The results presented in this paper yield three main results. First, similar to other studies, sickle cell trait (SCT) was found to be protective against malaria, with an estimated incidence reduction of 29% in fully adjusted models. Despite this reduced incidence of malaria, individuals with SCT did not show any greater educational attainment. However when analysis was restricted to individuals with SCT, exposure to malaria was associated with reduced school enrollment, even after adjusting for geographic and socioeconomic differences.
With respect to estimated effect sizes, the protective effect of SCT on malaria observed in this sample was notably smaller than recent estimates from Kenya, where a 50% reduction in the incidence of mild malaria, a 75% reduction in hospitalization and 90% reduction for severe malaria  was found, but similar to a recent study from Ghana, where a relative risk of 0.82 was found for subjects with SCT . Interestingly, in both the Kenya study  and the study presented here, reduced exposure to confirmed cases of malaria did not result in reduced exposure to fevers more generally. One possible explanation for the relatively smaller protective effect observed in the study setting may have been the average age of subjects. An average age of 16 years old at the study endpoint implies that many participants were observed after the likely development of immunity to malaria for the entire 7 year period of febrile illness monitoring. The lower protective effect could also have been due to the rapidly dropping malaria burden, which has been observed in the study region after 2008 by several analyses [18, 20] and can very easily be seen in Fig. 1 of this paper as well. While the determinants of this decline are still not well understood, it seems likely that malaria control interventions such as Tanzania’s large scale bed net distribution campaign for all children under 5 years in 2008–2009 and for every sleeping space in 2010–2011, and the change in first line treatment to artemisinin combination therapy in 2007, played a major role. Other possible contributing factors include changes in climate, improved health service provision, and socio-economic development. The smaller estimated effects for fever incidence could be interpreted as evidence for SCT being associated with an increased incidence of other infections. However, the sample size of this study is not large enough to precisely estimate such differences.
Despite finding that SCT conferred protection from malaria, no associations between SCT and educational attainment were observed. This lack of association could partially have been due to the relatively small sample of 704 individuals, with only 81 SCT cases. (The sample was limited to 704 cases because these were the only individuals who were genotyped for SCD within the study area.) As a result, the study was only powered to reliably detect relatively large effect sizes. For example, in unadjusted models, the study was powered to detect an increase of 0.8 years of school attainment with 80% power. While the minimum detectable effect was smaller in adjusted models, because covariates such as age explain a great deal of the variation in schooling, power nonetheless remains a limitation of this study.
It is also possible that with half of the study population still in school, differences in educational attainment may not have fully emerged yet. Another possibility is that despite its frequent use in this literature [7,8,9,10,11,12], educational attainment is not an ideal measure for the underlying trait of cognitive improvement. While some studies have identified a link between malaria protection and schooling attainment , others have found cognition effects without educational attainment effects. For example a recent study which found links between birth year exposure to malaria eradication in Mexico and cognitive gains as measured by Raven progressive matrices nonetheless did not find schooling attainment gains . In settings where poverty is a barrier to continued education, increased ability may not translate directly into increased educational attainment.
It is also worth highlighting that in the six villages studied, starting in 2007 malaria treatment was provided by community health workers, who used rapid diagnostic tests (RDTs) to diagnose malaria. The presence of trained CHWs may have reduced the risk of malaria cases progressing in severity, and thus lowered the overall impact of malaria exposure. This would have had the effect of dampening the sickle-cell trait-induced differences in malaria morbidity between HbAS (SCT) and HbAA groups. Another potential reason why increased education as a result of sickle cell trait was not observed could be because individuals with and without sickle cell trait differ on unobserved characteristics in addition to their differential susceptibility to malaria. Table 1 shows relatively modest differences across the two groups on observed characteristics, but other unmeasured or unobservable differences between HbAS (SCT) and HbAA households are possible. For example, individuals with sickle cell trait are more likely to have a sibling with sickle cell disease, a serious illness which could necessitate that family resources are devoted to medical care rather than education.
Finally, within the SCT group, malaria was associated with lower levels of school enrollment, even after controlling for a range of socioeconomic and demographic factors. This suggests that even in the SCT group, which was relatively protected from malaria, there may have been subpopulations which are particularly vulnerable to acute episodes of malaria that have deleterious effects on longer run social and developmental outcomes. This is an area that should be researched further.
Given the wide range of studies which suggest long run benefits to malaria protection in childhood [7,8,9,10,11,12], the relationship between SCT and long run cognitive development should be further investigated. This study points towards two potential avenues for future research. First, researchers could follow up on this or similar populations to determine whether SCT-induced protection from malaria translates into cognitive differences when measured directly via standard batteries of cognitive tests, rather than the proxy of educational attainment. Second, alternative empirical strategies can be applied to isolate the causal effect of reduced malaria morbidity on cognitive ability. In this study, just 145 out of 704 children were genotyped together with other members of their household, which was too small of a sample to estimate household fixed effects models. Future data collection efforts could be designed to exploit within-household variation on hemoglobin genotype, thereby eliminating the possibility that differences in household level characteristics such as wealth or parental education are confounding the hypothesized relationship of SCT to educational or cognitive outcomes.