Bias and precision in early phase adaptive oncology studies and its consequences for confirmatory trials

The need for a more efficient drug development process led to migration from the traditional fixed-sample clinical trial designs to group-sequential and adaptive designs, especially in early phases of clinical drug development. This, however, came with challenges in inference, since many of these newly proposed designs come without respective methods for statistical inference. In this dissertation, we study the estimation methods for oncology phase II group-sequential and adaptive designs in terms of bias and precision, and we propose new estimation methods for a new class of adaptive designs. We then evaluate the consequences, in terms of power, of using estimates from these designs to plan phase III trial. We also study and propose new approaches to adjust these estimates, based on the observed data, before employing them in planning of phase III sample size, in order to reach the desired power. Literature review showed that many estimation methods have been proposed for the classical single-arm two-stage group-sequential designs with a binary endpoint, which are the most commonly used designs in oncology trials of phase II. Simulation studies showed that the uniformly minimum variance unbiased estimator is the best amongst them in terms of bias and mean square error. However, for the adaptive group-sequential designs, these estimation methods have poor performance. Our proposed estimation methods in oncology phase II adaptive designs showed better performance as compared to the naive maximum likelihood estimator. A direct use of estimates from phase II adaptive designs to plan phase III results in underpowered phase III trials. Therefore, adjusting (discounting) these estimates beforehand is necessary. The amount of discounting, however, depends on the estimator, with our proposed estimators requiring less discounting as compared to the naive maximum likelihood estimator. Our proposed adjustment approaches show power improvements, which are similar across different estimators and design scenarios

Household modifications after the indoor residual spraying (IRS) campaign in Mozambique reduce the actual spray coverage and efficacy

Indoor residual spraying of insecticides (IRS) is a key malaria vector control strategy. Whilst human attitude towards IRS is monitored before or shortly after implementation, human activities leading to the modification of insecticide-treated walls post-IRS are not. This could inadvertently reduce the protective effects of IRS. We monitored the extent of modifications to the sprayed indoor wall surfaces by household owners for six months post-IRS campaigns in two districts targeted for malaria elimination in southern Mozambique. In parallel, we assessed building of any additional rooms onto compounds, and mosquito net use. We quantified the contribution of wall modifications, added rooms, prolonged spray campaigns, and product residual efficacies on actual IRS coverage and relative mosquito bite reduction, using a mechanistic approach. Household owners continually modified insecticide-treated walls and added rooms onto compounds. Household surveys in southern Mozambique showed frequent modification of indoor walls (0–17.2% of households modified rooms monthly) and/or added rooms (0–16.2% of households added rooms monthly). Actual IRS coverage reduced from an assumed 97% to just 39% in Matutuine, but only from 96% to 91% in Boane, translating to 43% and 5.8% estimated increases in relative daily mosquito bites per person. Integrating post-IRS knowledge, attitude, and practice (KAP) surveys into programmatic evaluations to capture these modification and construction trends can help improve IRS program efficiency and product assessment

Patterns of age-specific mortality in children in endemic areas of sub-Saharan Africa.

Understanding of the age- and season- dependence of malaria mortality is an important prerequisite for epidemiologic models of malaria immunity. However, most studies of malaria mortality have aggregated their results into broad age groups and across seasons, making it hard to predict the likely impact of interventions targeted at specific age groups of children. We present age-specific mortality rates for children aged < 15 years for the period of 2001-2005 in 7 demographic surveillance sites in areas of sub-Saharan Africa with stable endemic Plasmodium falciparum malaria. We use verbal autopsies (VAs) to estimate the proportion of deaths by age group due to malaria, and thus calculate malaria-specific mortality rates for each site, age-group, and month of the year. In all sites a substantial proportion of deaths (ranging from 20.1% in a Mozambican site to 46.2% in a site in Burkina Faso) were attributed to malaria. The overall age patterns of malaria mortality were similar in the different sites. Deaths in the youngest children (< 3 months old) were only rarely attributed to malaria, but in children over 1 year of age the proportion of deaths attributed to malaria was only weakly age-dependent. In most of the sites all-cause mortality rates peaked during the rainy season, but the strong seasonality in malaria transmission in these sites was not reflected in strong seasonality in the proportion of deaths attributed to malaria, except in the two sites in Burkina Faso. Improvement in the specificity of malaria verbal autopsies would make it easier to interpret the age and season patterns in such data

Spatio-seasonal modeling of the incidence rate of malaria in Mozambique

<p>Abstract</p> <p>Background</p> <p>The objective was to study the seasonal effect on the spatial distribution of the incidence of malaria in children under 10 years old living in the Manhiça district, Mozambique.</p> <p>Methods</p> <p>The data of the clinical malaria incidence were obtained from a study of two cohorts of children followed from December 1996 to July 1999. The cases were obtained by the active detection method. Hierarchical Bayesian models were used to model the incidence of malaria, including spatial correlation nested to climatic season. The models were compared with the deviance information criterion. The age and gender of the children were also taken into account.</p> <p>Results</p> <p>The incidence of malaria is associated with age, period and climate season. The incidence presents a clear spatial pattern, with a higher incidence in the neighbourhoods situated in the north and northeast of the Manhiça area. The transmission of malaria is highest during the wet season but the spatial pattern of malaria does not differ from that during the dry season.</p> <p>Conclusion</p> <p>The incidence of malaria in Manhiça presents a spatial pattern which is independent of the seasonal climatic conditions. The climate modifies the incidence of malaria in the entire region but does not change the spatial pattern of the incidence of this disease. These findings may be useful for the planning of malaria control activities. These activities can be performed taking account that the neighbourhoods with more incidence of malaria do not change over the annual climate seasons.</p

Levels and trends of demographic indices in southern rural Mozambique: evidence from demographic surveillance in Manhica district

Background: In Mozambique most of demographic data are obtained using census or sample survey including indirect estimations. A method of collecting longitudinal demographic data was introduced in southern Mozambique since 1996 (DSS -Demographic Surveillance System in Manhiça district, Maputo province), but the extent to which it yields demographic measures that are typical of southern rural Mozambique has not been evaluated yet. Methods: Data from the DSS were used to estimate the levels and trends of fertility, mortality and migration in Manhiça, between 1998 and 2005. The estimates from Manhiça were compared with estimates from Maputo province using the 1997 National census and 1997 Demographic and Health Survey (DHS). The DHS data were used to estimate levels and trends of adult mortality using the siblings' histories and the orphanhood methods. Results: The populations in Manhiça and in Maputo province are young (44% <15 years in Manhiça and 42% in Maputo); with reduced adult males when compared to females (all ages sex ratio of 78.7 in Manhiça and 89 in Maputo). Fertility in Manhiça is at a similar level as in Maputo province and has remained around 5 children per woman, during the eight years of surveillance in Manhiça. Although the infant mortality rate (IMR) in Mozambique has decreased during the last two decades (from 148 deaths per 1000 live births in 1980 to 101 in 2003), it has remained stable around 80 in Manhiça during the surveillance period. Adult mortality has increased both in Manhiça (probability of dying from ages 15 to 60 increased from 0.4 in 1998 to 0.6 in 2005 in Manhiça, from 0.3 in 1992 to 0.4 in 1997 in Maputo province and from 0.1 in 1980 to 0.6 in 2000 in Mozambique). Consequently, the life expectancy decreased from 53 to 46 in Manhiça and from 42 years in 1997 to 38 in 2004 in Mozambique. Migration is high in Manhiça but tends to stabilise after the movements of resettlement that followed the end of the civil war in 1992. Conclusion: The population under demographic surveillance in Manhiça district presents characteristics that are typical of southern rural Mozambique, with predominance of young people and reduction of adult males. Labour migration and excess adult male mortality are the major factors for the reduction of adult males. Mortality is high and only infant mortality has started to stabilise while adult mortality has increased, and as consequence, life expectancy has decreased. The Manhiça DSS is an adequate tool to report demographic measures for southern rural Mozambique

Determinants of household demand for bed nets in a rural area of southern Mozambique

<p>Abstract</p> <p>Background</p> <p>A key to making insecticide-treated nets (ITNs) a long-term, sustainable solution to the spread of malaria is understanding what drives their purchase and use. Few studies have analysed the determinants of demand for bed nets for malaria prevention at the household level, and in particular, how demand for nets compares with demand for other mosquito prevention methods.</p> <p>Methods</p> <p>This study uses a household survey to assess the determinants of demand for bed nets in an area of endemic malaria transmission in rural, southern Mozambique. The study looks at willingness to pay (WTP) for bed nets, net ownership, usage, and past purchase behaviour, alongside expenditure and frequency of use of alternate methods for malaria prevention.</p> <p>Results</p> <p>While overall net ownership in the sample is low, the evidence fails to suggest that poorer households are less likely to own bed nets, when controlling for covariates, nor does the likelihood of receiving a free net depend on socioeconomic status (SES). Formal schooling and market knowledge seem to indicate higher average willingness to pay, while use of alternate methods for malaria prevention, and receipt of Indoor Residual Spraying (IRS) are found to decrease demand for bed nets.</p> <p>Conclusion</p> <p>For long-term sustainability of ITNs to be realized, results suggest that either full or partial subsidies may be necessary in some contexts to encourage households to obtain and use nets. Given the possible substitution effects of combined malaria control interventions, and the danger of not taking into consideration household preferences for malaria prevention, successful malaria control campaigns should invest a portion of their funds towards educating recipients of IRS and users of other preventive methods on the importance of net use even in the absence of mosquitoes.</p

Spatio-temporal analysis of mortality among children under the age of five in Manhiça (Mozambique) during the period 1997-2005

<p>Abstract</p> <p>Background</p> <p>Reducing childhood mortality is the fourth goal of the Millennium Development Goals agreed at the United Nations Millennium Summit in September 2000. However, childhood mortality in developing countries remains high. Providing an accurate picture of space and time-trend variations in child mortality in a region might generate further ideas for health planning actions to achieve such a reduction. The purpose of this study was to examine the spatio-temporal variation for child mortality rates in Manhiça, a district within the Maputo province of southern rural Mozambique during the period 1997-2005 using a proper generalized linear mixed model.</p> <p>Results</p> <p>The results showed that childhood mortality in all the area was modified from year to year describing a convex time-trend but the spatial pattern described by the neighbourhood-specific underlying mortality rates did not change during the entire period from 1997 to 2005, where neighbourhoods with highest risks are situated in the peripheral side of the district. The spatial distribution, though more blurred here, was similar to the spatial distribution of child malaria incidence in the same area. The peak in mortality rates observed in 2001 could have been caused by the precipitation system that started in early February 2000, following which heavy rains flooded parts of Mozambique's southern provinces. However, the mortality rates at the end of the period returned to initial values.</p> <p>Conclusions</p> <p>The results of this study suggest that the health intervention programmes established in Manhiça to alleviate the effects of flooding on child mortality should cover a period of around five years and that special attention might be focused on eradicating malaria transmission. These outcomes also suggest the utility of suitably modelling space-time trend variations in a region when a point effect of an environmental factor affects all the study area.</p

Levels and trends of demographic indices in southern rural Mozambique: evidence from demographic surveillance in Manhiça district

BACKGROUND: In Mozambique most of demographic data are obtained using census or sample survey including indirect estimations. A method of collecting longitudinal demographic data was introduced in southern Mozambique since 1996 (DSS -Demographic Surveillance System in Manhiça district, Maputo province), but the extent to which it yields demographic measures that are typical of southern rural Mozambique has not been evaluated yet. METHODS: Data from the DSS were used to estimate the levels and trends of fertility, mortality and migration in Manhiça, between 1998 and 2005. The estimates from Manhiça were compared with estimates from Maputo province using the 1997 National census and 1997 Demographic and Health Survey (DHS). The DHS data were used to estimate levels and trends of adult mortality using the siblings' histories and the orphanhood methods. RESULTS: The populations in Manhiça and in Maputo province are young (44% <15 years in Manhiça and 42% in Maputo); with reduced adult males when compared to females (all ages sex ratio of 78.7 in Manhiça and 89 in Maputo). Fertility in Manhiça is at a similar level as in Maputo province and has remained around 5 children per woman, during the eight years of surveillance in Manhiça. Although the infant mortality rate (IMR) in Mozambique has decreased during the last two decades (from 148 deaths per 1000 live births in 1980 to 101 in 2003), it has remained stable around 80 in Manhiça during the surveillance period. Adult mortality has increased both in Manhiça (probability of dying from ages 15 to 60 increased from 0.4 in 1998 to 0.6 in 2005 in Manhiça, from 0.3 in 1992 to 0.4 in 1997 in Maputo province and from 0.1 in 1980 to 0.6 in 2000 in Mozambique). Consequently, the life expectancy decreased from 53 to 46 in Manhiça and from 42 years in 1997 to 38 in 2004 in Mozambique. Migration is high in Manhiça but tends to stabilise after the movements of resettlement that followed the end of the civil war in 1992. CONCLUSION: The population under demographic surveillance in Manhiça district presents characteristics that are typical of southern rural Mozambique, with predominance of young people and reduction of adult males. Labour migration and excess adult male mortality are the major factors for the reduction of adult males. Mortality is high and only infant mortality has started to stabilise while adult mortality has increased, and as consequence, life expectancy has decreased. The Manhiça DSS is an adequate tool to report demographic measures for southern rural Mozambique

Continuum of HIV Care in Rural Mozambique: The Implications of HIV Testing Modality on Linkage and Retention

INTRODUCTION: Context-specific improvements in the continuum of HIV care are needed in order to achieve the UNAIDS target of 90-90-90. This study aimed to assess the linkage to and retention in HIV care according to different testing modalities in rural southern Mozambique. METHODS: Adults newly diagnosed with HIV from voluntary counseling and testing (VCT), provider-initiated (PICT) and home-based HIV testing (HBT) services were prospectively enrolled between 2014- 2015 at the Manhica District. Patients were passively followed-up through chart examination .Tracing was performed at 12-months to ascertain causes of loss to follow-up. Fine and Grey competing risk analysis was performed to determine factors associated with the each step of the cascade. RESULTS: Overall linkage to care as defined by having a CD4 count at 3 months, was 43.7% (95CI% 40.8-46.6) and 25.2% of all participants initiated ART. Factors associated with increased linkage in multivariable analysis included testing at VCT, older age, having been previously tested for HIV, owning a cell phone, presenting with WHO clinical stages III/IV, self-reported illness-associated disability in the previous month , and later calendar month of participant recruitment. Ascertaining deaths and transfers allowed adjustment of the rate of 12-month retention in treatment from 75.6% (95% CI 70.2-80.5) to 84.2% (95% CI 79.2-88.5). CONCLUSIONS: HBT reached a socio-demographically distinct population from that of clinic based testing modalities but low linkage to care points to a need for facilitated linkage interventions. Distinguishing between true treatment defaulting and other causes of loss-to-follow-up can significantly change indicators of retention in care