A practical guide to pre-trial simulations for Bayesian adaptive trials using SAS and BUGS.

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. Before deciding on a particular design, it is generally advisable to carry out a simulation study to characterise the properties of candidate designs under a range of plausible assumptions. The implementation of such pre-trial simulation studies presents many challenges and requires considerable statistical programming effort and time. Despite the scale and complexity, there is little existing literature to guide the implementation of such projects using commonly available software. This Teacher's Corner article provides a practical step-by-step guide to implementing such simulation studies including how to specify and fit a Bayesian model in WinBUGS or OpenBUGS using SAS, and how results from the Bayesian analysis may be pulled back into SAS and used for adaptation of allocation probabilities before simulating subsequent stages of the trial. The interface between the two software platforms is described in detail along with useful tips and tricks. A key strength of our approach is that the entire exercise can be defined and controlled from within a single SAS program.

Contraceptive practices, sexual and reproductive health needs of HIV-positive and negative female sex workers in Goa, India.

OBJECTIVES: In India, female sex workers (FSWs), suffer from high HIV prevalence and abortions. Contraceptive use among general population women is well understood. However, FSWs contraceptives practices and reproductive health needs are under-researched. We investigated contraceptive practices among HIV-positive and negative FSWs in Goa, India and explored its association with socio-demographic and sex work related factors. METHODS: Cross-sectional study using respondent driven sampling recruited 326 FSWs. They completed an interviewer-administered questionnaire and were screened for STI/HIV. Multivariable logistic regression was used to explore factors associated with sterilisation relative to no contraception. RESULTS: HIV prevalence was high (26%). Of the 59 FSWs planning pregnancy, 33% were HIV-positive and 5-7% had Gonorrhoea, Chlamydia and Trichomonas. 25% and 65% of FSWs screened-positive for Syphilis and Herpes simplex virus type 2 antibodies respectively. Among the 260 FSWs analysed for contraceptive use, 39% did not use contraceptives, and 26% had experienced abortion. Half the FSWs had undergone sterilisation, and only 5% used condoms for contraception. Among HIV-positive FSWs, 45% did not use contraceptives. Sterilisation was independently associated with older age, illiteracy, having an intimate non-paying male partner, having children and financial autonomy. Exposure to National AIDS Control Organisation's HIV-prevention interventions was reported by 34% FSWs and was not significantly associated with contraceptive use (adjusted odds ratio 1.4, 95% CI 0.7 to 2.9). CONCLUSION: HIV-prevention interventions should promote contraception, especially among young and HIV-positive FSWs. Integrating HIV treatment and care services with HIV-prevention interventions is vital to avert HIV-positive births.

Low dose dexamethasone as treatment for women with heavy menstrual bleeding: A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM).

BACKGROUND: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB? METHODS: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data. TRIAL REGISTRATION: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects. INTERPRETATION: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation. FUNDING: UK MRC DCS/DPFS grant MR/J003611/1.

Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover.

BACKGROUND: The aim of this exploratory study was to establish whether we could improve skeletal health with a physiological regimen of SSR in young women with premature ovarian failure (POF). PATIENTS AND METHODS: In an open-label randomized controlled crossover trial, 34 women with POF were randomized to 4-week cycles of pSSR (transdermal oestradiol, 100 µg daily for week 1, 150 µg for weeks 2-4; vaginal progesterone, 200 mg twice daily for weeks 3-4) or standard hormone replacement treatment (sHRT) (oral ethinyloestradiol 30 µg and 1·5 mg norethisterone daily for weeks 1-3, week 4 'pill-free') for 12 months. Bone mineral density (BMD) was measured by DEXA at study entry and after each 12-month treatment period. Blood samples for hormones and markers of bone formation (bone alkaline phosphatase, BALP and type I collagen N-terminal propeptide, PINP) and bone resorption (CrossLaps) were collected pre-/postwashout and after 3, 6 and 12 months of each treatment. RESULTS: Eighteen women, mean 27 (range 19-39) years, completed the study. Both regimens caused similar suppression of LH and FSH. Mean baseline lumbar spine BMD z-score was -0·89 (95% CI -1·27 to -0·51) and increased by +0·17 (CI +0·07 to +0·27) in response to pSSR (P = 0·003), compared with +0·07 (CI -0·03 to +0·18) during standard HRT (P = 0·2). During pSSR, the increment in lumbar spine BMD z-score was related positively to oestradiol (r = +0·49, P = 0·04) and inversely to FSH (r = -0·65, P = 0·004). Bone formation markers, BALP and P1NP increased in the pSSR arm (anova P < 0·001) but decreased in the sHRT arm (P < 0·01). Both treatments suppressed the bone resorption marker, CrossLaps (P < 0·001). CONCLUSION: We conclude that pSSR over 12 months has a beneficial affect on bone mass acquisition on the lumbar spine in women with POF, mediated by increased bone formation and decreased bone resorption.

A review of methods used in comprehensive, descriptive studies that relate red blood cell transfusion to clinical data.

BACKGROUND: Red blood cell (RBC) use varies greatly between countries but the underlying reasons are not well understood. Some insight might be gained from blood utilization studies that provide a complete view of the clinical conditions that place individuals at risk of transfusion. This review considers the methodology of published studies that might provide such information and proposes requirements for future studies. STUDY DESIGN AND METHODS: A literature search was performed to identify quantitative studies of RBC use related to clinical data, for which the findings are representative of well-defined populations. Extraction and analysis of methodologic information and epidemiologic data were performed. RESULTS: The 13 studies identified for inclusion varied in their approach to defining the population from which the study sample was selected, classification of clinical data, and method of attributing transfusion events to clinical case groups, including the observational time frame. CONCLUSION: Variability in methods prevents useful interpretation or comparison of the findings. Standardization and transparency of methodology and definitions are essential if future studies are to enable comparison of the factors associated with RBC transfusion in different populations and to improve understanding of the wide variations in RBC use.

Why are rates of sterilization in decline? A pilot study designed to explore reasons for declining female sterilization in Scotland.

BACKGROUND: In the last decade, female sterilization had been in decline throughout the UK. It is not clear whether fewer women are requesting sterilization or whether the universal enthusiasm for long-acting reversible methods is leading health professionals to discourage women from being sterilized. Since correct and consistent use of alternative, reversible contraceptive methods depends somewhat on their acceptability, it is important to determine whether women are being refused sterilization or whether they are freely choosing other methods. This study aims to explore whether female sterilization is being widely considered as a contraceptive method, the reasons for choosing or rejecting it, and whether women are being discouraged by health professionals from being sterilized. STUDY DESIGN: A self-completed questionnaire survey among 205 women aged 30 to 50 years who felt that their family was complete attending a family planning clinic in Scotland. RESULTS: Of the 203 women included in the study, 151 (74.4%) had heard of female sterilization, 90 had discussed it with someone (60%) and 87 (58%) had considered it as a contraceptive option. Of the 56 women who consulted their family doctor about sterilization, almost half (27; 48%) were not referred to a hospital and fewer than one (17, 30.4%) in three of them was eventually sterilized or had arrangements in place to get it done. Free-text comments from the women revealed a variety of reasons for not choosing female sterilization and suggested that some women are being deterred from sterilization. CONCLUSION: The study suggests that some women are being actively encouraged by health professionals to use long-acting reversible contraceptive methods and discouraged from choosing sterilization. However, other women recognize for themselves the wisdom of keeping their fertility options open.

What aspects of periods are most bothersome for women reporting heavy menstrual bleeding? Community survey and qualitative study.

BACKGROUND: Heavy menstrual bleeding is a common symptom amongst women of reproductive age, yet questions remain about why some women experience this as a problem while others do not. We investigated the concerns of women who reported heavy menstrual bleeding on questionnaire. METHODS: A cross-sectional postal survey and qualitative interviews were carried out amongst a community-based sample of women in Lothian, Scotland. 906 women aged 25 to 44 reported heavy or very heavy periods in response to a postal survey of 2833 women registered with 19 general practices. Amongst those who had reported heavy menstrual bleeding, analysis was carried out of responses to the free text questionnaire item, "What bothers you most about your periods?" In addition, 32 of these women participated in qualitative interviews and their accounts were analysed to explore how menstrual symptoms and 'problems' with periods were experienced. RESULTS: Even amongst this subgroup of women, selected on the basis of having reported their periods as heavy in the survey, pain was the aspect of their periods that 'most bothered' them, followed by heaviness, mood changes or tiredness, and irregularity or other issues of timing. Interviewees' accounts similarly suggested that a range of menstrual symptoms were problematic and some women did not disentangle which was worst. Judgements of periods as a problem were based on the impact of menstrual symptoms on daily life and this was contingent on social circumstances such as type of paid work and other responsibilities. Although women spoke readily of whether their periods were a problem, there was less clarity in accounts of whether or not menstrual loss was 'heavy'; women said they made judgements based on what was normal for them, degree of difficulty in containing blood loss and pattern of loss. CONCLUSION: Women with heavy periods are bothered by a range of menstrual symptoms and their impact on everyday life. Clinical emphasis should be on clarifying the presenting problem and providing help and advice for this, as well as on excluding serious disease. Sometimes simple approaches, such as help with analgesia, may be all that is required.

Inside the Premier/CMS Pay-for-Performance Project.

In an H&HN exclusive roundtable discussion, representatives from the five top-performing hospitals describe what they've learned so far from the Premier/CMS Pay-for-Performance Project. For hospitals around the country, so-called value-based ent will soon be the primary way they get paid by both public and commercial insurers. The Premier/CMS participants offer valuable insights--and warnings--about the challenges ahead.

Development of a Bayesian response-adaptive trial design for the Dexamethasone for Excessive Menstruation study.

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. This article describes the preparatory simulation study for a Bayesian response-adaptive dose-finding trial design. Dexamethasone for Excessive Menstruation aims to assess the efficacy of Dexamethasone in reducing excessive menstrual bleeding and to determine the best dose for further study. To maximise learning about the dose response, patients receive placebo or an active dose with randomisation probabilities adapting based on evidence from patients already recruited. The dose-response relationship is estimated using a flexible Bayesian Normal Dynamic Linear Model. Several competing design options were considered including: number of doses, proportion assigned to placebo, adaptation criterion, and number and timing of adaptations. We performed a fractional factorial study using SAS software to simulate virtual trial data for candidate adaptive designs under a variety of scenarios and to invoke WinBUGS for Bayesian model estimation. We analysed the simulated trial results using Normal linear models to estimate the effects of each design feature on empirical type I error and statistical power. Our readily-implemented approach using widely available statistical software identified a final design which performed robustly across a range of potential trial scenarios.

A Scottish postal survey suggested that the prevailing clinical preoccupation with heavy periods does not reflect the epidemiology of reported symptoms and problems.

OBJECTIVE: To determine the prevalence of self-reported menstrual symptoms and problem periods and explore their relationship with sociodemographic factors, parity, long-standing illness, and hormonal contraceptive use. STUDY DESIGN AND SETTING: Postal questionnaire survey of 4,610 women aged 25-44 registered with 19 general practices in Lothian, Scotland. RESULTS: Among menstruating women, 30% reported heavy periods, a further 5% very heavy periods and 15% severe period pain. Although 39% of women reported either heaviness or pain or both, only 22% reported their periods as a marked or severe problem. Multivariate logistic regression showed that reporting problem periods was associated with long-standing illness, heaviness of bleeding, menstrual pain and inversely associated with hormonal contraceptive use. Reporting problem periods was strongly associated with severe pain (OR = 21, 95% CI = 15-28) and with very heavy loss (OR = 14, 95% CI = 8.0-24). CONCLUSIONS: Reporting heavy or painful periods was common but reporting problem periods was less so. Reporting severe pain was at least as strongly associated with problem periods as very heavy periods and severe pain affected many more women than very heavy periods. Therefore the clinical preoccupation with heavy periods does not reflect the epidemiology of menstrual symptoms or problem.

Women's experiences of Chlamydia screening. Qualitative interviews with women in primary care.

BACKGROUND: Plans are underway to introduce Chlamydia screening in UK primary care. The success of a screening programme depends upon many factors including its acceptability to the population being screened. The experiences of women who have taken part in a pilot study of screening are therefore important in ensuring that services are developed in such a way to maximise health benefits. OBJECTIVES: To explore the experiences of Chlamydia screening among women with both positive and negative results and women who were still waiting for results; to reflect on the implications of their views for primary care based screening programmes. METHODS: Interviews were carried out with twenty women who had participated in a pilot of opportunistic Chlamydia screening carried out in eight general practices in Edinburgh. Four participants had received a positive result, 14 had a negative result and two were still waiting for results. Qualitative analysis was carried out on interview transcripts using the framework approach. RESULTS: Most women saw themselves as at low risk of Chlamydia infection because: it was not perceived as a common infection (many had never heard of it before); they felt that their sexual history did not put them at risk; or because they had no symptoms (although Chlamydia is frequently asymptomatic). Women interviewed welcomed the offer of Chlamydia screening because of the importance of preventing infertility, the ease of testing, and the knowledge that the infection could easily be treated with antibiotics. However, women stressed that it was important to receive adequate information in order to make an informed choice about whether or not to accept the test. CONCLUSIONS: The complexity of messages to be conveyed when offering a Chlamydia screening test, for instance regarding the symptomless nature of the infection and the implications of a positive result, mean that the time taken to communicate this adequately should not be underestimated.

Prevalence of influenza A (H1N1) seropositivity in unvaccinated healthcare workers in Scotland at the height of the global pandemic.

BACKGROUND: We set out to identify the level of previous exposure to influenza A (H1N1) in unvaccinated healthcare workers (HCWs) at the peak of the pandemic outbreak in the UK, with control samples collected prior to the outbreak. METHODS: Cross-sectional study (seroprevalence assessed before and at pandemic peak, with questionnaire data collected at peak of outbreak) in HCWs in Scotland. RESULTS: The prevalence of seropositivity in 493 HCWs at pandemic peak was 10.3%, which was higher than the prepandemic level by 3.7 percentage points (95% CI 0.3% to 7.3%, P = 0.048). Seropositivity rates for frontline and nonfrontline HCWs were similar. CONCLUSION: At pandemic peak, only 10.3% of HCWs were seropositive for influenza A (H1N1), so the great majority were still susceptible to infection at the introduction of the vaccination programme. Few studies have reported on seroprevalence in unvaccinated and asymptomatic participants, so our findings may have relevance to the wider population.