to act out of a desire to avoid liability, even when information regarding the accuracy and validity of the testing were not easily accessible. This case outlines lessons that can easily be translated into clinical practice, not only by genetic counselors, but also by family physicians, medical specialists and members of the public.

A Systematic Review on the Cost-Effectiveness of Genetic and Electrocardiogram Testing for Long QT Syndrome in Infants and Young Adults.

BACKGROUND: Recent improvements in the identification of the genetic basis of long QT syndrome (LQTS) have led to significant changes in the diagnosis and management of this life-threatening condition. Genetic and electrocardiogram (ECG) tests are the most relevant examples among testing strategies for LQTS, yet their cost-effectiveness remains controversial. OBJECTIVE: The aim of this work was to review the available evidence on the cost-effectiveness of genetic and ECG testing strategies for the diagnosis of LQTS. METHODS: We performed a systematic review of the literature on the cost-effectiveness of genetic and ECG screening strategies for the early detection of LQTS using MEDLINE, EMBASE, and CRD databases between 2000 and 2013. A weighted version of Drummond checklist was instrumental in further assessing the quality of the included studies. RESULTS: We identified four eligible articles. Among them, genetic testing in the early detection of LQTS was cost-effective compared with no testing in symptomatic cases and not cost-effective when compared with watchful waiting in asymptomatic first-degree relatives of patients with established LQTS although it reached cost-effectiveness in higher risk subgroups, whereas ECG testing in neonates was highly cost-effective when compared with any screening strategy. CONCLUSIONS: LQTS profiling and patients' stratification have the potential to improve the disease management. Because of the limited current knowledge in this field, the present review recommends to perform further cost-effectiveness evaluations of the genetic and ECG screening alternatives, especially within European health care systems, which are still not available in the literature on genetic testing.

Sertindole in schizophrenia: efficacy and safety issues.

INTRODUCTION: Despite substantial progress in the pharmacological treatment of schizophrenia, antipsychotic drugs are associated with insufficient effects on negative and cognitive symptoms, adverse events, poor compliance and drug discontinuation. Sertindole , first withdrawn from the market for cardiovascular safety concerns, is currently available in many countries. It has high affinity for dopamine D2, serotonin 5-HT2A, 5-HT2C and a1-adrenergic receptors, and a low potential for extrapyramidal symptoms. AREAS COVERED: The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and tolerability, and cost-effectiveness of sertindole are covered in this article, based on a literature review (PubMed) from 1990 to 2014. EXPERT OPINION: The reviewed studies suggest a beneficial effect of sertindole on positive, negative and cognitive symptoms, and on relapse prevention. Although generally well tolerated, sertindole is associated with a dose-related QT-interval prolongation; thus, its administration requires electrocardiogram screening and monitoring. The presence of congenital long QT syndrome, prolongated QTc at baseline, cardiac disease and drug interactions should be carefully considered before prescribing sertindole. Further direct 'head-to-head' comparisons with other second-generation antipsychotics (SGAs), trials on special populations and further clarification on cardiac safety are needed to better define the role of sertindole in the treatment of schizophrenia.

Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases.

BACKGROUND: Genetic testing for long QT syndrome (LQTS) has been available in a research setting for the past decade, and a commercial test has recently become available. However, the costs and effectiveness of genetic testing have not been estimated. OBJECTIVES: The purpose of this study was to conduct a cost-effectiveness analysis of genetic testing in the management of patients who have or are suspected to have familial LQTS. METHODS: We examined the incremental cost-effectiveness of genetic testing compared with no genetic testing for symptomatic index cases and how this varied according to changes in assumptions and data inputs. Data were obtained from the published literature and a clinical cohort. RESULTS: We found that genetic testing is more cost-effective than not testing for symptomatic index cases at an estimated cost of 2,500 US dollar per year of life saved. These results were generally robust, although they were sensitive to some data inputs such as the cost of testing and the mortality rate among untreated individuals with LQTS. CONCLUSION: A genetic test for familial LQTS is cost-effective relative to no testing, given our assumptions about the population to be tested and the relevant probabilities and costs. The primary benefit of testing is to more accurately diagnose and treat individuals based on a combination of clinical scores and test results. Future economic analyses of testing for familial LQTS should consider the potential benefits of genetic testing of broader populations, including family members.

Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation.

Regulatory authorities require new drugs to be investigated using a so-called "thorough QT/QTc study" to identify compounds with a potential of influencing cardiac repolarization in man. Presently drafted regulatory consensus requires these studies to be powered for the statistical detection of QTc interval changes as small as 5 ms. Since this translates into a noticeable drug development burden, strategies need to be identified allowing the size and thus the cost of thorough QT/QTc studies to be minimized. This study investigated the influence of QT and RR interval data quality and the precision of heart rate correction on the sample sizes of thorough QT/QTc studies. In 57 healthy subjects (26 women, age range 19-42 years), a total of 4,195 drug-free digital electrocardiograms (ECG) were obtained (65-84 ECGs per subject). All ECG parameters were measured manually using the most accurate approach with reconciliation of measurement differences between different cardiologists and aligning the measurements of corresponding ECG patterns. From the data derived in this measurement process, seven different levels of QT/RR data quality were obtained, ranging from the simplest approach of measuring 3 beats in one ECG lead to the most exact approach. Each of these QT/RR data-sets was processed with eight different heart rate corrections ranging from Bazett and Fridericia corrections to the individual QT/RR regression modelling with optimization of QT/RR curvature. For each combination of data quality and heart rate correction, standard deviation of individual mean QTc values and mean of individual standard deviations of QTc values were calculated and used to derive the size of thorough QT/QTc studies with an 80% power to detect 5 ms QTc changes at the significance level of 0.05. Irrespective of data quality and heart rate corrections, the necessary sample sizes of studies based on between-subject comparisons (e.g., parallel studies) are very substantial requiring >140 subjects per group. However, the required study size may be substantially reduced in investigations based on within-subject comparisons (e.g., crossover studies or studies of several parallel groups each crossing over an active treatment with placebo). While simple measurement approaches with ad-hoc heart rate correction still lead to requirements of >150 subjects, the combination of best data quality with most accurate individualized heart rate correction decreases the variability of QTc measurements in each individual very substantially. In the data of this study, the average of standard deviations of QTc values calculated separately in each individual was only 5.2 ms. Such a variability in QTc data translates to only 18 subjects per study group (e.g., the size of a complete one-group crossover study) to detect 5 ms QTc change with an 80% power. Cost calculations show that by involving the most stringent ECG handling and measurement, the cost of a thorough QT/QTc study may be reduced to approximately 25%-30% of the cost imposed by the simple ECG reading (e.g., three complexes in one lead only).

Cost-effectiveness and implications of newborn screening for prolongation of QT interval for the prevention of sudden infant death syndrome.

OBJECTIVE: To determine the cost-effectiveness of universal and high-risk neonatal electrocardiographic (ECG) screening for QT prolongation as a predictor of sudden infant death syndrome (SIDS) risk in a theoretical group of neonates. STUDY DESIGN: Incremental cost-effectiveness analysis with decision analytic modeling. A hypothetical cohort of healthy, term infants was modeled, comparing options of no screening, high-risk neonate screening, and universal screening. The high-risk strategy is speculative, because no currently accepted methodology is known for identifying infants at high risk for SIDS. Given the uncertain mechanisms of association between prolonged corrected QT interval (QTc) and SIDS, analyses were repeated under different assumptions. Sensitivity analyses were also performed on all input variables for both costs and effectiveness. RESULTS: Under the assumption that neonatal electrocardiographic screening detects long QT syndrome responsive to conventional therapy, the cost-effectiveness of high-risk screening was $3403 per life year gained, whereas universal screening cost $18,465 per additional life year gained. However, if the effectiveness of SIDS therapy falls below 10%, the cost-effectiveness deteriorates to $28,376 per life year saved for the high-risk strategy and $118,900 for universal screening. The analyses were robust to a broad array of sensitivity analyses. CONCLUSIONS: The acceptability of the cost-effectiveness of neonatal electrocardiographic screening is heavily dependent on the pathophysiologic mechanism of SIDS and on the efficacy of monitoring and antiarrhythmic treatment. The nature of this association must be elucidated before routine neonatal electrocardiographic screening is warranted.