Methods for observed-cluster inference when cluster size is informative: a review and clarifications.

Clustered data commonly arise in epidemiology. We assume each cluster member has an outcome Y and covariates X. When there are missing data in Y, the distribution of Y given X in all cluster members ("complete clusters") may be different from the distribution just in members with observed Y ("observed clusters"). Often the former is of interest, but when data are missing because in a fundamental sense Y does not exist (e.g., quality of life for a person who has died), the latter may be more meaningful (quality of life conditional on being alive). Weighted and doubly weighted generalized estimating equations and shared random-effects models have been proposed for observed-cluster inference when cluster size is informative, that is, the distribution of Y given X in observed clusters depends on observed cluster size. We show these methods can be seen as actually giving inference for complete clusters and may not also give observed-cluster inference. This is true even if observed clusters are complete in themselves rather than being the observed part of larger complete clusters: here methods may describe imaginary complete clusters rather than the observed clusters. We show under which conditions shared random-effects models proposed for observed-cluster inference do actually describe members with observed Y. A psoriatic arthritis dataset is used to illustrate the danger of misinterpreting estimates from shared random-effects models.SRS is funded by MRC grants U1052 60558 and MC_US_A030_0015, AJC and MP by MRC grant G0600657

How important is randomisation in a stepped wedge trial?

In cluster randomised trials, randomisation increases internal study validity. If enough clusters are randomised, an unadjusted analysis should be unbiased. If a smaller number of clusters are included, stratified or matched randomisation can increase comparability between trial arms. In addition, an adjusted analysis may be required; nevertheless, randomisation removes the possibility for systematically biased allocation and increases transparency. In stepped wedge trials, clusters are randomised to receive an intervention at different start times ('steps'), and all clusters eventually receive it. In a recent study protocol for a 'modified stepped wedge trial', the investigators considered randomisation of the clusters (hospital wards), but decided against it for ethical and logistical reasons, and under the assumption that it would not add much to the rigour of the evaluation. We show that the benefits of randomisation for cluster randomised trials also apply to stepped wedge trials. The biggest additional issue for stepped wedge trials in relation to parallel cluster randomised trials is the need to control for secular trends in the outcome. Analysis of stepped wedge trials can in theory be based on 'horizontal' or 'vertical' comparisons. Horizontal comparisons are based on measurements taken before and after the intervention is introduced in each cluster, and are unbiased if there are no secular trends. Vertical comparisons are based on outcome measurements from clusters that have switched to the intervention condition and those from clusters that have yet to switch, and are unbiased under randomisation since at any time point, which clusters are in intervention and control conditions will have been determined at random. Secular outcome trends are a possibility in many settings. Many stepped wedge trials are analysed with a mixed model, including a random effect for cluster and fixed effects for time period to account for secular trends, thereby combining both vertical and horizontal comparisons of intervention and control clusters. The importance of randomisation in a stepped wedge trial is that the effects of time can be estimated from the data, and bias from secular trends that would otherwise arise can be controlled for, provided the trends are correctly specified in the model

Estimands in cluster-randomized trials: choosing analyses that answer the right question

Background Cluster-randomized trials (CRTs) involve randomizing groups of individuals (e.g. hospitals, schools or villages) to different interventions. Various approaches exist for analysing CRTs but there has been little discussion around the treatment effects (estimands) targeted by each. Methods We describe the different estimands that can be addressed through CRTs and demonstrate how choices between different analytic approaches can impact the interpretation of results by fundamentally changing the question being asked, or, equivalently, the target estimand. Results CRTs can address either the participant-average treatment effect (the average treatment effect across participants) or the cluster-average treatment effect (the average treatment effect across clusters). These two estimands can differ when participant outcomes or the treatment effect depends on the cluster size (referred to as ‘informative cluster size’), which can occur for reasons such as differences in staffing levels or types of participants between small and large clusters. Furthermore, common estimators, such as mixed-effects models or generalized estimating equations with an exchangeable working correlation structure, can produce biased estimates for both the participant-average and cluster-average treatment effects when cluster size is informative. We describe alternative estimators (independence estimating equations and cluster-level analyses) that are unbiased for CRTs even when informative cluster size is present. Conclusion We conclude that careful specification of the estimand at the outset can ensure that the study question being addressed is clear and relevant, and, in turn, that the selected estimator provides an unbiased estimate of the desired quantity

Investigating the relationship between HIV testing and risk behaviour in Britain: National Survey of Sexual Attitudes and Lifestyles 2000.

OBJECTIVES: To estimate the prevalence of, and identify factors associated with, HIV testing in Britain. DESIGN: A large, stratified probability sample survey of sexual attitudes and lifestyles. METHODS: A total of 12,110 16-44 year olds completed a computer-assisted face-to-face interview and self-interview. Self-reports of HIV testing, i.e. the timing, reasons for and location of testing, were included. RESULTS: A total of 32.4% of men and 31.7% of women reported ever having had an HIV test, the majority of whom were tested through blood donation. When screening for blood donation and pregnancy were excluded, 9.0% of men and 4.6% of women had had a voluntary confidential HIV test (VCT) in the past 5 years. However, one third of injecting drug users and men who have sex with men had a VCT in the past 5 years. VCT in the past 5 years was significantly associated with age, residence, ethnicity, self-perceived HIV risk, reporting greater numbers of sexual partners, new sexual partners from abroad, previous sexually transmitted infection diagnosis, and injecting non-prescribed drugs for men and women, and same-sex partners (men only). Whereas sexually transmitted disease clinics were important sites for VCT, general practice accounted for almost a quarter of VCT. CONCLUSION: HIV testing is relatively common in Britain; however, it remains largely associated with population-based blood donation and antenatal screening programmes. In contrast, VCT remains highly associated with high-risk (sexual or drug-injecting) behaviours or population sub-groups at high risk. Strategies to reduce undiagnosed prevalent HIV infection will require further normalization and wider uptake of HIV testing

Increasing prevalence of male homosexual partnerships and practices in Britain 1990-2000: evidence from national probability surveys.

OBJECTIVES: To estimate the prevalence and timing of homosexual experience among British men; to explore the patterns of sexual practices and partnerships in 2000, and behavioural and attitudinal changes between 1990 and 2000 among men who have sex with men (MSM). DESIGN: Two large, stratified probability sample surveys of the general population. METHODS: Trained interviewers administered a combination of face-to-face and self-completion questionnaires to men aged 16 to 44 years resident in Britain (n = 6000 in 1990 and n = 4762 in 2000). RESULTS: In 2000, 2.8% of British men reported sex with men in the past 5 years. 46.0% of MSM reported five or more partners in the past 5 years, and 59.8% reported unprotected anal intercourse in the past year. A total of 33.0% of MSM reported one or more female partner(s) in the past year. In comparison with 1990, there was a significant increase in the proportion of MSM in the population in 2000, and among these men, in the proportion reporting receptive anal intercourse in the past year [age-adjusted odds ratio (OR), 2.08; 95% confidence interval (CI), 1.08-4.00], but no significant change in self-perceived HIV-risk (age-adjusted OR, 1.11; 95% CI, 0.49-2.51) or HIV testing in past 5 years (age-adjusted OR, 1.14; 95% CI, 0.57-2.25). CONCLUSIONS: Evidence of increasing prevalence of homosexual intercourse among the British male population coupled with increases in some HIV-risk behaviours among MSM suggests overall increasing numbers at risk in the population. Although these changes may partly reflect an increased willingness to report these behaviours, our results are consistent with increasing incidence of sexually transmitted infections and behavioural surveillance data

Designing a stepped wedge trial: three main designs, carry-over effects and randomisation approaches.

BACKGROUND: There is limited guidance on the design of stepped wedge cluster randomised trials. Current methodological literature focuses mainly on trials with cross-sectional data collection at discrete times, yet many recent stepped wedge trials do not follow this design. In this article, we present a typology to characterise the full range of stepped wedge designs, and offer guidance on several other design aspects. METHODS: We developed a framework to define and report the key characteristics of a stepped wedge trial, including cluster allocation and individual participation. We also considered the relative strengths and weaknesses of trials according to this framework. We classified recently published stepped wedge trials using this framework and identified illustrative case studies. We identified key design choices and developed guidance for each. RESULTS: We identified three main stepped wedge designs: those with a closed cohort, an open cohort, and a continuous recruitment short exposure design. In the first two designs, many individuals experience both control and intervention conditions. In the final design, individuals are recruited in continuous time as they become eligible and experience either the control or intervention condition, but not both, and then provide an outcome measurement at follow-up. While most stepped wedge trials use simple randomisation, stratification and restricted randomisation are often feasible and may be useful. Some recent studies collect outcome information from individuals exposed a long time before or after the rollout period, but this contributes little to the primary analysis. Incomplete designs should be considered when the intervention cannot be implemented quickly. Carry-over effects can arise in stepped wedge trials with closed and open cohorts. CONCLUSIONS: Stepped wedge trial designs should be reported more clearly. Researchers should consider the use of stratified and/or restricted randomisation. Trials should generally not commit resources to collect outcome data from individuals exposed a long time before or after the rollout period. Though substantial carry-over effects are uncommon in stepped wedge trials, researchers should consider their possibility before conducting a trial with closed or open cohorts

Ethnic variations in sexual behaviour in Great Britain and risk of sexually transmitted infections: a probability survey.

BACKGROUND: Ethnic variations in the rate of diagnosed sexually transmitted infections (STIs) have been reported in many developed countries. We used data from the second British National Survey of Sexual Attitudes and Lifestyles (Natsal 2000) to investigate the frequency of high-risk sexual behaviours and adverse sexual health outcomes in five ethnic groups in Great Britain. METHODS: We did a stratified probability sample survey of 11161 men and women aged 16-44 years, resident in Great Britain, using computer-assisted interviews. Additional sampling enabled us to do more detailed analyses for 949 black Caribbean, black African, Indian, and Pakistani respondents. We used logistic regression to assess reporting of STI diagnoses in the past 5 years, after controlling for demographic and behavioural variables. FINDINGS: We noted striking variations in number of sexual partnerships by ethnic group and between men and women. Reported numbers of sexual partnerships in a lifetime were highest in black Caribbean (median 9 [IQR 4-20]) and black African (9 [3-20]) men, and in white (5 [2-9]) and black Caribbean (4 [2-7]) women. Indian and Pakistani men and women reported fewer sexual partnerships, later first intercourse, and substantially lower prevalence of diagnosed STIs than did other groups. We recorded a significant association between ethnic origin and reported STIs in the past 5 years with increased risk in sexually active black Caribbean (OR 2.74 [95% CI 1.22-6.15]) and black African (2.95 [1.45-5.99]) men compared with white men, and black Caribbean (2.41 [1.35-4.28]) women compared with white women. Odds ratios changed little after controlling for age, number of sexual partnerships, homosexual and overseas partnerships, and condom use at last sexual intercourse. INTERPRETATION: Individual sexual behaviour is a key determinant of STI transmission risk, but alone does not explain the varying risk across ethnic groups. Our findings suggest a need for targeted and culturally competent prevention interventions

Exploring the costs and outcomes of sexually transmitted infection (STI) screening interventions targeting men in football club settings: preliminary cost-consequence analysis of the SPORTSMART pilot randomised controlled trial

Background: The objective of this study was to compare the costs and outcomes of two sexually transmitted infection (STI) screening interventions targeted at men in football club settings in England, including screening promoted by team captains. Methods: A comparison of costs and outcomes was undertaken alongside a pilot cluster randomised control trial involving three trial arms: (1) captain-led and poster STI screening promotion; (2) sexual health advisor-led and poster STI screening promotion and (3) poster-only STI screening promotion (control/comparator). For all study arms, resource use and cost data were collected prospectively. Results: There was considerable variation in uptake rates between clubs, but results were broadly comparable across study arms with 50% of men accepting the screening offer in the captain-led arm, 67% in the sexual health advisor-led arm and 61% in the poster-only control arm. The overall costs associated with the intervention arms were similar. The average cost per player tested was comparable, with the average cost per player tested for the captain-led promotion estimated to be £88.99 compared with £88.33 for the sexual health advisor-led promotion and £81.87 for the poster-only (control) arm. Conclusions: Costs and outcomes were similar across intervention arms. The target sample size was not achieved, and we found a greater than anticipated variability between clubs in the acceptability of screening, which limited our ability to estimate acceptability for intervention arms. Further evidence is needed about the public health benefits associated with screening interventions in non-clinical settings so that their cost-effectiveness can be fully evaluated

Examining the potential public health benefit of offering STI testing to men in amateur football clubs: evidence from cross-sectional surveys

Background: In Britain, young people continue to bear the burden of sexually transmitted infections (STIs) so efforts are required, especially among men, to encourage STI testing. The SPORTSMART study trialled an intervention that sought to achieve this by offering chlamydia and gonorrhoea test-kits to men attending amateur football clubs between October and December 2012. With football the highest participation team sport among men in England, this paper examines the potential public health benefit of offering STI testing to men in this setting by assessing their sociodemographic characteristics, sexual behaviours, and healthcare behaviour and comparing them to men in the general population. Methods: Data were collected from 192 (male) members of 6 football clubs in London, United Kingdom, aged 18–44 years via a 20-item pen-and-paper self-completion questionnaire administered 2 weeks after the intervention. These were compared to data collected from 409 men of a similar age who were resident in London when interviewed during 2010–2012 for the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3), a national probability survey that used computer-assisted-personal-interviewing with computer-assisted-self-interview. Age standardisation and multivariable regression were used to account for sociodemographic differences between the surveys. Results: Relative to men in the general population, SPORTSMART men were younger (32.8 % vs. 21.7 % aged under 25 y), and more likely to report (all past year) at least 2 sexual partners (adjusted odds ratio, AOR: 3.25, 95 % CI: 2.15–4.92), concurrent partners (AOR: 2.05, 95 % CI: 1.39–3.02), and non-use of condoms (AOR: 2.17, 95 % CI: 1.39–3.41). No difference was observed in STI/HIV risk perception (AOR for reporting “not at all at risk” of STIs: 1.25, 95 % CI: 0.76–2.04; of HIV: AOR: 1.54, 95 % CI: 0.93–2.55), nor in reporting STI testing in the past year (AOR: 0.83, 95 % CI: 0.44–1.54), which was reported by only one in six men. Conclusions: Relative to young men in the general population, football club members who completed the SPORTSMART survey reported greater sexual risk behaviour but similar STI/HIV risk perception and STI testing history. Offering STI testing in amateur football clubs may therefore widen access to STI testing and health promotion messages for men at higher STI risk, which, given the minority currently testing and the popularity of football in England, should yield both individual and public health benefit

Consistency in reporting sensitive sexual behaviours in Britain: change in reporting bias in the second and third National Surveys of Sexual Attitudes and Lifestyles (Natsal-2 and Natsal-3).

OBJECTIVES: Britain's second National Survey of Sexual Attitudes and Lifestyles (Natsal-2) was conducted in 1999-2001 and the third (Natsal-3) was conducted in 2010-2012 to update prevalence estimates of sexual behaviours and assess changes over time. We investigated whether there was a change in reporting bias between these two cross-sectional surveys. METHODS: We analysed data from the 'common birth cohort' of participants born during 1956-1983, who were eligible to take part in Natsal-2 (n=10 764) and Natsal-3 (n=6907). We compared estimates for outcomes that occurred before Natsal-2 and expected these to be consistent between surveys if no change in reporting bias had occurred. RESULTS: A greater proportion of non-white men and women were in Natsal-3 consistent with demographic changes in Britain. Reporting behaviours was largely consistent between surveys for men. Fewer women in Natsal-3 reported early first intercourse or having child(ren) before age 20; they were also more likely to report not discussing sex with their parents at age 14. Men and women in Natsal-3 were more likely to report tolerant attitudes towards same-sex partnerships but less tolerance towards unfaithfulness in marriage and one-night-stands. CONCLUSIONS: We found little evidence of change in reporting bias among men since Natsal-2. Among women, a modest change in reporting bias was observed for a small number of experiences, possibly due to changes in participation, social acceptability and methodological differences between surveys. Changes in the reporting of sexual behaviours and attitudes over time observed in the wider Natsal-3 study are therefore likely to largely reflect real changes in the population