Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials.

BACKGROUND: Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of anti-malarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. Therefore, a systematic review was conducted to establish the current practice in statistical analysis for preventive antimalarial drug safety in pregnancy. METHODS: The search included five databases (PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials) to identify original English articles reporting Phase III randomized controlled trials (RCTs) on anti-malarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. RESULTS: Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/counts (n = 18, 100%) and mean/median (n = 2, 11.1%). Results presentation included tabular (n = 16, 88.9%) and text description (n = 2, 11.1%). Univariate inferential methods were reported in most trials (n = 16, 88.9%); including Chi square/Fisher's exact test (n = 12, 66.7%), t test (n = 2, 11.1%) and Mann-Whitney/Wilcoxon test (n = 1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n = 3, 16.7%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n = 7, 38.9%). CONCLUSION: The review demonstrated that statistical analysis of safety data in anti-malarial drugs for malarial chemoprevention in pregnancy RCTs is inadequate. The analyses insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise anti-malarial drug safety evidence development, based on the available data.

Systematic review of analytical methods applied to longitudinal studies of malaria.

BACKGROUND: Modelling risk of malaria in longitudinal studies is common, because individuals are at risk for repeated infections over time. Malaria infections result in acquired immunity to clinical malaria disease. Prospective cohorts are an ideal design to relate the historical exposure to infection and development of clinical malaria over time, and analysis methods should consider the longitudinal nature of the data. Models must take into account the acquisition of immunity to disease that increases with each infection and the heterogeneous exposure to bites from infected Anopheles mosquitoes. Methods that fail to capture these important factors in malaria risk will not accurately model risk of malaria infection or disease. METHODS: Statistical methods applied to prospective cohort studies of clinical malaria or Plasmodium falciparum infection and disease were reviewed to assess trends in usage of the appropriate statistical methods. The study was designed to test the hypothesis that studies often fail to use appropriate statistical methods but that this would improve with the recent increase in accessibility to and expertise in longitudinal data analysis. RESULTS: Of 197 articles reviewed, the most commonly reported methods included contingency tables which comprised Pearson Chi-square, Fisher exact and McNemar's tests (n = 102, 51.8%), Student's t-tests (n = 82, 41.6%), followed by Cox models (n = 62, 31.5%) and Kaplan-Meier estimators (n = 59, 30.0%). The longitudinal analysis methods generalized estimating equations and mixed-effects models were reported in 41 (20.8%) and 24 (12.2%) articles, respectively, and increased in use over time. A positive trend in choice of more appropriate analytical methods was identified over time. CONCLUSIONS: Despite similar study designs across the reports, the statistical methods varied substantially and often represented overly simplistic models of risk. The results underscore the need for more effort to be channelled towards adopting standardized longitudinal methods to analyse prospective cohort studies of malaria infection and disease.

Exposure to and experiences of violence among adolescents in lower socio-economic groups in Johannesburg, South Africa.

BACKGROUND: We explored exposure to and experiences of violence and their risk factors amongst ethnically diverse adolescents from lower socio economic groups in Johannesburg. METHODS: This cross-sectional study recruited a stratified sample of 16-18 year old adolescents from four low socio-economic suburbs in Johannesburg to reflect ethnic group clustering. We collected socio-demographic, sexual behaviour, alcohol and drug use and trauma events data. Proportions and risk factors were assessed by chi-square and logistic regression. RESULTS: Of 822 adolescents, 57% (n = 469) were female. Approximately 62% (n = 506) were Black, 13% (n = 107) Coloured, 13% (n = 106) Indian and 13% (n = 103) White. Approximately 67% (n = 552) witnessed violence to a non-family member, 28% (n = 228) experienced violence by a non-family member, and 10% (n = 83) reported sexual abuse. Multivariate analysis determined that witnessing violence in the community was associated with being Black (OR: 4.6, 95%CI: 2.7-7.9), Coloured (OR: 3.9, 95%CI: 2.0-7.4) or White (OR: 8.0, 95%CI:4.0-16.2), repeating a grade (OR: 1.5, 95%CI: 1.01-2.1), having more than one sexual partner (OR: 1.7, 95%CI: 1.1-2.5) and ever taking alcohol (OR: 2.1, 95%CI: 1.5-2.9). Witnessing violence in the family was associated with being female (OR: 1.8, 95%CI: 1.3-2.6), being Black (OR: 2.2, 95%CI: 1.1-4.1), or White (OR: 3.0, 95%CI: 1.4-6.4), repeating a grade (OR: 1.6, 95%CI: 1.1-2.2) and ever taking alcohol (OR: 2.9, 95%CI: 2.0-4.3). CONCLUSIONS: In low socio-economic areas in Johannesburg, Black, White and Coloured adolescents experience a high burden of violence. Interventions to mitigate the effects of violence are urgently required.

Correlates of sexual risk among sexual minority and heterosexual South African youths.

We explored psychosocial correlates of sexual risk among heterosexual and sexual minority youths (SMYs) in Johannesburg, South Africa. Young people 16 to 18 years old (n = 822) were administered surveys assessing demographic characteristics, sexual behaviors, mental health, and parent-child communication. Adjusted multivariate regressions examining correlates of sexual risk revealed that SMYs had more sexual partners than heterosexual youths (B = 3.90; SE = 0.95; P < .001) and were more likely to engage in sex trading (OR = 3.11; CI = 1.12-8.62; P < .05). South African SMYs are at increased risk relative to their heterosexual peers.

Psychosocial correlates of alcohol and other substance use among low-income adolescents in peri-urban Johannesburg, South Africa: A focus on gender differences.

Alcohol and other drug use is prevalent among peri-urban, South African adolescents. We identified correlates of alcohol and other drug use by gender among adolescents (age = 16-18 years; N = 822) in peri-urban Johannesburg. Interviewer-administered surveys assessed sexual activity, alcohol and other drug use, and relevant psychosocial factors. In separate logistic regression models of alcohol and other drug use stratified by gender, violence exposure and sexual activity were associated with alcohol use for both males and females. For females only, depressive symptoms were associated with drug use. For males only, being older and sexually active were associated with drug use. Substance use interventions for South African adolescents should consider psychological health, sexual health, and tailoring by gender.

A review of the study designs and statistical methods used in the determination of predictors of all-cause mortality in HIV-infected cohorts: 2002-2011.

BACKGROUND: Research in the predictors of all-cause mortality in HIV-infected people has widely been reported in literature. Making an informed decision requires understanding the methods used. OBJECTIVES: We present a review on study designs, statistical methods and their appropriateness in original articles reporting on predictors of all-cause mortality in HIV-infected people between January 2002 and December 2011. Statistical methods were compared between 2002-2006 and 2007-2011. Time-to-event analysis techniques were considered appropriate. DATA SOURCES: Pubmed/Medline. STUDY ELIGIBILITY CRITERIA: Original English-language articles were abstracted. Letters to the editor, editorials, reviews, systematic reviews, meta-analysis, case reports and any other ineligible articles were excluded. RESULTS: A total of 189 studies were identified (n = 91 in 2002-2006 and n = 98 in 2007-2011) out of which 130 (69%) were prospective and 56 (30%) were retrospective. One hundred and eighty-two (96%) studies described their sample using descriptive statistics while 32 (17%) made comparisons using t-tests. Kaplan-Meier methods for time-to-event analysis were commonly used in the earlier period (n = 69, 76% vs. n = 53, 54%, p = 0.002). Predictors of mortality in the two periods were commonly determined using Cox regression analysis (n = 67, 75% vs. n = 63, 64%, p = 0.12). Only 7 (4%) used advanced survival analysis methods of Cox regression analysis with frailty in which 6 (3%) were used in the later period. Thirty-two (17%) used logistic regression while 8 (4%) used other methods. There were significantly more articles from the first period using appropriate methods compared to the second (n = 80, 88% vs. n = 69, 70%, p-value = 0.003). CONCLUSION: Descriptive statistics and survival analysis techniques remain the most common methods of analysis in publications on predictors of all-cause mortality in HIV-infected cohorts while prospective research designs are favoured. Sophisticated techniques of time-dependent Cox regression and Cox regression with frailty are scarce. This motivates for more training in the use of advanced time-to-event methods.

Factors associated with mortality in HIV-infected people in rural and urban South Africa.

BACKGROUND: Factors associated with mortality in HIV-infected people in sub-Saharan Africa are widely reported. However rural-urban disparities and their association with all-cause mortality remain unclear. Furthermore, commonly used classical Cox regression ignores unmeasured variables and frailty. OBJECTIVE: To incorporate frailty in assessing factors associated with mortality in HIV-infected people in rural and urban South Africa. DESIGN: Using data from a prospective cohort following 6,690 HIV-infected participants from Soweto (urban) and Mpumalanga (rural) enrolled from 2003 to 2010; covariates of mortality were assessed by the integrated nested Laplace approximation method. RESULTS: We enrolled 2,221 (33%) rural and 4,469 (67%) urban participants of whom 1,555 (70%) and 3,480 (78%) were females respectively. Median age (IQR) was 36.4 (31.0-44.1) in rural and 32.7 (28.2-38.1) in the urban participants. The mortality rate per 100 person-years was 11 (9.7-12.5) and 4 (3.6-4.5) in the rural and urban participants, respectively. Compared to those not on HAART, rural participants had a reduced risk of mortality if on HAART for 6-12 (HR: 0.20, 95% CI: 0.10-0.39) and >12 months (HR: 0.10, 95% CI: 0.05-0.18). Relative to those not on HAART, urban participants had a lower risk if on HAART >12 months (HR: 0.35, 95% CI: 0.27-0.46). The frailty variance was significant and >1 in rural participants indicating more heterogeneity. Similarly it was significant but <1 in the urban participants indicating less heterogeneity. CONCLUSION: The frailty model findings suggest an elevated risk of mortality in rural participants relative to the urban participants potentially due to unmeasured variables that could be biological, socio-economic, or healthcare related. Use of robust methods that optimise data and account for unmeasured variables could be helpful in assessing the effect of unknown risk factors thus improving patient management and care in South Africa and elsewhere.

Factors associated with not testing for HIV and consistent condom use among men in Soweto, South Africa.

BACKGROUND: Besides access to medical male circumcision, HIV testing, access to condoms and consistent condom use are additional strategies men can use to prevent HIV acquisition. We examine male behavior toward testing and condom use. OBJECTIVE: To determine factors associated with never testing for HIV and consistent condom use among men who never test in Soweto. METHODS: A cross-sectional survey in Soweto was conducted in 1539 men aged 18-32 years in 2007. Data were collected on socio-demographic and behavioral characteristics to determine factors associated with not testing and consistent condom use. RESULTS: Over two thirds (71%) of men had not had an HIV test and the majority (55%, n = 602) were young (18-23). Of those not testing, condom use was poor (44%, n = 304). Men who were 18-23 years (aOR: 2.261, CI: 1.534-3.331), with primary (aOR: 2.096, CI: 1.058-4.153) or high school (aOR: 1.622, CI: 1.078-2.439) education, had sex in the last 6 months (aOR: 1.703, CI: 1.055-2.751), and had ≥1 sexual partner (aOR: 1.749, CI: 1.196-2.557) were more likely not to test. Of those reporting condom use (n = 1036, 67%), consistent condom use was 43% (n = 451). HIV testing did not correlate with condom use. CONCLUSION: Low rates of both condom use and HIV testing among men in a high HIV prevalence setting are worrisome and indicate an urgent need to develop innovative behavioral strategies to address this shortfall. Condom use is poor in this population whether tested or not tested for HIV, indicating no association between condom use and HIV testing.

The effect of a maturing antiretroviral program on early mortality for patients with advanced immune-suppression in Soweto, South Africa.

OBJECTIVE: We hypothesize that time to initiate care and maturity of a treatment program impact on outcome of severely immuno-compromised patients with higher risk of mortality. DESIGN: We conducted a retrospective cohort analysis at the Perinatal HIV Research Unit Adult ART clinic, Soweto, South Africa. METHODS: ELIGIBILITY CRITERIA FOR THIS ANALYSIS WERE: attendance for minimum one visit between August 2004 and August 2010, age >18 years, CD4 count < 50 cells/mm(3) and ART-naïve at screening. We followed participants up to one year after ART initiation. We defined years 2004-2007 and 2008-2010 as the early and late eras respectively. Chi-square test and survival analysis methods were used for mortality comparisons between eras. RESULTS: Of 2357 patients eligible for antiretroviral treatment, 395 (17%) had CD4 counts < 50 cells/mm(3) and ART-naïve at screening. Overall 261 (66%) were women. Patients had similar median age (35 vs. 33.5 years, p=0.08), time to HAART initiation (7 days, p=0.18) and baseline CD4 count (20 vs. 23 cells/mm(3), p=0.5) between eras. Overall 63 (16%) patients died in their first year of treatment (2 per 100 person-months) and the main cause of death was tuberculosis (n=23, 37%). The proportion of deaths (52/262 vs. 11/133, p=0.003) and time to death from enrolment (logrank p=0.04) were significantly different between eras. CONCLUSION: Mortality decreased as the ART program matured in Soweto while time to initiation of treatment remained similar in both eras. Because ART guidelines were consistent during both eras, it is possible that with time, management of patients improved as expertise was gained.

Willingness to participate in biomedical HIV prevention studies after the HVTN 503/Phambili trial: a survey conducted among adolescents in Soweto, South Africa.

OBJECTIVES: Adolescents may be appropriate for inclusion in biomedical HIV prevention trials. Adolescents' overall willingness to participate (WTP) in biomedical HIV prevention trials was examined, including after the prematurely discontinued phase IIb HVTN 503/Phambili HIV vaccine trial, in Soweto, South Africa. METHODS: An interview-administered cross-sectional survey was conducted among 506 adolescents (16-18 years) between October 2008 and March 2009. The assessment included WTP in HIV prevention trials, sexual and substance use behavior, and related psychosocial constructs. Multivariate logistic regression analyses examined predictors of WTP in biomedical prevention trials. RESULTS: The sample primarily consisted of female participants (n = 298, 59%), and 50% of all participants were sexually active. WTP in general was high (93%), with 75% WTP in a vaccine trial after being informed about the HVTN 503/Phambili trial. Less exposure to stressors [odds ratio (OR): 2.8, confidence interval (CI): 1.3 to 6.3] was associated with adolescents' WTP in HIV biomedical prevention trials overall. Those with less exposure to stressors (OR: 1.7, CI: 1.1 to 2.8) and not sexually active (OR: 2.1, CI: 1.4 to 3.3) were predictive of WTP after the HVTN 503/Phambili trial. A higher number of sexual partners were associated with unwillingness to participate more generally (P = 0.039) and specifically after the HIV vaccine trial (P = 0.0004). CONCLUSIONS: The high level of adolescents' WTP in biomedical prevention trials is encouraging, especially after the prematurely discontinued HVTN 503/Phambili HIV vaccine trial. High-risk youth were less likely to be WTP, although those not yet sexually active were more WTP. Future biomedical HIV prevention trials should address challenges to enrollment of high-risk adolescents who may show less WTP.

Improving national data collection systems from voluntary counselling and testing centres in Kenya.

PROBLEM: Voluntary counselling and testing (VCT) data from the registered sites in Kenya have been fraught with challenges, leading to insufficient statistics in the national office for planning purposes. An exercise was carried out to determine the barriers to the flow of data in VCT sites in Kenya. APPROACH: A record-based survey was conducted at 332 VCT sites in Kenya. Data from on-site records were compared with those in the national office. The exercise was conducted in 2004 between 5 September and 15 October. LOCAL SETTING: All registered VCT sites in Kenya. RELEVANT CHANGES: After the exercise, various measures to enhance VCT data collection and reporting were implemented. They include the provision of a uniform data collection and reporting tool to all the districts in the country, the strengthening of a feedback mechanism to update provinces and districts on their reporting status and increased support to the data component of the national quality assurance for VCT. LESSONS LEARNED: Periodical field visits by the national officials to offer on-the-job training about data management to data collectors and to address data quality issues can dramatically improve the quality and completeness of VCT reports. The perceived relevance of the data and the data collection process to those working at the sites is the critical factor for data quality and timeliness of reporting.