Cervical cancer precursors and hormonal contraceptive use in HIV-positive women: application of a causal model and semi-parametric estimation methods.

OBJECTIVE: To demonstrate the application of causal inference methods to observational data in the obstetrics and gynecology field, particularly causal modeling and semi-parametric estimation. BACKGROUND: Human immunodeficiency virus (HIV)-positive women are at increased risk for cervical cancer and its treatable precursors. Determining whether potential risk factors such as hormonal contraception are true causes is critical for informing public health strategies as longevity increases among HIV-positive women in developing countries. METHODS: We developed a causal model of the factors related to combined oral contraceptive (COC) use and cervical intraepithelial neoplasia 2 or greater (CIN2+) and modified the model to fit the observed data, drawn from women in a cervical cancer screening program at HIV clinics in Kenya. Assumptions required for substantiation of a causal relationship were assessed. We estimated the population-level association using semi-parametric methods: g-computation, inverse probability of treatment weighting, and targeted maximum likelihood estimation. RESULTS: We identified 2 plausible causal paths from COC use to CIN2+: via HPV infection and via increased disease progression. Study data enabled estimation of the latter only with strong assumptions of no unmeasured confounding. Of 2,519 women under 50 screened per protocol, 219 (8.7%) were diagnosed with CIN2+. Marginal modeling suggested a 2.9% (95% confidence interval 0.1%, 6.9%) increase in prevalence of CIN2+ if all women under 50 were exposed to COC; the significance of this association was sensitive to method of estimation and exposure misclassification. CONCLUSION: Use of causal modeling enabled clear representation of the causal relationship of interest and the assumptions required to estimate that relationship from the observed data. Semi-parametric estimation methods provided flexibility and reduced reliance on correct model form. Although selected results suggest an increased prevalence of CIN2+ associated with COC, evidence is insufficient to conclude causality. Priority areas for future studies to better satisfy causal criteria are identified.

Assessing Surveillance Elements of the Zanzibar Malaria Elimination Program to Support Malaria Elimination in Zanzibar

Though significant progress has been made through control efforts in recent years, malaria remains a leading cause of morbidity and mortality throughout the world, with 3.2 billion people at risk of developing the disease. Zanzibar is currently pursuing malaria elimination through the Zanzibar Malaria Elimination Program (ZAMEP), and is working toward a goal of no locally acquired malaria cases by 2018. A comprehensive and well functioning malaria surveillance program is central to achieving this goal. Under ZAMEP’s current surveillance strategy, District Malaria Surveillance Officers (DMSOs) respond to malaria case notifications through the reactive case detection (RACD) system. Three malaria screening and treatment strategies are undertaken in response to this system, including household-level (HSaT), focal-level (FSaT), and mass-level (MSaT). Each strategy is triggered by a different case threshold and tests different-sized populations. The aims of this study were to (1) assess the cost effectiveness of three malaria screening and treatment strategies; (2) assess the timeliness and completeness of ZAMEP’s RACD system; (3) and qualitatively explore the roles of DMSOs.

Screening disposition and budget information for 2014 screening and treatment strategies was analyzed to determine prevalence rates in screened populations and the cost effectiveness of each strategy. Prevalence rates within the screened population varied by strategy: 6.1 percent in HSaT, 1.2 percent in FSaT, and 0.9 percent in MSaT. Of the various costing scenarios considering cost per person screened, MSaT was the most cost-effective, with costs ranging from $9.57 to $12.57 per person screened. Of the various costing scenarios considering cost per case detected, HSaT was the most cost-effective, at $385.51 per case detected.

Case data from 2013 through mid-2015 was used to assess the timeliness and completeness of the RACD system. The average number of RACD activities occurring within 48 hours of notification improved slightly between 2013 and the first half of 2015, from 90.7 percent to 93.1 percent. The average percentage of household members screened during RACD also increased over the same time period, from 84 percent in 2013 to 89.9 percent in the first half of 2015.

Interviews with twenty DMSOs were conducted to gain insights into the challenges to malaria elimination both from the health system and the community perspectives. Major themes discussed in the interviews include the need for additional training, inadequate information capture at health facility, resistance to household testing, transportation difficulties, inadequate personnel during the high transmission season, and community misinformation.

Zanzibar is now considered a low transmission setting, making elimination feasible, but also posing new challenges to achieving this goal. The findings of this study provide insight into how surveillance activities can be improved to support the goal of malaria elimination in Zanzibar. Key changes include reevaluating the use of MSaT activities, improving information capture at health facilities, hiring additional DMSOs during the high transmission season, and improving community communication.