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. 2020 Sep 10;15(9):e0238504. doi: 10.1371/journal.pone.0238504

Bayesian spatio-temporal modeling of malaria risk in Rwanda

Muhammed Semakula 1,3,*, Franco̧is Niragire 2, Christel Faes 1
Editor: Emanuele Giorgi4
PMCID: PMC7482939  PMID: 32911503

Abstract

Every year, 435,000 people worldwide die from Malaria, mainly in Africa and Asia. However, malaria is a curable and preventable disease. Most countries are developing malaria elimination plans to meet sustainable development goal three, target 3.3, which includes ending the epidemic of malaria by 2030. Rwanda, through the malaria strategic plan 2012-2018 set a target to reduce malaria incidence by 42% from 2012 to 2018. Assessing the health policy and taking a decision using the incidence rate approach is becoming more challenging. We are proposing suitable statistical methods that handle spatial structure and uncertainty on the relative risk that is relevant to National Malaria Control Program. We used a spatio-temporal model to estimate the excess probability for decision making at a small area on evaluating reduction of incidence. SIR and BYM models were developed using routine data from Health facilities for the period from 2012 to 2018 in Rwanda. The fitted model was used to generate relative risk (RR) estimates comparing the risk with the malaria risk in 2012, and to assess the probability of attaining the set target goal per area. The results showed an overall increase in malaria in 2013 to 2018 as compared to 2012. Ofall sectors in Rwanda, 47.36% failed to meet targeted reduction in incidence from 2012 to 2018. Our approach of using excess probability method to evaluate attainment of target or identifying threshold is a relevant statistical method, which will enable the Rwandan Government to sustain malaria control and monitor the effectiveness of targeted interventions.

1 Introduction

Malaria remains a public health threat in developing countries, even though it is a preventable and curable disease. Every two minutes, the life of a child under age five is lost due to the disease [1]. There are a total of 435,000 deaths per year because of malaria, mainly in Africa and Asia [2]. Though some countries have successfully eliminated malaria, those with a high burden of disease have recorded an increase in malaria cases for the last decade. Sub-Saharan Africa and India contributed eight percent to the global burden [2].

The World Health Organization (WHO) Global Technical Strategy for malaria (GTS) aims to eliminate malaria worldwide by 2030. WHO classified countries and communities based on progress towards elimination of malaria (Control or Elimination). Malaria elimination is defined as the interruption of local transmission by reducing the rate of malaria cases to zero for a specific malaria parasite in a defined geographic area over particular time period. Malaria control is defined as a reduction of disease incidence, prevalence, morbidity or mortality to a locally acceptable level as a result of deliberate efforts. Most countries have placed malaria elimination by 2020 on their health agenda, though fewer than 30 countries worldwide were certified malaria-free by WHO in the last 60 years [3, 4].

The Malaria elimination feasibility studies proved that it can be eliminated. Elimination of malaira requires a strong health system that where communities have to access quality services, strong health information systems for tracking progress, effective surveillance, and system for public health response [3].

The Malaria Strategic Plan (MSP) 2012-2018 contained ambitious goals aimed at eliminating malaria death and reducing malaria morbidity by 2018, with a testing yield less than 5% test positivity rate by 2018 [5]. Contrary to expectation, the number of malaria cases increased in Rwanda, with 10 times more cases in 2017 as compared to 2011. The increase in malaria cases is often associated with the direct and indirect influence of climate change [6]. The 2016 Mid-Term Review Report (MTR) of MSP concluded that it is unlikely that Rwanda will meet the pre-elimination objectives and recommended not to review applicability and implementation of pre-elimination in line with WHO Guidelines. The MTR acknowledged the performance level of health management information system (HMIS) [5, 7].

The Rwanda health sector strategic plan (HSSP III) presented five key strategies for the pre-elimination phases and five indicators to be tracked that including (1) reducing malaria prevalence among women and children under-five, (2) the reduction of malaria incidence from 26 per 1000 in 2011 to 20 per 1000 in 2015 and to 15 per 1000 in 2018 (with a positivity rate less than 5%), (3) increasing the number children under five sleeping in Long-Lasting Insecticidal Nets(LLIN) to 82% in 2018 from 15% in 2011, (4)reducing malaria proportional morbidity from 4 to 3 in 2018; (5) and increasing the percentage of households with at least 1 LLIN installed from 82% to above 85% in 2018 [8].

The elimination of malaria requires a strong surveillance system to detect malaria infections early and enable a rapid and effective response. The World Health Organization and Global Fund promote the use of a health information system. Most developing countries adopted District Health Information Software (DHIS) [9]. The DHIS is a free and open source platform for the management of routine health information with a primary focus on producing health statistics [10]. Rwanda’s health system uses DHIS for data recording, reporting, and analysis. The statistical analyses offered by DHIS include basic descriptive statistics and data visualizations. For the epidemiological surveillance of malaria, HMIS enables aggregation of data in one platform from all health facilities in Rwanda. Those data are used for further statistical analysis to inform evidence-based strategies to control malaria. The Rwanda Malaria control program uses WHO recommended operational methods to detect the epidemic threshold. The method is to compare the constant case count with mean ± 2 SD (standard deviation) or median + the upper third quintile of the previous year’s series data [11]. The incidence maps used for decision making rely on a fixed cut off to determine a high or low incidence rate. However, none of those estimation methods take into consideration the spatial uncertainty or account for the population at risk. Nevertheless, those methods are sensitive to outliers and unlikely to detect malaria patterns in low transmission areas [12]. These approaches can help to visualize the overall dispersion around prevalence or incidence estimates but do not provide any information linked to the uncertainty of exceeding probability or incidence threshold [13].

Currently, there is an increase in the use of model-based approaches with data from surveys as suggested by authors of the feasibility of the malaria elimination phase [14]. The surveys are often inadequately powered to detect very low levels of heterogeneous transmission and those surveys are performed periodically, most often every five years. In contrast, routinely collected clinical data are timely and local. Few studies have combined model-based approaches, routinely collected clinical data, and population census data to inform national malaria elimination efforts.

A model-based approach of studying geospatial malaria trends is useful in identifying risk factors in the general population and informing evidence based-decisions. The statistical models allow the inclusion of a variety of features that capture the variation of disease risk [15]. In this paper, spatio-temporal methods will be used to investigate the geographical variation of malaria risk. We use routinely collected malaria data from health facilities in each sector of Rwanda to illustrate a formal assessment of pre-specified target goals, which can be used to evaluate reduction of incidence and progress towards targets. Understanding geographic disparities at a broad level is useful to a certain extent, but is unlikely to accurately reflect the heterogeneity in outcomes at the local level [16]. Malaria elimination efforts can benefit greatly by quantifying the variation across population groups and small geographical areas. An understanding of the geographic patterns of malaria can inform decision making by the government, and non-governmental organizations for policy development, targeted interventions and the adequate allocation resources at the area with the most acute need.

2 Materials and methods

2.1 Data source

We used data on malaria cases from the Rwanda health information system (HMIS) for the period from January 1, 2012 through December 31,2018. Over 95% of malaria cases reported through HMIS in Rwanda are laboratory confirmed [17]. Data on the number of malaria cases are available at the level of the health centre and are disaggregated by sex and age. Rwanda’s health system is organized into hierarchy of five levels: (1) referral hospitals provide the highest levels of specialty care, followed by (2) district hospitals and (3) health centers at the sector level. Below health centres are community-based health services including (4) health posts and (5) community health workers. Rwanda has 416 administration sectors and each has at least one health centre. For this analysis, we analyzed malaria cases at the sector level. For the children under five, which constituted 12% of cases, data is not disaggregated by sex. Therefore, these cases were excluded from the analysis.

Population data for 2012 were taken directly from the 2012 census. For population estimates in the period from 2013 to 2018. We used projections based on the 2012 census. Population data were downloaded from the following link www.statistics.gov.rw/datasource/42.

2.2 SIR

We adapted the traditional approach of calculating the Standardized Incidence Ratio (SIR) in each area i (i = 1, …, n) and year t (t = 2012, 2013, …, 2018), correcting for the age, and gender- demographic structure in an area. We will use the SIR as a tool to investigate the change in malaria risk at time t as compared to a certain reference year, in our case, the year 2012. As result, we define the SIR as the ratio of the number of observed cases yit to the number of expected cases Eit in the ith area at time t:

SIRit=yitEit, (1)

with the expected number of cases calculated as

Eit=j=1JNijtrj (2)

the rj is the reference rates in age and gender-group j and Nijt is the population in the area i, age-gender group j and time t:

rj=yj2012Nj2012 (3)

where yj2012 are the cases observed in age/gender group j in Rwanda in 2012, and Nj2012 is the census population for 2012 in Rwanda in the corresponding age/gender group.

To evaluate progress towards the targeted reduction of malaria incidence in the Malaria strategic plan 2012-2018, the reference rate is based on the malaria incidence in year 2012. This will enable comparison of malaria rates with subsequent years. The expected counts therefore represent the total number of malaria cases that one would expect if the population in area i contracted the disease at the same rate as in 2012.

2.3 Model specification

As SIR uses information only from within an area, it might produce uncertain estimates for small areas. Classical methods do not take into account the spatial dependence among the areas. Therefore, we used Bayesian disease mapping approaches that take into account the spatial dependence among neighboring areas.

A Bayesian disease mapping model consists of three components: the data model (i.e. the distribution of the data given the parameters), the process model (i.e. a description of underlying spatial trend) and the parameter model (i.e. the prior distribution of the parameters to be estimated) [18]. The data model is given by

YitPoisson(Eitθit), (4)

where a Poisson distribution is appropriate since disease data are counts (number of cases and are non-negative). It is assumed that the mean is a product of the expected count Eit and the relative risk θit.

The process model describes the underlying structure of the relative risks. We used the spatio-temporal extension of the spatial Besag-York-Mollie (BYM) model, which is the CAR convolution model with two random effects, one spatially-structured area-specific random effect and one unstructured area-specific random effect [19, 20]

log(θi)=α+ui+υi+γt+ψt+δit (5)

where, ui is the spatially-structured area-specific random effect which allows for smoothing amongst adjacent areas, namely [19]

ui|ujN(μ¯δi,σu2nδi)

with δi and nδi respectively, the set of neighbours and number of neighbours for a specific area i. The unstructured component υi is modeled using as a Gaussian process

υiN(0,συ2),

and allows for extra heterogeneity in the counts due to unobserved (and spatially unstructured) risk factors. The γt term represents the temporally structured effect, modeled dynamically using random walk of order 2 (RW of order 2) and defined as

γt|γt-1,γt-2N(2γt-1+γt-2,σ2).

The term ψt is specified by means of Gaussian exchangeable prior, defined as ψtN(0,1τψ). In order to allow for interaction between space and time, which explain differences in the time trend of malaria risk for different areas, the parameter δit follow a Gaussian Distribution with a precision matrix given by τδRδ, where τδ is unknown scalar, while Rδ is the structure matrix, identifying the type of temporal and/ or spatial dependence between the elements of δ. Rδ can be factorized as the Kronecker product of the structure matrix of corresponding main effects which interact. There are four ways to define the structure matrix as presented in literature [21] and reported in Table 1. We fitted models that consider three different types of interactions.

Table 1. Interaction types: Parameter interacting and rank of Rδ.

Type of interaction structure matrix Rank
Type I interaction Rδ = RυRψ = II = I nT
Type II interaction Rδ = RυRγ n(T − 2) for RW2
Type III interaction Rδ = RψRu (n − 1)T

The best model was chosen basing on deviance information criterion (DIC) [18], sensitivity analysis and condition predictive ordinate (CPO) [22]. The DIC is a popular choice for model selection, although it has been demonstrated that DIC might be problematic in practice [23]. It is based on the productive accuracy of the estimated model, connecting for the number of parameters to be estimated after incorporating the prio information. The CPO is defined as CPOi=π(yiobs|y-i); yi denotes the observations y with the i-th component omitted. Therefore, it is leave one out cross-validation scare. it expresses the posterior probability of observing value yi, when the model is fitted to all data except yi. Based on the CPO-values a logarthmic score is defined as −∑logCPOI. Smaller values of this scare indicates a better predictive quality of the model. The CPO are computed after description of models in R-INLA routenely via importance sampling without rerunning the model [24].

The type I interaction corresponds to a combination of an independent spatial and temporal random effect. As the spatial effect, temporal effect are assumed to be independent, an interaction of those have the correlation matrix Rδ = RυRψ = II = I,. Thus, we assume no spatial and /or temporal structure on the interaction either and therefore δitNormal(0,1τδ).

The Type II interaction combines a structured temporal effect with an unstructured spatial effect. The structure matrix therefore is defined as Rδ = RυRγ, where Rυ = I and Rδ is the neighborhood structure specified for instance through a first or second order random walk. This leads to an interaction term which is temporally correlated whith each spatial unit, while the time trends in the defferent areas are independent. The Type III interaction combines an unstructured temporal effect with a spatially structured effect. The structure matrix is defined as Rδ = RψRu, where Rψ = I and Ru is a neighboring defined through the CAR specification. This leads to the assumption that the parameters t′ ≠ t at time point t {δt, …, δnt}, have a spatial structure independent from the other time points.

We assigned a gamma distribution with shape equal 0.5 and rate equal to 0.00149 following the approach of Fong et al.(2010) [25] and it was not sensitive to arbitrary choices after sensitivity analysis. For the remaining parameters, we assigned prior distributions to scaled precision matrix parameters based on their marginal standard deviations on its diagonal following methods proposed by Sorby and Rue (2013) [26].

In order to investigate whether or not a reduction of malaria was observed compared to the overall incidence rate in 2012, we make use of excess probability. The probability that the malaria risk has decreased by c% is calculated as the posterior probability P(θit < (100 − c)%). If |P| is large, the set goal is likely reached in that area, while if |P| small, it is very likely that is has not been reached.

2.4 Estimation methods

We used Integrated Nested Laplace approximation (INLA) for estimation. The INLA is a deterministic algorithm for Bayesian inference and is designed for latent Gaussian models and spatial models. Bayesian estimation using the INLA methodology takes much less time as compared to estimation using Markov Chain Monte Carlo Methods (MCMC) [27].

We performed a sensitivity analysis on a variety of model formulations for the latent level due to the inherent issues that come with each formulation. It is well known from literature that in the BYM model, the spatially structured component cannot be seen independently from the unstructured component. BYM2 model is an alternative to improve parameter control by allowing the parameter to be seen independently from each other [26]. We fitted both models (BYM and BYM2) using the same priors. Results from both models were similar.

3 Results

The results are presented into two parts. The first part provides summary descriptive statistics of malaria cases and estimates from the fitted spatio-temporal model. The second part presents an evaluation of Rwanda’s malaria policy on the reduction of incidence using the excess probability approach. We introduced formal friendly interpretation and classification based on the excess probability approach for decision making during the malaria pre-elimination phase.

3.1 Malaria cases in Rwanda 2012-2018

Rwanda experienced an increase in malaria cases from 2012 to 2016, with 398,287 cases during 2012 to 2,956,337 cases in 2016. However, during 2017 and 2018, the total number of cases decreased to 1,978,450 and 1,725,522 respectively. Fig 1 shows the overall trend as well as the trend by age groups and sex from 2012 to 2018. The highest number of cases were reported in all age and sex groups in 2015 and 2016.

Fig 1. Malaria cases over time by sex.

Fig 1

3.2 Malaria relative risk in Rwanda 2012-2018: BYM

We have fitted spatio-temporal models for the period from 2012-2018, taking into account both structured and unstructured random effects (BYM and BYM2 models) as it provides a compromise between spatial correlation and extra heterogeneity over time. Since the results of those models are similar, we present the BYM model fitted with type II interaction based on Deviance Information Criterion (DIC) and Watanabe Akaike Information Criterion (WAIC) 2. The DIC is a tool for model selection in Bayesian context [28]; we computed a Bayesian measure of complexity (pD) and Bayesian deviance (D), DICc adjusted and WAIC that is also used for Bayesian model selection [29]. Both DIC and WAIC appraoch suggested mod.intII as the best model compared to others models fitted as Table 2 shows. In addition, we used predictive ordinate (CPO) for cross-validation of model.

Table 2. Comparison of models basing on DIC and WIAC.

Model D pD DIC DICc WAIC
model.ST1 2848807 284.9672 2849092 2849422 2300753
mod.intI 640735.1 5251.247 645986.3 657421.2 941846.9
mod.intII 40046.5 14499.43 54545.93 91864.38 70889.18
mod.intIII 41886.02 16217.6 58103.63 97675.84 76402.72

Those models provide the estimates at the smallest available geographical scale, that might be an added value to drive oriented and targeted interventions to control malaria in Rwanda.

Estimates of variances due to random effects are presented in Table 3, the contribution of variance can be summarized, as follows: approximately 50% is explained by a spatial component, and 50% by an unstructured component. This is also visible in Fig 2, which presents estimated relative risks for each year, compared with the overall incidence rate year in 2012.

Table 3. Posterior mean and 95% Credibility interval for fixed effect of α.

Year Parameter Estimate SD LL UL
2012 σu2 0.2703 0.0877 0.1414 0.4822
σv2 0.2407 0.0278 0.19 0.2991
Fracspatial Varu/(Varu+σv2) 52%
2013 σu2 0.2696 0.0822 0.1454 0.4657
σv2 0.2668 0.0309 0.2107 0.332
Fracspatial Varu/(Varu+σv2) 49%
2014 σu2 0.2942 0.0889 0.159 0.5059
σv2 0.2775 0.0307 0.2216 0.3421
Fracspatial Varu/(Varu+σv2) 50.5%
2015 σu2 0.3981 0.1455 0.1925 0.7558
σv2 0.2928 0.0318 0.2342 0.3594
Fracspatial Varu/(Varu+σv2) 56%
2016 σu2 0.6749 0.2602 0.3131 1.3203
σv2 0.3877 0.0392 0.3153 0.4691
Fracspatial Varu/(Varu+σv2) 62%
2017 σu2 0.4947 0.1602 0.2576 0.8805
σv2 0.4135 0.0442 0.3326 0.5059
Fracspatial Varu/(Varu+σv2) 53%
2018 σu2 0.3466 0.1016 0.192 0.5879
σv2 0.4846 0.0615 0.3735 0.6147
Fracspatial Varu/(Varu+σv2) 41%
2012-2018 Fracspatial
Varu/(Varu+σv2) 52%

SD:Standard Deviation, LL: Lower Level, UL: Upper Level

Fig 2. Malaria relative risk from year 2012 to 2018.

Fig 2

Fig 3 shows an increasing trend effect for malaria relative risk in Rwanda with 95% Credible Interval over years.

Fig 3. Posterior temporal trend effect for malaria relative risk in Rwanda: Exp(ϕt + γt) with 95% credible interval.

Fig 3

In general, the spatio-temporal contribution to geographic variability is important, as there is a tendency to see low relative risks in the North-West of Rwanda, and high relative risk in the East and in the South of Rwanda. We also observe a large amount of heterogeneity amongst areas, as some of the areas with high relative risk for malaria are surrounded by areas with low risk (and vice versa). Table 4 shows the number of sectors with RR’s within specific intervals.

Table 4. Malaria RR per year as compared to the year 2012.

Year [0,1) [1,4) [4,10) [10,15) [15,24)
2012 307(73.80%) 75(18.03%) 23(5.53%) 7(1.68%) 4(0.96%)
2013 290(69.71%) 92(22.12%) 25(6.01%) 7(1.68%) 2(0.48%)
2014 278(66.83%) 102(24.52%) 30(7.21%) 3(0.72%) 3(0.72%)
2015 250(60.10%) 144(34.62%) 18(4.33%) 3(0.72%) 1(0.24%)
2016 246(59.13%) 141(33.89%) 27(6.49%) 2(0.48%) 0(0%)
2017 258(62.02%) 120(28.85%) 36 (8.65%) 2(0.48%) 0(0%)
2018 259(62.26%) 125(30.05%) 26(6.25%) 5(1.20%) 1(0.24%)

In 2012, 73.8% (307) of all sectors (416) had a RR < 1,(a lower than average disease rate), while 18.03% (75) of the sectors had a RR above one but below 4, and 5.53% (23) had a RR above 4 but below 10. In 11 sectors, the RR was above ten, including four sectors with a RR greater than 15. Those four sectors were in the City of Kigali, with the highest RR observed in Gasabo District Gikomero sector (RR = 19.6, 95% CI = 19.13, 20.05). The two other sectors were in the Southern province Kigoma sector in Nyanza District (RR = 19.7, 95% CI = 19.23, 20.25) and Gikonko sector in Gisagara District with a RR 16.8, 95% CI = 16.42, 17.20). In the Eastern province in, Nyagatare District, was Nyagatare sector with a RR = of 15.75, (95% CI = 15.51, 16.01). This indicates that the malaria cases are concentrated in a few areas, while the disease rate is low in most sectors.

In 2013, there was an increase in the number of sectors with RR ranging between one and four, an increase of 22.12% as compared to 2012. In 2014, 36 (8.65%) sectors had RR > 4. For the year 2015, 39.9% sectors had a RR > 1, and 5.3% of sectors had a RR > 4. In 2016, 40.87% of all the sectors had RR >1 and 6.97% of sectors had RR > 4. In 2017, 37.98% of sectors had a RR > 1 and 9.13 of sectors had a RR > 4. Similar to the previous year, in 2018 37.74% of sectors had RR > 1 and 7.69% of sectors had RR > 4. In conclusion, compared to the overall risk in the year 2012, the risk has increased in later years. In addition, the number of sectors with lower than average risk in the year 2012 decreased over time.

3.3 Assessment of Malaria policy to reduce incidence in Rwanda

Rwanda Malaria’s strategic plan 2012-2018 [5] aimed to reduce malaria incidence by 20% in 2015 and 42% in 2018. These results show the probability taking into account spatial uncertainty as it provides local details of the spatial variation of the risk. Figs 4 and 5 present the area-specific probabilities of failing to reach the target goals. Areas colored red have a high probability (above 80%) having failed to reach the target goal, while areas in yellow have high probability (above 80%) of having successfully reached the target goal. For areas in orange, we are uncertain about whether or not the sectors succeeded in achieving the target goals.

Fig 4. The area-specific probabilities of not reaching the target goal of 2015 (reduction of 20% as compared to 2012).

Fig 4

Fig 5. The area-specific probability of not reaching the target goal of 2018 (reduction of 42% as compared to 2012).

Fig 5

At the baseline year 2012, 29.33% (122) and 33.65% (140) of sectors had a high probability (> 0.80) of having a smaller than average risk (< 0.58 and < 0.80, respectively). The number of sectors that failed to reach the target of 20% reduction increased over the years. Similarly, the number of sectors that failed to reach the target of 42% also increased over the years.

This is due to increased malaria incidence across all the sectors from 2012 to 2016. In 2017 and 2018, the incidence decreased, but did not reach levels lower than the incidence 2012. While there was an improvement in progress towards reaching the target in some years for certain areas, the improvement did not persist over the entire follow-up period. After insecticide residual spry (IRS) intervention in 2015, 2016 and, 2017 the sectors of Nyagatare (North-East) and Kirehe (South-East) showed a reduction in incidence. At the same time, we see that in the South-West, while targets were reached in the earlier years, these areas failed to sustain progress. Table 5 shows a summary of the number of sectors that did not achieve the targets set out by Rwanda’s malaria strategic plan with a certain probability.

Table 5. The sectors that did not achieve reducing the targets.

Year Target of reducing 20%
[0,0.2) [0.2,0.4) [0.4,0.6) [0.6,0.8) [0.8,1)
2012 289(69.47%) 1(0.24%) 4(0.96%) 0(0%) 122(29.33%)
2013 271(65.14%) 4(0.96%) 4(0.96%) 0(0%) 137(32.93%)
2014 258(62.02%) 1(0.24%) 1(0.24%) 4(0.96%) 152(36.54%)
2015 222(53.37%) 4 (0.96%) 0(0%) 5(1.20%) 185(44.47%)
2016 218(52.40%) 3(0.72%) 0(0%) 2(0.48%) 193(46.39%)
2017 236(56.73%) 2 (0.48%) 2(0.48%) 3(0.72%) 175(41.59%)
2018 241(57.93%) 2(0.48%) 2(0.48%) 2(0.48%) 169(40.62%)
Target of reducing 42% by 2018
2012 273(65.62%) 1(0.24%) 1(0.24%) 1(0.24%) 140(33.65%)
2013 250(60.10%) 3 (0.72%) 2(0.48%) 2 (0.48%) 159(38.22%)
2014 235(56.49%) 3(0.72%) 6(1.44%) 4(0.96%) 168(40.38%)
2015 200(48.08%) 2 (0.48%) 0(0%) 0(0%) 214(51.44%)
2016 187(44.59%) 1(0.24%) 2(0.48%) 0(0%) 226(54.33%)
2017 203(48.80%) 6(1.44%) 4(0.96%) 3(0.72%) 200(48.08%)
2018 216(51.92%) 0(0%) 3(0.72%) 4(0.96%) 193(46.39%)

4 Discussion

Spatial data has increased substantially due to the advances in computational tools that allow collection and integration of diverse real-time data sources. This goes in hand with the development of less or complex innovative statistical models to deal with the spatial structure of data in hand [21]. Model-based statistical methods are useful in low resource settings for estimating disease risk by health decision-making units as well as in the analysis of uncertainty for survey data [30]. In this paper, the utility of model based statistical methods in estimating the probability of reaching specific targets is presented.

In the past, data quality concerns restricted the use of health facility data as a source of population based statistics. Introduction of web-based information systems for health facility data and the implementation of universal health policy contributed the completeness and accuracy of data at local level and population-based statistics based on those data. This success was prompted by the intensive monitoring of sustainable development goals [31, 32]. Data from health facilities in Rwanda are generally of high quality, though successfully integrating these data into health policy and decision-making throughout the health system is an ongoing challenge. [33].

The spatial modeling analysis for malaria data in Rwanda suggested an overall increase in relative risk (RR) in almost all sectors of Rwanda from 2012 to 2016, with a slight decrease from 2017 and 2018. The number of sectors with RR > 1 increased tremendously. In some sectors, the RR was above 10. This implies that malaria incidence increased considerably over time in all sectors of Rwanda but the increase was not consistent over the years.

The estimated probability of achieving the target for reduction of malaria incidence showed that, almost half (47.36%) of all sectors failed to meet the target of reducing 42% of malaria incidence by 2018, with 80% or 90% certainty. Contrary to expectations from the Malaria Strategic plan [5], malaria incidence increased in East, South, Central, and South-West of Rwanda. Those areas of Rwanda are known as high malaria risk zones [5]. This means that the malaria control program should concentrate efforts on reducing transmission through preventive interventions such as indoor residual spraying (IRS) and bed-net distribution. As Figs 4 and 5 demonstrate in 2013, 2015, 2016 and, 2017 in the North East (Nyagatare) and South East (Kirehe); the reduction may be due to the IRS intervention that occurred in the same period in those Districts. With 90% probability, 51.92% of sectors reduced malaria incidence as planned; however, those sectors belong in Northern provinces and North-West of Rwanda where malaria cases are often lower than other parts of Rwanda. Despite this encouraging success, much work remains to reduce the incidence of malaria across the country. Implementing pre-elimination strategies in those sectors should be premature, instead the focus should be implementing malaria control strategies.

The results presented here are based of malaria cases from health facilities and the population distribution, and the database had limited variables that could have been included in the analysis to explain increased relative risk and the reasons for failing to achieve the target of reducing incidence as planned. We limited our scope on statistical method to evaluate reduction of malaria incidence using an excess probability approach. This approach is a relevant tool to guide decision makers and develop health policy. This model and results can contribute to improvement of malaria surveillance to ensure implementation of interventions in the right place and at the right time.

A disease like malaria requires a strong surveillance system that can enable a quick response to any changes in behaviors related to malaria. Efficient algorithms that can be deployed in response to real-time data collection and make inferences would contribute to a fast response to potential public health threats. [15]

5 Conclusion

In summary, we recommend the approach of using spatio-temporal models and routinely collected facility-based data to assess achievement of targets related to malaria incidence and estimate malaria relative risk at the local level. This approach enables us to generate maps that provide information about the probability and uncertainty of reaching the targets, as well as providing information on the spatial contribution to malaria burden in the country. The proposed approach is not only limited to malaria data, but can also be applied in other areas of health care delivery. Spatio-temporal specifications with interactions of both time and space were considered but were not successful.

This era of sustainable development goals (SDGs), especially SDG 3 and its target 3.3 of ending malaria by 2030, requires a tool like the one presented here for planning, monitoring, and evaluation. The excess probability can be applied to survey or routine data from health facilities. It uses routine data efficiently to permanently monitor the changes in malaria transmission and evaluate progress towards national targets. Though survey data are important, provided that data quality are high, routinely collected data are collected more frequently and thus provide more timely assessments of health burden. Many surveys only publish new evidence every five years (such as Demographic and Health survey) and often do not provide estimates at a local level.

Supporting information

S1 Data

(R)

S2 Data

(R)

S3 Data

(R)

Acknowledgments

The authors are grateful to Rwanda Biomedical Center, Malaria and other Parasitic Diseases division, for collaboration and discussion on Rwanda’s Malaria’s strategic plan evaluation approaches. We are grateful for Rwanda malaria resource materials shared by Dr. Aimable Mbituyumuremyi, Malaria Division manager and technical support provided by Mr. Hamza Ndabateze, HMIS officer, to extract data from Rwanda health information system (HMIS).

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

References

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Decision Letter 0

Emanuele Giorgi

26 Nov 2019

PONE-D-19-30728

Bayesian spatial modeling of malaria risk in Rwanda

PLOS ONE

Dear Mr Semakula,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I would like to point out that both reviewers have stated that the methodology used in the paper is only partly sound and I concur with them. The major issue that the authors should address in their revision is the improvement of the spatio-temporal analysis, which is currently carried out by fitting a model year by year. This is not just unconventional in spatio-temporal modelling, it is also less statistically efficient than developing a spatio-temporal model that exploits correlation between years. Unless there are scientific reasons for this, which are not explained, I cannot see any justification for the adopted modelling approach.  This point will be crucial in deciding whether the re-submitted manuscript will be rejected or not.

We would appreciate receiving your revised manuscript by Jan 10 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

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We look forward to receiving your revised manuscript.

Kind regards,

Emanuele Giorgi

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Routine data are becoming increasingly important as countries adopt DHIS2 across sub-Sahara Africa. The approaches presented in the paper are important to allow national malaria control programmes assess progress (or lack of it) at sub national units of decision making. I have the following comments.

1. What’s the fidelity of the data used: were there facilities that were no reporting in some months or not reporting at all? The authors should summarize the completeness of data (how many facilities reported 12 times in year? How many did not report at all?

2. Clarify on the manuscript if all data used was lab confirmed

3. Why was the sector used as the unit of analysis? is this the unit of decision used by the national malaria control programme?

4. Often individuals are assigned based on the health facility they attend as opposed to their residential locations in DHIS2. This means the risk in certain sector is not the actual risk because it’s based on patients from that sector and the neighbouring sectors. Can the authors elaborate in the Rwanda case and how they handle this issue?

5. How were neighbouring areas defined? (queen, rook, based on distance etc.?) and why the choice? It has been shown different choices yield different results

6. Likewise, why the BYM model? they are several other choices (Besag, Besag2, BYM2, Leroux CAR, proper CAR etc.) BYM2 handles identifiability and scaling better

7. The choice of priors and justification is not provided

8. Why were different models fitted by year instead of a spatio-temporal model to also account for temporal correlation and where necessary space-time interactions?

9. The first two paragraphs of 3.2 should be in the methods section

10. Why were there no covariates used to assist in the estimation process?

11. Are the data used (as indicated) to model and accompanied code provided? Coukld not find the URL to either of the two

Reviewer #2: Review comments

The paper addresses an important issue on using population data and clinical routine malaria data for decision making in control/elimination of malaria. The paper uses a model based approach in the analysis and mapping of malaria incidence in Rwanda, for the period from 2012 to 2018.

A) Minor comments

a. Abstract: specify the SDG number that is being referred to there.

b. Abstract: “The results showed an increase of risk of malaria and 47.36% of sectors in Rwanda” is not very clear. Is this increase national or in specific sectors only?

c. Line 9:10, do the authors mean “categorised” when they mention “situated”?

d. Line 14: Most countries “placed”….

e. Line 36 – 37: …finally increasing %... use “percentage” instead of the symbol.

f. Line 45: For the “epidemiological”….

g. Line 46 – 47: Re-write to make it clear.

h. Line 54 – 55: …. Patterns in low areas transmission should change to …. “patterns in low transmission areas”.

i. Line 91 – 92: Can authors specify what percentage of the total was not included in the final analysis?

j. Line 97 – 102: Authors need to indicate by properly subscripting the count for time as rightly done for geographic areas in the same paragraph.

k. In Table 1, can the authors add footnotes (or in the caption) to explain what SD, LL and UL are?

l. Line 228: Change “sound statistics” to “accurate statistics”.

m. Line 234 – 236 is not clear in the current form.

n. Line 237: This in the current form is misleading. Should it be reading: .... almost half (47.36%) of all sectors....

o. On lines 246 – 249, what threshold is being looked at here? It’s not coming out very clearly.

p. Figures are not (properly) captioned, making it difficult to follow or align the text to the Figures.

i. The Figure (Fig1_Desc2), titled “The under-five Malaria 2012 0 2018” with no sex specified seems redundant as it is adding very little information. The information presented in the graph can be explained in the text.

ii. The Y-axis on Fig1_Desc5 “Overall malaria per year” is misleading. The Figure needs to be re-done to properly convey the correct information.

iii. The legends in Figures 2 – 4 should be properly positioned, interfering with maps currently.

q. Go through the manuscript to correct typos and grammatical errors.

B) Major comments

a. The language in the current form of the paper still needs extensive editing to make things clear.

i. Abbreviations are not properly defined throughout the document i.e. figure 3 instead of Figure 3 etc.

ii. Capitalisation is not properly used throughout the document.

iii. Several sentences are not very clear as indicated in the minor comments above.

iv. Several places missing commas and full stops – distorting the message

v. Inappropriate tenses used.

vi. Inappropriate use of directions i.e. “east north” as indicated on lines 237 - 250 instead of “North east”

b. Lines 119 – 122: Authors indicate that they use Bayesian methods for the analysis, and. Have taken the time to explain both the data and process models. However, conspicuously missing are details on the priors used in model fitting.

c. Line 132 – 136: Authors introduce the concept of calculating policy relevant threshold. Three issues arise here.

i. How is the threshold “c” determined or reached at? This is not clearly explained in the document. For the reader to understand the policy relevant goals, determination of these thresholds needs to be clearly explained.

ii. In line 135, authors claim that: “If |P| is large, the set goal is likely reached in that area.” What is |P| being compared to?

iii. In P(Theta_it < (100 - c)%), is the relative risk based on the observed data? If so, this has to be explicitly stated.

d. The authors have 7 years worthy of data. Enough data to enable a proper spatio-temporal model. However, in lines 157 – 159, they indicate that they have fitted separate models for each year. I find this problematic in the sense that they are underutilising the data and not fully leveraging the information therein. A spatio-temporal model will enable borrowing strengths in the data across both space and time, therefore giving a complete picture of how malaria incidence has changed since the base year of 2012. The model fitted currently has huge implications on the conclusions authors draw in the paper. I comment on this in later sections below.

e. In Tables 2 and 4 and lines 174 – 192, authors present malaria relative risk per year as compared to base year of 2012. They group RR into 5 groups: 0-1, 1 – 4, 4 – 10, 10 – 15, and 15 – 24. They use square braces. This presents several challenges in the sense that:

i. The mathematical/statistical meaning of these braces means that these groups are not distinct, meanwhile in text, these groups of RR are presented as distinct. Authors should not [0, 1] and [0, 1) will mean two different things.

ii. Again, for example, column one has [0, 1] and column two has [1, 4]. Does this mean that these two RR groups contain both the 1? This is same for all the groups and it is misleading.

iii. More confusing is the fact that in the text, they resort to using round braces. For reasons in point 1 above, this becomes more confusing.

iv. Therefore lines 184 – 192 need to be re-written with correct presentation of Table 2.

f. In section 3.3, lines 193 - 215 authors present an “assessment of Malaria policy to reduce incidence in Rwanda.” With this goal of analysis in mind, it makes more sense to use spatio-temporal model, so that the available data take into account the trends leading up to the target year (2015 and 2018) for the target non-exceedance thresholds of 20% and 42% respectively. See comment in point (d) above.

g. Lines 203 – 205: The authors should endeavor to quantify this increase, for it to be helpful and relevant to policy makers.

h. Lines 206 – 209 should be re-written to properly convey the message contained in there. More importantly, the claims raised in these lines can be affirmed by using a proper spatio-temporal analysis in relation to the concerns raised in points (d) and (f) above.

i. Line 237 – 239. Authors claim that almost half (47.36%) of the sectors did not meet the targets with 80 or 90% certainty. What would be helpful is for the authors to show clearly each of these certainties on map. See, for example:

i. Giorgi et. al. (2018), Using non-exceedance probabilities of—relevant malaria prevalence thresholds to identify areas of low transmission in Somalia. Malar J. 2018;17:88.

ii. Macharia et. al. (2019), Spatio-temporal analysis of Plasmodium falciparum prevalence to understand the past and chart the future of malaria control in Kenya

iii. Yankson et. al. (2019), Geostatistical analysis and mapping of malaria risk in children under 5 using point-referenced prevalence data in Ghana

j. In their discussion, on lines 250 – 251, authors mention that “Implementing pre-elimination strategies in those sectors should be considered consciously.” With the the incidence presented here, it’s not proper for the authors to start talking about pre-elimination. The message to policy implementers should rather be to focus on control strategies at this point.

k. On lines 258 – 259, authors mention that “It can contribute to improve Malaria surveillance to ensure appropriate intervention in the right place and most needed time.” This is very correct, but based on the statistical analysis presented here, authors should be cautious in their statements on conclusions made. A proper spatio-temporal analysis would be required to make this conclusion on time.

**********

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Reviewer #1: Yes: Peter M Macharia: KEMRI Wellcome Trust Research Programme

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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Attachment

Submitted filename: PONE-D-19-30728.pdf

Decision Letter 1

Emanuele Giorgi

18 Feb 2020

PONE-D-19-30728R1

Bayesian spatio-temporal modeling of malaria risk in Rwanda

PLOS ONE

Dear Mr Semakula,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The revised submission is  a substantial improvement over the the original submission and the authors are on the right track. I see two outstanding issues which I believe the authors can successfully address.

 1) Provide a model selection approach that is not not exclusively based on indices as those used in Table 2. One approach might be to identify models that give more precise and accurate predictions as well as reliable 95% confidence intervals using a hold out sample. I am not convinced that  model.intIV has extremely large values for the the chosen indices due to numerical instability.

2) Provide a more clear explanation of the spatio-temporal models. For example the verb "to combine" is too vague and it is not clear what that mean mathematically. Also, the fact that some covariance matrices have Kroncker products is because the authors have multiplied main spatial and temporal effects (in which case "to combine" means "to multiply")? The authors could provide more explanation of this either in the main manuscript or in the supplementary material, as they prefer. 

In the revision, please also consider any of the remaining points raised by one of the reviewers. 

We would appreciate receiving your revised manuscript by Apr 03 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Emanuele Giorgi

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: My comments have been addressed satisfactorily and the paper is now in a format that can be published

Reviewer #2: I appreciate the opportunity to review this revised paper. The authors have resolved some of the initial problems in the analysis, particularly the issue of using an appropriate modelling approach for the kind of data and objectives of analysis at hand. There are however still a few issues remaining. See attached

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Peter Macharia: KEMRI Wellcome Trust Research Programme

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: PONE-D-19-30728_R1.pdf

Attachment

Submitted filename: PONE-D-19-30728_R1_reviewer_comments.pdf

PLoS One. 2020 Sep 10;15(9):e0238504. doi: 10.1371/journal.pone.0238504.r004

Author response to Decision Letter 1


21 Apr 2020

Dear Reviewer,

Thank you for your comments. We have addressed all the comments and response to the reviewer letter is attached.

Attachment

Submitted filename: Response to the reviewer.docx

Decision Letter 2

Emanuele Giorgi

28 Apr 2020

PONE-D-19-30728R2

Bayesian spatio-temporal modeling of malaria risk in Rwanda

PLOS ONE

Dear Mr Semakula,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The revised submission is  a substantial improvement over the the original submission and the authors are on the right track. I see two outstanding issues which I believe the authors can successfully address.

 1) Provide a model selection approach that is not not exclusively based on indices as those used in Table 2. One approach might be to identify models that give more precise and accurate predictions as well as reliable 95% confidence intervals using a hold out sample. I am not convinced that  model.intIV has extremely large values for the the chosen indices due to numerical instability.

2) Provide a more clear explanation of the spatio-temporal models. For example the verb "to combine" is too vague and it is not clear what that mean mathematically. Also, the fact that some covariance matrices have Kroncker products is because the authors have multiplied main spatial and temporal effects (in which case "to combine" means "to multiply")? The authors could provide more explanation of this either in the main manuscript or in the supplementary material, as they prefer.

We would appreciate receiving your revised manuscript by Jun 12 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

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  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Emanuele Giorgi

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

I did provide comments in the previous decision letter from the journal but I notice these have not been considered. I paste those comments below.

I see two outstanding issues which I believe the authors can successfully address.

1) Provide a model selection approach that is not not exclusively based on indices as those used in Table 2. One approach might be to identify models that give more precise and accurate predictions as well as reliable 95% confidence intervals using a hold out sample. I am not convinced that model.intIV has extremely large values for the the chosen indices due to numerical instability.

2) Provide a more clear explanation of the spatio-temporal models. For example the verb "to combine" is too vague and it is not clear what that mean mathematically. Also, the fact that some covariance matrices have Kroncker products is because the authors have multiplied main spatial and temporal effects (in which case "to combine" means "to multiply")? The authors could provide more explanation of this either in the main manuscript or in the supplementary material, as they prefer.

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Sep 10;15(9):e0238504. doi: 10.1371/journal.pone.0238504.r006

Author response to Decision Letter 2


15 Jun 2020

Response to the reviewer’s comments

Manuscript Title: Spatio-temporal modeling for malaria risk in Rwanda

Date: May 30, 2020

1. Provide a model selection approach that is not not exclusively based on indices as those used in Table 2. One approach might be to identify models that give more precise and accurate predictions as well as reliable 95% confidence intervals using a hold out sample. I am not convinced that model.intIV has extremely large values for the the chosen indices due to numerical instability..

Response:

Thank you for your advice. Indeed, you are right, the model.intIV did not converge. It was not chosen neither discussed in this manuscript due to convergence issues. We decided to remove the model.intIV from the Table 2 since it is not part of final findings and DIC are not reasonable.

In addition to DIC, sensitivity analysis for model selection, we have added Conditional predictive ordinate, that split data into the two groups. The model is run on yf so that posterior distribution for the parameters p(θ| yf ) is obtained; R-INLA runs the so-called leave one out cross validation ,which assumes that yf =y_i yc =yi. The CPO was computed in R-INLA.

2. Provide a more clear explanation of the spatio-temporal models. For example the verb "to combine" is too vague and it is not clear what that mean mathematically. Also, the fact that some covariance matrices have Kroncker products is because the authors have multiplied main spatial and temporal effects (in which case "to combine" means "to multiply")? The authors could provide more explanation of this either in the main manuscript or in the supplementary material, as they prefer.

Response:

This comment is relevant. More clarification was provided on sptio-temporal models, and particularly on Kronecker products. The explanation is provided on lines 140-149.

In fact, there are Kronecker products because there is interaction between space and time. Therefore, the structure matrix is factorized as a Kronecker product of corresponding main effects which interact. The detailed materials are provided in R codes annexed.

Thank you very much for all your comments. We are very grateful.

Attachment

Submitted filename: Response to the reviewer.docx

Decision Letter 3

Emanuele Giorgi

18 Jun 2020

PONE-D-19-30728R3

Bayesian spatio-temporal modeling of malaria risk in Rwanda

PLOS ONE

Dear Dr. Semakula,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 02 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Emanuele Giorgi

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

I think this is an improvement over the previous version but there are still some aspects that, in my view, still require a major revision.

- More explanation about the condition predictive ordinate needs to be provided. Simply mentioning that this available in INLA is not enough and does not provide the reader with enough information to assess the validity of this approach.

- The explanation given for the models in Table 1 is not clear. Especially, it is impossible for the reader to understand what is the difference between the models from Type II to Type IV.

- Discarding model Type IV because of failure to converge is not a valid justification because it also implies that using a different fitting algorithm may indeed lead to convergence. However, a plausible explanation may also be that the model of Type IV is indeed too complex for the data. The authors should think of how to show evidence that this is indeed the case. In a non-Bayesian context, a natural approach would be to show that the profile likelihood for the covariance parameters is flat and the 95% confidence interval based on that is indeed too wide.

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Sep 10;15(9):e0238504. doi: 10.1371/journal.pone.0238504.r008

Author response to Decision Letter 3


30 Jul 2020

Response to Reviewer’s comments

1. - More explanation about the condition predictive ordinate needs to be provided. Simply mentioning that this available in INLA is not enough and does not provide the reader with enough information to assess the validity of this approach.

Answer:

Thank you for this comment, we have provided more explanation from line 144 to 155 to enable the reader to have enough information and understanding on CPO

2. -The explanation given for the models in Table 1 is not clear. Especially, it is impossible for the reader to understand what is the difference between the models from Type II to Type IV.

Answer:

Thank you, we have provided more explanation on the table 1 by adding three paragraphs. Line 156 to 183. We explained each type of interaction in details to enable the reader to have a good understanding of each type of model interaction (Type I to IV)

3. - Discarding model Type IV because of failure to converge is not a valid justification because it also implies that using a different fitting algorithm may indeed lead to convergence. However, a plausible explanation may also be that the model of Type IV is indeed too complex for the data. The authors should think of how to show evidence that this is indeed the case. In a non-Bayesian context, a natural approach would be to show that the profile likelihood for the covariance parameters is flat and the 95% confidence interval based on that is indeed too wide.

Answer:

Thank you, though model Type IV converged the variance is too small (Stdev: 0.00269982) due to

overspecification. Therefore, it is hard to see the differences as compared to type II.

Attachment

Submitted filename: Response to Reviewer.docx

Decision Letter 4

Emanuele Giorgi

31 Jul 2020

PONE-D-19-30728R4

Bayesian spatio-temporal modeling of malaria risk in Rwanda

PLOS ONE

Dear Dr. Semakula,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 14 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Emanuele Giorgi

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The last remaining point is that the Type IV specification of the sptatio-temporal correlation.

Fail to convergence in the INLA software does not invalidate a model.

The authors should consider two options in their revision: 1) explaining this issue more in details and provide evidence of overspefication, which is completely absent from the paper; 2) remove this model from the methods and explaining in the conclusion that spatio-temporal specifications with interactions were considered but were not successful.

In both option, please, provide a clear definition of "overspefication" without assuming the reader is familiar with this concept.

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Sep 10;15(9):e0238504. doi: 10.1371/journal.pone.0238504.r010

Author response to Decision Letter 4


6 Aug 2020

Response to Reviewer’s comments

The last remaining point is that the Type IV specification of the sptatio-temporal correlation. Fail to convergence in the INLA software does not invalidate a model.

The authors should consider two options in their revision: 1) explaining this issue more in details and provide evidence of overspefication, which is completely absent from the paper; 2) remove this model from the methods and explaining in the conclusion that spatio-temporal specifications with interactions were considered but were not successful.

In both option, please, provide a clear definition of "overspefication" without assuming the reader is familiar with this concept.

Answer:

Thank you for this comment, as you suggested we have removed TYP IV model from the methods and we provided explanations in conclusion as suggested.

( lines 171- 175, 223-223 in track change version were removed ) and (lines 337 and 338 were added in manuscript)

The term overspecification does not appear anywhere in paper more since it was related the type IV model.

Decision Letter 5

Emanuele Giorgi

19 Aug 2020

Bayesian spatio-temporal modeling of malaria risk in Rwanda

PONE-D-19-30728R5

Dear Dr. Semakula,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Emanuele Giorgi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Emanuele Giorgi

24 Aug 2020

PONE-D-19-30728R5

Bayesian spatio-temporal modeling of malaria risk in Rwanda

Dear Dr. Semakula:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Emanuele Giorgi

Academic Editor

PLOS ONE

Associated Data

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