BACKGROUND AND AIM

1. Challenges in conducting a systematic review of the diagnostic accuracy of genetic tests: an example of the genetic diagnosis of familial hypercholesterolaemia P Sharma1, G Mowatt1, F Stewart1, C Boachie1, Z Miedzybrodzka2, W Simpson4, D Boyers1,3, M Kilonzo3, P McNamee3 Health Services Research Unit, University of Aberdeen, 2. Clinical Genetics Centre, University of Aberdeen, 3. Health Economics Research Unit, University of Aberdeen, 4. Clinical Biochemistry Laboratory, NHS Grampian, Aberdeen. CONTACT: Pawana Sharma at p.sharma@abdn.ac.uk RESULTS - QUALITATIVE ANALYSIS BACKGROUND AND AIM The availability and uptake of genetic tests is increasing. In 2010 the Aberdeen HTA group were commissioned by the UK National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme to undertake a systematic review of Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia1on behalf of the National Institute for Health and Care Excellence (NICE) Diagnostics Assessment Programme. Figure 1: Key methodological challenges in conducting a systematic review of the diagnostic accuracy of genetic tests AIM: To explore the methodological challenges involved in undertaking a systematic review of the diagnostic accuracy of genetic tests. METHODS • 1) Descriptive analysis of the issues encountered and measures undertaken to resolve these issues during the conduct of the systematic review1(Table 1). • 2) Comparative analysis to assess the extent to which the issues faced during this review were also encountered by other reviews. This comprised: • Overview of systematic reviews of the diagnostic accuracy of genetic tests • Qualitative analysis of the methodological aspects (for example, whether or not meta-analysis was performed, susceptibility to bias, quality of reporting etc.) • Quantitative assessment of clinical validity,(for example, by comparing the proportion of studies that reported diagnostic indices such as sensitivity, specificity, and the variability of these results) RESULTS - QUANTITATIVE ASSESSMENT OF CLINICAL VALIDITY RESULTS - DESCRIPTIVE ANALYSIS Figure 2: Diagnostic indices and variability of these results as reported by the studies included in three reviews Table 1: Examples of issues encountered, measures undertaken to resolve the issues and suggested recommendations CONCLUSIONS • Genetic tests are continuing to evolve, reviewers should obtain input from scientific/technical experts from the study design phase and undertake intensive scoping of the review question. • The paucity of well designed studies included in the three genetic test reviews made a valid assessment of the tests difficult. Study investigators should design studies to allow calculation of specificity as well as sensitivity where possible. REFERENCES • Sharma P et al. Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia: a systematic review and economic evaluation. Health Technol Assess 2012;16(17). • Bryant J et al. A systematic review of the clinical validity and clinical utility of DNA testing for hereditary haemochromatosis type 1 in at-risk populations. J Med Genet 2008;45:513-518. • Gerhardus A et al. Diagnostic accuracy of methods for the detection of BRCA1 and BRCA2 mutations: a systematic review. European Journal of Human genetics, 2007;15:619-627. ACKNOWLEDGMENTS RESULTS - COMPARATIVE ANALYSIS The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.  The systematic review of Elucigene FH20 and LIPOchip was funded by the HTA programme (project number 10/70/01) and published in Health Technol. Assess. 2012;16(17).  Further information available at: http://www.hta.ac.uk/project/2450.asp. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Chief Scientist Office, HTA programme, NIHR, NICE, NHS or the Department of Health. We thank the NICE assessment subgroup specialist members and Lara Kemp, Cynthia Fraser and Graeme MacLennan for their support. Two additional systematic reviews2,3 of the diagnostic accuracy of genetic tests were selected for comparison. Six major methodological challenges were identified from the three reviews (Figure 1). A quantitative assessment of clinical validity is presented in Figure 2. Website: http://www.abdn.ac.uk/hsru