Research Conducted Using Data Obtained through Online Communities: Ethical Implications of Methodological Limitations

An Essay by A. Cecile Janssens and Peter Kraft discusses the limitations inherent in research involving collection of self-reported data by self-selected participants, and makes proposals for upfront communication of such limitations to study participants

Perspectives on the Use of Multiple Sclerosis Risk Genes for Prediction

Objective: A recent collaborative genome-wide association study replicated a large number of susceptibility loci and identified novel loci. This increase in known multiple sclerosis (MS) risk genes raises questions about clinical applicability of genotyping. In an empirical set we assessed the predictive power of typing multiple genes. Next, in a modelling study we explored current and potential predictive performance of genetic MS risk models. Materials and Methods: Genotype data on 6 MS risk genes in 591 MS patients and 600 controls were used to investigate the predictive value of combining risk alleles. Next, the replicated and novel MS risk loci from the recent and largest international genome-wide association study were used to construct genetic risk models simulating a population of 100,000 individuals. Finally, we assessed the required numbers, frequencies, and ORs of risk SNPs for higher discriminative accuracy in the future. Results: Individuals with 10 to 12 risk alleles had a significantly increased risk compared to individuals with the average population risk for developing MS (OR 2.76 (95% CI 2.02-3.77)). In the simulation study we showed that the area under the receiver operating characteristic curve (AUC) for a risk score based on the 6 SNPs was 0.64. The AUC increases to 0.66 using the well replicated 24 SNPs and to 0.69 when including all replicated and novel SNPs (n = 53) in the risk model. An additional 20 SNPs with allele frequency 0.30 and ORs 1.1 would be needed to increase the AUC to a slightly higher level of 0.70, and at least 50 novel variants with allele frequency 0.30 and ORs 1.4 would be needed to obtain an AUC of 0.85. Conclusion: Although new MS risk SNPs emerge rapidly, the discriminatory ability in a clinical setting will be limited

PredictABEL: an R package for the assessment of risk prediction models

The rapid identification of genetic markers for multifactorial diseases from genome-wide association studies is fuelling interest in investigating the predictive ability and health care utility of genetic risk models. Various measures are available for the assessment of risk prediction models, each addressing a different aspect of performance and utility. We developed PredictABEL, a package in R that covers descriptive tables, measures and figures that are used in the analysis of risk prediction studies such as measures of model fit, predictive ability and clinical utility, and risk distributions, calibration plot and the receiver operating characteristic plot. Tables and figures are saved as separate files in a user-specified format, which include publication-quality EPS and TIFF formats. All figures are available in a ready-made layout, but they can be customized to the preferences of the user. The package has been developed for the analysis of genetic risk prediction studies, but can also be used for studies that only include non-genetic risk factors. PredictABEL is freely available at the websites of GenABEL (http://www.genabel.org) and CRAN (http://cran.r-project.org/)

Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement

Cecile Janssens and colleagues present the GRIPS Statement, a checklist to help strengthen the reporting of genetic risk prediction studies

Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration

The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis

The ‘Common Disease-Common Variant’ Hypothesis and Familial Risks

The recent large genotyping studies have identified a new repertoire of disease susceptibility loci of unknown function, characterized by high allele frequencies and low relative risks, lending support to the common disease-common variant (CDCV) hypothesis. The variants explain a much larger proportion of the disease etiology, measured by the population attributable fraction, than of the familial risk. We show here that if the identified polymorphisms were markers of rarer functional alleles they would explain a much larger proportion of the familial risk. For example, in a plausible scenario where the marker is 10 times more common than the causative allele, the excess familial risk of the causative allele is over 10 times higher than that of the marker allele. However, the population attributable fractions of the two alleles are equal. The penetrance mode of the causative locus may be very difficult to deduce from the apparent penetrance mode of the marker locus

Clinical characteristics of subsequent histologically confirmed meningiomas in long-term childhood cancer survivors:A Dutch LATER study

Background: Meningiomas are the most frequent brain tumours occurring after pediatric cranial radiotherapy (CrRT). Data on course of disease, to inform clinical management of meningiomas, are sparse. This study reports the clinical characteristics of histologically confirmed meningiomas in childhood cancer survivors (CCS) in the Netherlands.& nbsp; Methods: In total, 6015 CCS from the Dutch Long-Term Effects After Childhood Cancer (LATER) cohort were eligible, including 1551 with prior CrRT. These CCS were diagnosed with cancer ag