Model-based sensitivity analysis for outcome reporting bias in the meta analysis of benefit and harm outcomes

Outcome reporting bias occurs when outcomes in research studies are selectively reported, the selection being influenced by the study results. For benefit outcomes, we have shown how risk assessments using the Outcome Reporting Bias in Trials risk classification scale can be used to calculate bias-adjusted treatment effect estimates. This paper presents a new and simpler version of the benefits method, and shows how it can be extended to cover the partial reporting and non-reporting of harm outcomes. Our motivating example is a Cochrane systematic review of 12 studies of Topiramate add-on therapy for drug-resistant partial epilepsy. Bias adjustments for partially reported or unreported outcomes suggest that the review has overestimated the benefits and underestimated the harms of the test treatment

Pregnancy Intention and Pregnancy Outcome: Systematic Review and Meta-Analysis

Introduction Previous systematic reviews concluded that rigorous research on the relationships between pregnancy intentions and pregnancy outcomes is limited. They further noted that most studies were conducted in high-income countries and had methodological limitations. We aim to assess the current evidence base for the relationship between pregnancy intention and miscarriage, stillbirth, low birthweight (LBW) and neonatal mortality. In March 2015 Embase, PubMed, Scopus and PsychInfo were searched for studies investigating the relationship between pregnancy intention and the outcomes of interest. Methods Studies published since 1975 and in English, French or Spanish were included. Two reviewers screened titles and abstracts, read the full text of identified articles and extracted data. Meta-analyses were conducted where possible. Results Thirty-seven studies assessing the relationships between pregnancy intention and LBW were identified. A meta-analysis of 17 of these studies found that unintended pregnancies are associated with 1.41 times greater odds of having a LBW baby (95%CI 1.31, 1.51). Eight studies looking at miscarriage, stillbirth or neonatal death were found. The limited data concerning pregnancy loss and neonatal mortality precluded meta-analysis but suggest these outcomes may be more common in unintended pregnancies. Discussion While there seems to be an increased risk of adverse pregnancy outcome in unintended pregnancies, there has been little improvement in either the quantity of evidence from low-income countries or in the quality of evidence generally. Longitudinal studies of pregnancy intention and pregnancy outcome, where pregnancy intention is assessed prospectively with a validated measure and where analyses include confounding or mediating factors, are required in both high- and low-income countries

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

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

Varicella Pneumonia Complicating Pregnancy: A Report of Seven Cases

Background: Pneumonia is the most common complication of varicella-zoster infection in adults and has potentially devastating effects when complicating pregnancy. Due to the significant morbidity and mortality associated with this complication during pregnancy and the small number of reported cases in the literature, we present this report to help educate physicians who care for pregnant women

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

Prevalence and Determinants of Unintended Pregnancy in Mchinji District, Malawi; Using a Conceptual Hierarchy to Inform Analysis

Background: In 2012 there were around 85 million unintended pregnancies globally. Unintended pregnancies unnecessarily expose women to the risks associated with pregnancy, unsafe abortion and childbirth, thereby contributing to maternal mortality and morbidity. Studies have identified a range of potential determinants of unplanned pregnancy but have used varying methodologies, measures of pregnancy intention and analysis techniques. Consequently there are many contradictions in their findings. Identifying women at risk of unplanned pregnancy is important as this information can be used to help with designing and targeting interventions and developing preventative policies. Methods: 4,244 pregnant women from Mchinji District, Malawi were interviewed at home between March and December 2013. They were asked about their pregnancy intention using the validated Chichewa version of the London Measure of Unplanned Pregnancy, as well as their socio-demographics and obstetric and psychiatric history. A conceptual hierarchical model of the determinants of pregnancy intention was developed and used to inform the analysis. Multiple random effects linear regression was used to explore the ways in which factors determine pregnancy intention leading to the identification of women at risk of unplanned pregnancies. Results: 44.4% of pregnancies were planned. On univariate analyses pregnancy intention was associated with mother and father’s age and education, marital status, number of live children, birth interval, socio-economic status, intimate partner violence and previous depression all at p<0.001. Multiple linear regression analysis found that increasing socio-economic status is associated with increasing pregnancy intention but its effect is mediated through other factors in the model. Socio-demographic factors of importance were marital status, which was the factor in the model that had the largest effect on pregnancy intention, partner’s age and mother’s education level. The effect of mother’s education level was mediated by maternal reproductive characteristics. Previous depression, abuse in the last year or sexual abuse, younger age, increasing number of children and short birth intervals were all associated with lower pregnancy intention having controlled for all other factors in the model. This suggests that women in Mchinji District who are either young, unmarried women having their first pregnancy, or older, married women who have completed their desired family size or recently given birth, or women who have experienced depression, abuse in the last year or sexual abuse are at higher risk of unintended pregnancies. Conclusion: A simple measure of pregnancy intention with well-established psychometric properties was used to show the distribution of pregnancy planning among women from a poor rural population and to identify those women at higher risk of unintended pregnancy. An analysis informed by a conceptual hierarchical model shed light on the pathways that lead from socio-demographic determinants to pregnancy intention. This information can be used to target family planning services to those most at risk of unplanned pregnancies, particularly women with a history of depression or who are experiencing intimate partner violence

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

Sexual behaviour in Britain: partnerships, practices, and HIV risk behaviours.

BACKGROUND: Sexual behaviour is a major determinant of sexual and reproductive health. We did a National Survey of Sexual Attitudes and Lifestyles (Natsal 2000) in 1999-2001 to provide population estimates of behaviour patterns and to compare them with estimates from 1990-91 (Natsal 1990). METHODS: We did a probability sample survey of men and women aged 16-44 years who were resident in Britain, using computer-assisted interviews. Results were compared with data from respondents in Natsal 1990. FINDINGS: We interviewed 11161 respondents (4762 men, 6399 women). Patterns of heterosexual and homosexual partnership varied substantially by age, residence in Greater London, and marital status. In the past 5 years, mean numbers of heterosexual partners were 3.8 (SD 8.2) for men, and 2.4 (SD 4.6) for women; 2.6% (95% CI 2.2-3.1) of both men and women reported homosexual partnerships; and 4.3% (95% CI 3.7-5.0) of men reported paying for sex. In the past year, mean number of new partners varied from 2.04 (SD 8.4) for single men aged 25-34 years to 0.05 (SD 0.3) for married women aged 35-44 years. Prevalence of many reported behaviours had risen compared with data from Natsal 1990. Benefits of greater condom use were offset by increases in reported partners. Changes between surveys were generally greater for women than men and for respondents outside London. INTERPRETATION: Our study provides updated estimates of sexual behaviour patterns. The increased reporting of risky sexual behaviours is consistent with changing cohabitation patterns and rising incidence of sexually transmitted infections. Observed differences between Natsal 1990 and Natsal 2000 are likely to result from a combination of true change and greater willingness to report sensitive behaviours in Natsal 2000 due to improved survey methodology and more tolerant social attitudes