Simon Sanderson

Publications of Simon Sanderson

• Effectiveness of physical activity promotion based in primary care: systematic review and meta-analysis of randomised controlled trials.

  Authors: Gillian Orrow, Ann-Louise Kinmonth, Simon Sanderson, Stephen Sutton

  BMJ (Clinical research ed.). 01/2012; 344:e1389.

  To determine whether trials of physical activity promotion based in primary care show sustained effects on physical activity or fitness in sedentary adults, and whether exercise referralTo determine whether trials of physical activity promotion based in primary care show sustained effects on physical activity or fitness in sedentary adults, and whether exercise referral interventions are more effective than other interventions. Systematic review and meta-analysis of randomised controlled trials. Medline, CINAHL, PsycINFO, EMBASE, SPORTDiscus, Centre for Reviews and Dissemination, the Cochrane Library, and article reference lists. Review of randomised controlled trials of physical activity promotion in sedentary adults recruited in primary care, with minimum follow-up of 12 months, reporting physical activity or fitness (or both) as outcomes, and using intention to treat analyses. Two reviewers independently assessed studies for inclusion, appraised risk of bias, and extracted data. Pooled effect sizes were calculated using a random effects model. We included 15 trials (n=8745). Most interventions took place in primary care, included health professionals in delivery, and involved advice or counselling given face to face or by phone (or both) on multiple occasions. Only three trials investigated exercise referral. In 13 trials presenting self reported physical activity, we saw small to medium positive intervention effects at 12 months (odds ratio 1.42, 95% confidence interval 1.17 to 1.73; standardised mean difference 0.25, 0.11 to 0.38). The number needed to treat with an intervention for one additional sedentary adult to meet internationally recommended levels of activity at 12 months was 12 (7 to 33). In four trials reporting cardiorespiratory fitness, a medium positive effect at 12 months was non-significant (standardised mean difference 0.51, -0.18 to 1.20). Three trials of exercise referral found small non-significant effects on self reported physical activity at 12 months (odds ratio 1.38; 0.98 to 1.95; standardised mean difference 0.20, -0.21 to 0.61). Promotion of physical activity to sedentary adults recruited in primary care significantly increases physical activity levels at 12 months, as measured by self report. We found insufficient evidence to recommend exercise referral schemes over advice or counselling interventions. Primary care commissioners should consider these findings while awaiting further trial evaluation of exercise referral schemes and other primary care interventions, with longer follow-up and use of objective measures of outcome.

• What determines Self-Rated Health (SRH)? A cross-sectional study of SF-36 health domains in the EPIC-Norfolk cohort.

  Authors: Nahal Mavaddat, Ann Louise Kinmonth, Simon Sanderson, Paul Surtees, Sheila Bingham, Kay Tee Khaw

  Journal of epidemiology and community health. 09/2011; 65(9):800-6.

  Self-Rated Health (SRH) as assessed by a single-item measure is an independent predictor of health outcomes. However, it remains uncertain which elements of the subjective health experience it mostSelf-Rated Health (SRH) as assessed by a single-item measure is an independent predictor of health outcomes. However, it remains uncertain which elements of the subjective health experience it most strongly captures. In view of its ability to predict outcomes, elucidation of what determines SRH is potentially important in the provision of services. This study aimed to determine the extent to which dimensions of physical, mental and social functioning are associated with SRH. We studied 20,853 men and women aged 39-79 years from a population-based cohort study (European Prospective Investigation of Cancer study) who had completed an SRH (Short Form (SF)-1) measure and SF-36 questionnaire. SF-36 subscales were used to quantify dimensions of health best predicting poor or fair SRH within a logistic regression model. In multivariate models adjusting for age, gender, social class, medical conditions and depression, all subscales of the SF-36 were independently associated with SRH, with the Physical Functioning subscale more strongly associated with poor or fair compared with excellent, very good or good health (OR 3.7 (95% CI 3.3 to 4.1)) than Mental Health (OR 1.4 (95% CI 1.2 to 1.5)) or Social Functioning subscales (OR 1.8 (95% CI 1.6 to 2.0)) for those below and above the median. This study confirms that physical functioning is more strongly associated with SRH than mental health and social functioning, even where the relative associations between each dimension and SRH may be expected to differ, such as in those with depression. It suggests that the way people take account of physical, mental and social dimensions of function when rating their health may be relatively stable across groups.

• Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database.

  Authors: Ameet Sarpatwari, Dimitri Bennett, John W Logie, Amit Shukla, Kathleen J Beach, Adrian C Newland, Simon Sanderson, Drew Provan

  Haematologica. 02/2010; 95(7):1167-75.

  The risk of thromboembolic events in adults with primary immune thrombocytopenia has been little investigated despite findings of increased susceptibility in other thrombocytopenic autoimmuneThe risk of thromboembolic events in adults with primary immune thrombocytopenia has been little investigated despite findings of increased susceptibility in other thrombocytopenic autoimmune conditions. The objective of this study was to evaluate the risk of thromboembolic events among adult patients with and without primary immune thrombocytopenia in the UK General Practice Research Database. Using the General Practice Research Database, 1,070 adults (>or=18 years) with coded records for primary immune thrombocytopenia first referenced between January 1(st) 1992 and November 30(th) 2007, and having at least one year pre-diagnosis and three months post-diagnosis medical history were matched (1:4 ratio) with 4,280 primary immune thrombocytopenia disease free patients by age, gender, primary care practice, and pre-diagnosis observation time. The baseline prevalence and incidence rate of thromboembolic events were quantified, with comparative risk modelled by Cox's proportional hazards regression. Over a median 47.6 months of follow-up (range: 3.0-192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01-2.48), 1.37 (95% CI, 0.94-2.00), and 1.41 (95% CI, 1.04-1.91) were found for venous, arterial, and combined (arterial and venous) thromboembolic events, respectively, when comparing the primary immune thrombocytopenia cohort with the primary immune thrombocytopenia disease free cohort. Further event categorization revealed an elevated incidence rate for each occurring venous thromboembolic subtype among the adult patients with primary immune thrombocytopenia. Patients with primary immune thrombocytopenia are at increased risk for venous thromboembolic events compared with patients without primary immune thrombocytopenia.

• Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): randomised trial.

  Authors: Theresa M Marteau, Eleanor Mann, A Toby Prevost, Joana C Vasconcelos, Ian Kellar, Simon Sanderson, Michael Parker, Simon Griffin, Stephen Sutton, Ann Louise Kinmonth

  BMJ (Clinical research ed.). 01/2010; 340:c2138.

  To compare the effect of an invitation promoting informed choice for screening with a standard invitation on attendance and motivation to engage in preventive action. Randomised controlledTo compare the effect of an invitation promoting informed choice for screening with a standard invitation on attendance and motivation to engage in preventive action. Randomised controlled trial. Four English general practices. 1272 people aged 40-69 years, at risk for diabetes, identified from practice registers using a validated risk score and invited to attend for screening. Intervention was a previously validated invitation to inform the decision to attend screening, presenting diabetes as a serious potential problem, and providing details of possible costs and benefits of screening and treatment in text and pie charts. This was compared with a brief, standard invitation simply describing diabetes as a serious potential problem. The primary end point was attendance for screening. The secondary outcome measures were intention to make changes to lifestyle and satisfaction with decisions made among attenders. The primary end point was analysed for all 1272 participants. 55.8% (353/633) of those in the informed choice group attended for screening, compared with 57.6% (368/639) in the standard invitation group (mean difference -1.8%, 95% confidence interval -7.3% to 3.6%; P=0.51). Attendance was lower among the more deprived group (most deprived third 47.5% v least deprived third 64.3%; P<0.001). Interaction between deprivation and effect of invitation type on attendance was not significant. Among attenders, intention to change behaviour was strong and unaffected by invitation type. Providing information to support choice did not adversely affect attendance for screening for diabetes. Those from more socially deprived groups were, however, less likely to attend, regardless of the type of invitation received. Further attention to invitation content alone is unlikely to achieve equity in uptake of preventive services. Current Controlled Trials ISRCTN 73125647.

• Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects.

  Authors: Gurdeep S Sagoo, Adam S Butterworth, Simon Sanderson, Charles Shaw-Smith, Julian P T Higgins, Hilary Burton

  Genetics in medicine : official journal of the American College of Medical Genetics. 04/2009; 11(3):139-46.

  Array-based comparative genomic hybridization is being increasingly used in patients with learning disability (mental retardation) and congenital anomalies. In this article, we update our previousArray-based comparative genomic hybridization is being increasingly used in patients with learning disability (mental retardation) and congenital anomalies. In this article, we update our previous meta-analysis evaluating the diagnostic and false-positive yields of this technology. An updated systematic review and meta-analysis was conducted investigating patients with learning disability and congenital anomalies in whom conventional cytogenetic analyses have proven negative. Nineteen studies (13,926 patients) were included of which 12 studies (13,464 patients) were published since our previous analysis. The overall diagnostic yield of causal abnormalities was 10% (95% confidence interval: 8-12%). The overall number needed to test to identify an extra causal abnormality was 10 (95% confidence interval: 8-13). The overall false-positive yield of noncausal abnormalities was 7% (95% confidence interval: 5-10%). This updated meta-analysis provides new evidence to support the use of array-based comparative genomic hybridization in investigating patients with learning disability and congenital anomalies in whom conventional cytogenetic tests have proven negative. However, given that this technology also identifies false positives at a similar rate to causal variants, caution in clinical practice should be advised.

• Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): trial protocol.

  Authors: Eleanor Mann, A Toby Prevost, Simon Griffin, Ian Kellar, Stephen Sutton, Michael Parker, Simon Sanderson, Ann Louise Kinmonth, Theresa Marteau

  BMC public health. 03/2009; 9(1):63.

  ABSTRACT: BACKGROUND: Screening invitations have traditionally been brief, providing information only about population benefits. Presenting information about the limited individual benefits andABSTRACT: BACKGROUND: Screening invitations have traditionally been brief, providing information only about population benefits. Presenting information about the limited individual benefits and potential harms of screening to inform choice may reduce attendance, particularly in the more socially deprived. At the same time, amongst those who attend, it might increase motivation to change behavior to reduce risks. This trial assesses the impact on attendance and motivation to change behavior of an invitation that facilitates informed choices about participating in diabetes screening in general practice. Three hypotheses are tested: 1. Attendance at screening for diabetes is lower following an informed choice compared with a standard invitation. 2. There is an interaction between the type of invitation and social deprivation: attendance following an informed choice compared with a standard invitation is lower in those who are more rather than less socially deprived. 3. Amongst those who attend for screening, intentions to change behavior to reduce risks of complications in those subsequently diagnosed with diabetes are stronger following an informed choice invitation compared with a standard invitation. METHODS: 1500 people aged 40-69 years without known diabetes but at high risk are identified from four general practice registers in the east of England. 1200 participants are randomized by households to receive one of two invitations to attend for diabetes screening at their general practices. The intervention invitation is designed to facilitate informed choices, and comprises detailed information and a decision aid. A comparison invitation is based on those currently in use. Screening involves a finger-prick blood glucose test. The primary outcome is attendance for diabetes screening. The secondary outcome is intention to change health related behaviors in those attenders diagnosed with diabetes. A sample size of 1200 ensures 90% power to detect a 10% difference in attendance between arms, and in an estimated 780 attenders, 80% power to detect a 0.2 sd difference in intention between arms. DISCUSSION: The DICISION trial is a rigorous pragmatic denominator based clinical trial of an informed choice invitation to diabetes screening, which addresses some key limitations of previous trials.

• Impact of an informed choice invitation on uptake of screening for diabetes in primary care (DICISION): trial protocol

  Authors: Eleanor Mann, Prevost A Toby, Simon Griffin, Ian Kellar, Stephen Sutton, Michael Parker, Simon Sanderson, Ann Kinmonth, Theresa Marteau

  BMC Public Health. 01/2009;

  Abstract Background Screening invitations have traditionally been brief, providing information only about population benefits. Presenting information about the limited individual benefits andAbstract Background Screening invitations have traditionally been brief, providing information only about population benefits. Presenting information about the limited individual benefits and potential harms of screening to inform choice may reduce attendance, particularly in the more socially deprived. At the same time, amongst those who attend, it might increase motivation to change behavior to reduce risks. This trial assesses the impact on attendance and motivation to change behavior of an invitation that facilitates informed choices about participating in diabetes screening in general practice. Three hypotheses are tested: 1. Attendance at screening for diabetes is lower following an informed choice compared with a standard invitation. 2. There is an interaction between the type of invitation and social deprivation: attendance following an informed choice compared with a standard invitation is lower in those who are more rather than less socially deprived. 3. Amongst those who attend for screening, intentions to change behavior to reduce risks of complications in those subsequently diagnosed with diabetes are stronger following an informed choice invitation compared with a standard invitation. Method/Design 1500 people aged 40–69 years without known diabetes but at high risk are identified from four general practice registers in the east of England. 1200 participants are randomized by households to receive one of two invitations to attend for diabetes screening at their general practices. The intervention invitation is designed to facilitate informed choices, and comprises detailed information and a decision aid. A comparison invitation is based on those currently in use. Screening involves a finger-prick blood glucose test. The primary outcome is attendance for diabetes screening. The secondary outcome is intention to change health related behaviors in those attenders diagnosed with diabetes. A sample size of 1200 ensures 90% power to detect a 10% difference in attendance between arms, and in an estimated 780 attenders, 80% power to detect a 0.2 sd difference in intention between arms. Discussion The DICISION trial is a rigorous pragmatic denominator based clinical trial of an informed choice invitation to diabetes screening, which addresses some key limitations of previous trials. Trial registration Current Controlled Trials ISRCTN73125647

• Genetic tests for common diseases: new insights, old concerns.

  Authors: David Melzer, Stuart Hogarth, Katherine Liddell, Tom Ling, Simon Sanderson, Ron L Zimmern

  BMJ (Clinical research ed.). 04/2008; 336(7644):590-3.

• Turning the pump handle: evolving methods for integrating the evidence on gene-disease association.

  Authors: Julian P T Higgins, Julian Little, John P A Ioannidis, Molly S Bray, Teri A Manolio, Liam Smeeth, Jonathan A Sterne, Betsy Anagnostelis, Adam S Butterworth, John Danesh [......] Paul D Pharoah, Georgia Salanti, Simon Sanderson, Lesley A Smith, Emanuela Taioli, John R Thompson, Simon G Thompson, Neil Walker, Ron L Zimmern, Muin J Khoury

  American journal of epidemiology. 11/2007; 166(8):863-6.

• Joint effects of the N-acetyltransferase 1 and 2 (NAT1 and NAT2) genes and smoking on bladder carcinogenesis: a literature-based systematic HuGE review and evidence synthesis.

  Authors: Simon Sanderson, Georgia Salanti, Julian Higgins

  American journal of epidemiology. 11/2007; 166(7):741-51.

  Bladder cancer is an increasingly important international public health problem, with over 330,000 new cases being diagnosed each year worldwide. In a systematic review and evidence synthesis, theBladder cancer is an increasingly important international public health problem, with over 330,000 new cases being diagnosed each year worldwide. In a systematic review and evidence synthesis, the authors investigated the joint effects of the N-acetyltransferase genes NAT1 and NAT2 and cigarette smoking on bladder carcinogenesis. Studies were identified through an exhaustive search of multiple electronic databases and reference lists and through direct contact with study authors and experts. Random-effects meta-analysis was used within a Bayesian framework to investigate individual effects of NAT1 and NAT2 acetylation status on bladder cancer risk, while a novel approach was used to investigate joint effects of these two genes with cigarette smoking. An increased risk of bladder cancer was found in NAT2 slow acetylators (odds ratio = 1.46, 95% credible interval (CI): 1.26, 1.68) but not in NAT1 fast acetylators (odds ratio = 1.01, 95% CI: 0.86, 1.22). The joint effects in the highest risk category (NAT2 slow acetylator, NAT1 fast acetylator, and current or ever cigarette smoking) as compared with the reference category (NAT2 fast acetylator, NAT1 slow acetylator, and never smoking) were associated with an odds ratio of 2.73 (95% CI: 1.70, 4.31). The importance of considering joint effects between genetic and environmental factors in the etiology of common complex diseases is underlined.

• Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography.

  Authors: Simon Sanderson, Iain D Tatt, Julian P T Higgins

  International journal of epidemiology. 07/2007; 36(3):666-76.

  BACKGROUND: Assessing quality and susceptibility to bias is essential when interpreting primary research and conducting systematic reviews and meta-analyses. Tools for assessing quality in clinicalBACKGROUND: Assessing quality and susceptibility to bias is essential when interpreting primary research and conducting systematic reviews and meta-analyses. Tools for assessing quality in clinical trials are well-described but much less attention has been given to similar tools for observational epidemiological studies. METHODS: Tools were identified from a search of three electronic databases, bibliographies and an Internet search using Google. Two reviewers extracted data using a pre-piloted extraction form and strict inclusion criteria. Tool content was evaluated for domains potentially related to bias and was informed by the STROBE guidelines for reporting observational epidemiological studies. RESULTS: A total of 86 tools were reviewed, comprising 41 simple checklists, 12 checklists with additional summary judgements and 33 scales. The number of items ranged from 3 to 36 (mean 13.7). One-third of tools were designed for single use in a specific review and one-third for critical appraisal. Half of the tools provided development details, although most were proposed for future use in other contexts. Most tools included items for selection methods (92%), measurement of study variables (86%), design-specific sources of bias (86%), control of confounding (78%) and use of statistics (78%); only 4% addressed conflict of interest. The distribution and weighting of domains across tools was variable and inconsistent. CONCLUSION: A number of useful assessment tools have been identified by this report. Tools should be rigorously developed, evidence-based, valid, reliable and easy to use. There is a need to agree on critical elements for assessing susceptibility to bias in observational epidemiology and to develop appropriate evaluation tools.

• Array-based comparative genomic hybridization for investigating chromosomal abnormalities in patients with learning disability: systematic review meta-analysis of diagnostic and false-positive yields.

  Authors: Subu Subramonia-Iyer, Simon Sanderson, Gurdeep Sagoo, Julian Higgins, Hilary Burton, Ron Zimmern, Mark Kroese, Pippa Brice, Charles Shaw-Smith

  Genetics in medicine : official journal of the American College of Medical Genetics. 03/2007; 9(2):74-9.

  PURPOSE: Array-based comparative genomic hybridization is increasingly being used in patients with learning disability, in addition to existing cytogenetic techniques. This paper reports the resultsPURPOSE: Array-based comparative genomic hybridization is increasingly being used in patients with learning disability, in addition to existing cytogenetic techniques. This paper reports the results of an evaluation of this emerging technology and discusses the challenges faced in conducting the evaluation. METHODS: Systematic review and meta-analysis of studies investigating patients with learning disability and dysmorphic features in whom conventional cytogenetic analysis has proven negative. Conventional indices of clinical validity could not be calculated, and we use an alternative, based on the extent to which array-based comparative genomic hybridization met its clinical objectives. RESULTS: Seven studies (462 patients) were included. The overall diagnostic yield of causal abnormalities was 13% (95% confidence interval: 10-17%; heterogeneity test statistic I = 0%), and the overall number needed to test was eight (95% confidence interval: 6-10). The false-positive yield of noncausal abnormalities ranged from 5% to 67%, although this range was only 5% to 10% in six of the studies. CONCLUSION: Although promising, there is insufficient evidence to recommend introduction of this test into routine clinical practice. A number of important technical questions need answering, such as optimal array resolution, which clones to include, and the most appropriate platforms. A thorough assessment of clinical utility and cost-effectiveness compared with existing tests is also required.

• Closing the gaps--enhancing the regulation of genetic tests using responsive regulation.

  Authors: Stuart Hogarth, Kathy Liddell, Tom Ling, Simon Sanderson, Ron Zimmern, David Melzer

  Food and drug law journal. 02/2007; 62(4):831-48.

• Needs assessment and review of services for people with inherited metabolic disease in the United Kingdom.

  Authors: Hilary Burton, Simon Sanderson, Graham Shortland, Philip Lee

  Journal of inherited metabolic disease. 11/2006; 29(5):667-76.

  Patients with inherited metabolic diseases need to be viewed as a specialist care group because of the range of expertise required for their diagnosis and management. In the UK, professional concernsPatients with inherited metabolic diseases need to be viewed as a specialist care group because of the range of expertise required for their diagnosis and management. In the UK, professional concerns have been expressed that existing services would struggle to meet needs resulting from new diagnostic and screening techniques, new treatments and increased survival. This needs assessment and service review was therefore undertaken at the request of the Joint Committee on Medical Genetics, guided by a national multidisciplinary stakeholder group. All 24 specialist centres identified in the UK provided evidence for the review. Approximately 10 000 patients are known to services and their annual number of referrals is increasing. Possible shortfalls in the number of patients attending specialist services were estimated for the UK as a whole by extrapolating the results from the region with the most comprehensive service and comparing this with known patient numbers. This analysis suggests that a further 5600 children and 3300 adults are not looked after by specialist services or have been lost to follow-up. The comprehensiveness of services was assessed using a new scoring system for clinical and organizational criteria. There are major regional disparities in the comprehensiveness of service provision across the country, with some regions having little or no specialist service. Unmet need will increase as a result of new diagnostic technologies, more effective treatments and new neonatal screening programmes; specialist services need to be developed and expanded to provide a comprehensive and more equitable service to the UK population.

• How can the evaluation of genetic tests be enhanced? Lessons learned from the ACCE framework and evaluating genetic tests in the United Kingdom.

  Authors: Simon Sanderson, Ron Zimmern, Mark Kroese, Julian Higgins, Christine Patch, Jon Emery

  Genetics in medicine : official journal of the American College of Medical Genetics. 10/2005; 7(7):495-500.

  Advances in genetic technology are increasing the availability of genetic tests, not only for rare single gene disorders, but also for common diseases such as breast and colo-rectal cancer. BeforeAdvances in genetic technology are increasing the availability of genetic tests, not only for rare single gene disorders, but also for common diseases such as breast and colo-rectal cancer. Before there can be widespread uptake of these tests, they must be evaluated to confirm the benefits of their use. But how should genetic tests be evaluated, given the speed at which new tests are emerging? One highly influential approach is the analytic validity, clinical validity, clinical utility and ethical, legal and social issues (ACCE) framework, which has provided a benchmark for the evaluation of genetic tests. The approach has been adopted and adapted by the United Kingdom Genetic Testing Network, with the help of the Public Health Genetics Unit in Cambridge, to evaluate new genetic tests for use in the National Health Service. We discuss a number of conceptual, methodological, and practical issues concerning the evaluation of genetic tests, based on lessons learned from applying the ACCE framework and from the UK experience, and make a number of recommendations to further strengthen the evaluation of genetic tests.

• Narrative review: aspirin resistance and its clinical implications.

  Authors: Simon Sanderson, Jon Emery, Trevor Baglin, Ann Louise Kinmonth

  Annals of internal medicine. 04/2005; 142(5):370-80.

  Aspirin is currently the most cost-effective drug for the secondary prevention of cardiovascular disease, but treatment failures are relatively common. Several factors have been linked to theseAspirin is currently the most cost-effective drug for the secondary prevention of cardiovascular disease, but treatment failures are relatively common. Several factors have been linked to these recurrent vascular events in patients prescribed aspirin, including smoking, drug interactions, nonadherence, comorbid conditions, and aspirin resistance. The term aspirin resistance has been used to describe not only an absence of the expected pharmacologic effects of aspirin on platelets but also poor clinical outcomes, such as recurrent vascular events, in patients treated with aspirin. Aspirin resistance is perhaps more precisely understood as the phenomenon of measurable, persisting platelet activation that occurs in patients prescribed a therapeutic dose of aspirin and may underlie an unknown proportion of aspirin treatment failures. Key challenges for future research are to standardize a definition of aspirin resistance and to compare whether different measures of platelet activation, either alone or in combination, independently predict cardiovascular events. These challenges must be met before researchers conduct studies to assess the clinical utility of testing on patient outcomes and cost-effective prescribing.

• CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis.

  Authors: Simon Sanderson, Jon Emery, Julian Higgins

  Genetics in medicine : official journal of the American College of Medical Genetics. 03/2005; 7(2):97-104.

  PURPOSE: Two common variant alleles of the cytochrome CYP2C9 (CYP2C9*2 and CYP2C9*3) lead to reduced warfarin metabolism in vitro and in vivo. The study objective was to examine the strength andPURPOSE: Two common variant alleles of the cytochrome CYP2C9 (CYP2C9*2 and CYP2C9*3) lead to reduced warfarin metabolism in vitro and in vivo. The study objective was to examine the strength and quality of existing evidence about CYP2C9 gene variants and clinical outcomes in warfarin-treated patients. METHODS: The study was a systematic review and meta-analysis. Multiple electronic databases were searched, references identified from bibliographies were sought, and experts and authors of primary studies were also contacted. Strict review inclusion criteria were determined. Three reviewers independently extracted data using prepiloted proformas. RESULTS: In all, 11 studies meeting review inclusion criteria were identified (3029 patients). Nine were included in the meta-analyses (2775 patients). Random effects meta-analyses were performed; statistical heterogeneity and inconsistency was assessed. Twenty percent of patients studied carry a variant allele: CYP2C9*2 12.2% (9.7%-15.0%) and CYP2C9*3, 7.9% (6.5%-9.7%). Mean difference in daily warfarin dose: for CYP2C9*2, the reduction was 0.85 mg (0.60-1.11 mg), a 17% reduction. For CYP2C9*3, the reduction was 1.92 mg (1.37-2.47 mg), a 37% reduction. For CYP2C9*2 or *3, the reduction was 1.47 mg (1.24-1.71 mg), a 27% reduction. The relative bleeding risk for CYP2C9*2 was 1.91 (1.16-3.17) and for CYP2C9*3 1.77 (1.07-2.91). For either variant, the relative risk was 2.26 (1.36-3.75). CONCLUSIONS: Patients with CYP2C9*2 and CYP2C9*3 alleles have lower mean daily warfarin doses and a greater risk of bleeding. Testing for gene variants could potentially alter clinical management in patients commencing warfarin. Evidence for the clinical utility and cost-effectiveness of genotyping is needed before routine testing can be recommended.

• Obstacles and opportunities in meta-analysis of genetic association studies.

  Authors: Georgia Salanti, Simon Sanderson, Julian P T Higgins

  Genetics in medicine : official journal of the American College of Medical Genetics. 02/2005; 7(1):13-20.

  Genetic association studies have the potential to advance our understanding of genotype-phenotype relationships, especially for common, complex diseases where other approaches, such as linkage, areGenetic association studies have the potential to advance our understanding of genotype-phenotype relationships, especially for common, complex diseases where other approaches, such as linkage, are less powerful. Unfortunately, many reported studies are not replicated or corroborated. This lack of reproducibility has many potential causes, relating to study design, sample size, and power issues, and from sources of true variability among populations. Genetic association studies can be considered as more similar to randomized trials than other types of observational epidemiological studies because of "Mendelian randomization" (Mendel's second law). The rationale and methodology for synthesizing randomized trials is highly relevant to the meta-analysis of genetic association studies. Nevertheless, there are a number of obstacles to overcome when performing such meta-analyses. In this review, the impacts of Type I error, lack of power, and publication and reporting biases are explored, and the role of multiple testing is discussed. A number of special features of association studies are especially pertinent, because they may lead to true variability among study results. These include population dynamics and structure, linkage disequilibrium, conformity to Hardy-Weinberg Equilibrium, bias, population stratification, statistical heterogeneity, epistatic and environmental interactions, and the choice of statistical models used in the analysis. Approaches to dealing with these issues are outlined. The supreme importance of complete and consistent study reporting and of making data readily available is also highlighted as a prerequisite for sound meta-analysis. We believe that systematic review and meta-analysis has an important role to play in understanding genetic association studies and should help us to separate the wheat from the chaff.

• Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography

  Authors: Simon Sanderson, Iain D Tatt, Julian PT Higgins

  Background Assessing quality and susceptibility to bias is essential when interpreting primary research and conducting systematic reviews and meta-analyses. Tools for assessing quality in clinicalBackground Assessing quality and susceptibility to bias is essential when interpreting primary research and conducting systematic reviews and meta-analyses. Tools for assessing quality in clinical trials are well-described but much less attention has been given to similar tools for observational epidemiological studies. Methods Tools were identified from a search of three electronic databases, bibliographies and an Internet search using Google®. Two reviewers extracted data using a pre-piloted extraction form and strict inclusion criteria. Tool content was evaluated for domains potentially related to bias and was informed by the STROBE guidelines for reporting observational epidemiological studies. Results A total of 86 tools were reviewed, comprising 41 simple checklists, 12 checklists with additional summary judgements and 33 scales. The number of items ranged from 3 to 36 (mean 13.7). One-third of tools were designed for single use in a specific review and one-third for critical appraisal. Half of the tools provided development details, although most were proposed for future use in other contexts. Most tools included items for selection methods (92%), measurement of study variables (86%), design-specific sources of bias (86%), control of confounding (78%) and use of statistics (78%); only 4% addressed conflict of interest. The distribution and weighting of domains across tools was variable and inconsistent. Conclusion A number of useful assessment tools have been identified by this report. Tools should be rigorously developed, evidence-based, valid, reliable and easy to use. There is a need to agree on critical elements for assessing susceptibility to bias in observational epidemiology and to develop appropriate evaluation tools.

• Genetic tests and their evaluation: can we answer the key questions?

  Authors: Mark Kroese, Ron L Zimmern, Simon Sanderson

  Genetics in medicine : official journal of the American College of Medical Genetics. 6(6):475-80.

  The rapid pace of research in the field of genetics has already yielded many benefits. The development of new genetic tests is one such example. Before there can be widespread uptake of these testsThe rapid pace of research in the field of genetics has already yielded many benefits. The development of new genetic tests is one such example. Before there can be widespread uptake of these tests they need to be evaluated to confirm the benefits of their use. The authors review some of the key features of the evaluation of diagnostic tests focusing on analytical and clinical validity. Test properties such as sensitivity, specificity, likelihood ratios, positive and negative predictive values, and how they relate to molecular genetic testing are discussed. Associated issues such as the concepts of disease definition, imperfect reference standards, and false positives are also explored. The authors suggest possible approaches to addressing some of the problems identified.