Diagnostic performance of a single and duplicate Kato-Katz, Mini-FLOTAC, FECPAK G2  and qPCR for the detection and quantification of soil-transmitted helminths in three endemic countries

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Abstract

Background

Because the success of deworming programs targeting soil-transmitted helminths (STHs) is evaluated through the periodically assessment of prevalence and infection intensities, the use of the correct diagnostic method is of utmost importance. The STH community has recently published for each phase of a deworming program the minimal criteria that a potential diagnostic method needs to meet, the so-called target product profiles (TPPs).

Methodology

We compared the diagnostic performance of a single Kato-Katz (reference method) with that of other microscopy-based methods (duplicate Kato-Katz, Mini-FLOTAC and FECPAK ^G2) and one DNA-based method (qPCR) for the detection and quantification of STH infections in three drug efficacy trials in Ethiopia, Lao PDR, and Tanzania. Furthermore, we evaluated a selection of minimal diagnostic criteria of the TPPs.

Principal findings

All diagnostic methods showed a clinical sensitivity of ≥90% for all STH infections of moderate-to-heavy intensities. For infections of very low intensity, only qPCR resulted in a sensitivity that was superior to a single Kato-Katz for all STHs. Compared to the reference method, both Mini-FLOTAC and FECPAK ^G2 resulted in significantly lower fecal egg counts for some STHs, leading to a substantial underestimation of the infection intensity. For qPCR, there was a positive significant correlation between the egg counts of a single Kato-Katz and the DNA concentration.

Conclusions/Significance

Our results indicate that the diagnostic performance of a single Kato-Katz is underestimated by the community and that diagnostic specific thresholds to classify intensity of infection are warranted for Mini-FLOTAC, FECPAK ^G2 and qPCR. When we strictly apply the TPPs, Kato-Katz is the only microscopy-based method that meets the minimal diagnostic criteria for application in the planning, monitoring and evaluation phase of an STH program. qPCR is the only method that could be considered in the phase that aims to seek confirmation for cessation of program.

Trial registration

ClinicalTrials.gov NCT03465488

Author summary

To control the burden caused by intestinal worms, the World Health Organization recommends large-scale deworming programs where anti-worm drugs are administered to at-risk populations. The decision to scale down drug distribution is based on the periodically assessment of prevalence and intensity of infections using a standard diagnostic method. Today, the scientific community strongly doubts whether this method can be used throughout the program. This is in particular when it fails to detect infections of low intensity, and hence may result in prematurely stopping the distribution of drugs. We compared the diagnostic performance of alternative diagnostic methods in three drug efficacy trials in two African and one Asian country. The diagnostic methods were based on demonstration of worm eggs or worm DNA in stool. We also checked the results with minimal diagnostic criteria which have been recently been proposed by the scientific community. Our results indicate that of all diagnostic methods based on demonstration of worm eggs, only the current standard method fulfills the diagnostic criteria for planning, monitoring and evaluation phases of deworming program. Furthermore, we showed that DNA-based methods could be considered in the phase that aims to seek confirmation for cessation of the deworming program.

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Sensitivity of diagnostic tests for human soil-transmitted helminth infections: a meta-analysis in the absence of a true gold standard

Birgit Nikolay, Simon J. Brooker, Rachel L. Pullan (2014)

1 Introduction Reliable, sensitive and practical diagnostic tests are an essential tool in disease control programmes, including those for neglected tropical diseases. The requirements and expectations for a diagnostic tool in terms of technical performance, feasibility and costs change as control programmes progress through different phases, from initially high levels of infections to the confirmation of absence of infections. More precisely, during initial mapping to identify priority areas for control, when infection levels are typically highest, a diagnostic test with moderate sensitivity is acceptable, although the chosen tool needs to be easy to use, cost-effective and allow for the high-throughput screening of large populations (McCarthy et al., 2012; Solomon et al., 2012). Since mapping data can also serve as a baseline for the monitoring and evaluation of programme impact, diagnostic tests must have sufficient performance to detect changes in the prevalence and intensity of infection (Solomon et al., 2012). In later stages of programmes, when infection prevalence and intensity have decreased significantly, more sensitive diagnostic tools are needed to establish an endpoint of treatment programmes. If test sensitivity is insufficient at this point, light infections might be missed and this runs the risk of stopping control programmes too early, before programme endpoints have been achieved. Highly sensitive tests are also required for surveillance once treatment has been stopped to detect the potential re-occurrence of infections (McCarthy et al., 2012; Solomon et al., 2012). Finally, diagnostic tests play an important role in the assessment of treatment efficacy (Albonico et al., 2012) and in patient management. For the detection of the human soil-transmitted helminth (STH) species, Ascaris lumbricoides, Trichuris trichiura and the hookworms (Necator americanus and Ancylostoma duodenale), The World Health Organization (WHO) currently recommends the use of the Kato-Katz method, based on duplicate slides (WHO, 2002). Other commonly used methods include direct smear microscopy, formol-ether concentration (FEC), McMaster, FLOTAC and Mini-FLOTAC. All of these techniques rely on visual examination of a small sample of stool to determine the presence and number of STH eggs (WHO, 1994). Due to intra- and inter-sample variation in egg counts (Booth et al., 2003; Krauth et al., 2012), microscopy-based techniques can have differing sensitivities, especially in low transmission settings. Moreover, diagnostic methods vary considerably in the quantification of egg counts, which is necessary to establish intensity of infection and to evaluate treatment effects (Knopp et al., 2011; Albonico et al., 2012; Levecke et al., 2014). In order to better understand the suitability of diagnostic tools for various transmission settings and stages of disease control programmes, we performed a meta-analysis of the most commonly used copro-microscopic STH diagnostic tests. Our main study objective was an independent and global assessment of the relative performance of commonly used diagnostic methods for STH, as well as factors associated with heterogeneity in test sensitivity. Previous evaluations of STH diagnostics have generally relied on comparisons with a combined reference standard (generated by adding the results of several compared tests or consecutively obtained samples), an approach which has been widely criticised (Enoe et al., 2000; Ihorst et al., 2007). Moreover, the absence of a common reference standard has been a major obstacle for combined evaluations of diagnostic tests in the form of a meta-analysis. We have addressed this problem by using Bayesian latent class analysis (LCA), which allows simultaneous estimation of the unknown true prevalence of infection and the sensitivities and specificities of compared diagnostic tests. This approach has been previously applied to the evaluation of imperfect diagnostic tests for Chagas disease, leishmaniasis and malaria (Menten et al., 2008; de Araujo Pereira et al., 2012; Goncalves et al., 2012), as well as specific studies evaluating STH diagnostic methods (Booth et al., 2003; Tarafder et al., 2010; Assefa et al., 2014; Knopp et al., 2014). The approach has also been used for the meta-analyses of diagnostic test performance (Ochola et al., 2006; Menten et al., 2008; Limmathurotsakul et al., 2012). The current paper presents a Bayesian meta-analysis of different diagnostic tests for the detection of STH species. 2 Materials and methods 2.1 Literature search A systematic literature search was performed to identify publications presenting the evaluation of diagnostic techniques for the human STH species, A. lumbricoides, T. trichiura and hookworms (N. americanus and A. duodenale). Systematic searches were performed (date of search 25th February 2014) using the electronic databases PubMed (http://www.ncbi.nlm.nih.gov/), MEDLINE and EMBASE (via OvidSP) (http://ovidsp.uk.ovid.com/) and the medical subject headings and search terms as detailed in Supplementary Data S1. Articles were considered if written in English, German, French or Spanish. The search was validated by verifying that a number of previously identified key readings were included in the retrieved search results. The titles of initially obtained search results were screened for suitable content and all abstracts mentioning studies on helminths were retrieved. The abstracts were subsequently screened for studies using more than one diagnostic test for the determination of infections, even if not directly mentioning a comparison of test performances. Full texts were read and information on test outcomes, egg counts, age-groups, countries of the studies and years of publication was extracted where results were presented in a suitable format as explained below. Reference lists were screened for additional publications. The literature selection process is outlined in Fig. 1. Data were collected separately for A. lumbricoides, T. trichiura and hookworms, and restricted to the most commonly used diagnostic methods for STH, namely Kato-Katz (Katz et al., 1972), direct microscopy (WHO, 1994), formol-ether concentration (FEC) (Ritchie, 1948), McMaster (Ministry of Agriculture Fisheries and Food, 1986), FLOTAC (Cringoli et al., 2010) and Mini-FLOTAC (Barda et al., 2013a). Other techniques such as midi-Parasep, Koga Agar Plate, Willis technique and Spontaneous tube sedimentation technique (SSTT) were not included due to a lack of suitable data. As performance during field surveys was the main interest, evaluations of diagnostic tests on samples from diagnostic laboratories of hospitals were excluded. Only data provided in the form of 2 × 2 comparisons (T1+T2+, T1+T2−, T1−T2+, T1−T2−, where T1 and T2 are the two diagnostic methods and + and − indicate the observed positive or negative results) were retained. This also included data for which these 2 × 2 comparisons could be created by transforming the original data provided, e.g. where comparisons were made against a combined ‘gold standard’ of two diagnostic methods. Additionally, data on egg counts obtained by the various techniques were retrieved, including those studies that did not provide data in a suitable format for the LCA. Arithmetic mean egg counts were the most commonly reported measures and therefore used for the analysis. For articles where data could not be directly extracted, corresponding authors were invited to contribute additional study results. Three authors replied and provided four datasets for the analysis; we were also able to contribute a further two datasets to the analysis. 2.2 Bayesian LCA A Bayesian latent class model was used to estimate the sensitivity of different diagnostic tests as described elsewhere (Dendukuri and Joseph, 2001; Branscum et al., 2005). LCA allows estimation of the sensitivity and specificity of imperfect diagnostic tests by assuming a probabilistic model for the relationship between five unobserved, or latent, parameters: true disease prevalence π k and the sensitivities S i , S j and specificities C i , C j of diagnostic methods i and j (Pepe and Janes, 2007). The model additionally incorporates the covariance terms covD ij + , covD ij - to account for conditional dependency between compared diagnostic tests amongst infected and non-infected individuals, which is necessary as the included diagnostic tests are based on the same biological principle (detection of eggs under a microscope) and therefore factors other than the true infection status are likely to influence both test outcomes simultaneously (Dendukuri and Joseph, 2001). Thus, the joint distribution of the results of a 2 × 2 table follows a multinomial distribution, ( X k + + , X k + - , X k - + , X k - - ) ∼ Multi ( p k + + , p k + - , p k - + , p k - - , N k ) with the multinomial probabilities calculated as follows: p k + + = P ( T i + , T j + | k th population ) = [ S i S j + covD ij + ] π k + [ ( 1 - C i ) ( 1 - C j ) + covD ij - ] ( 1 - π k ) p k + - = P ( T i + , T j - | k th population ) = [ S i ( S j - 1 ) - covD ij + ] π k + [ ( 1 - C i ) C j - covD ij - ] ( 1 - π k ) p k - + = P ( T i - , T j + | k th population ) = [ ( S i - 1 ) S j - covD ij + ] π k + [ C i ( 1 - C j ) - covD ij - ] ( 1 - π k ) p k - - = P ( T i - , T j - | k th population ) = [ ( S i - 1 ) ( S j - 1 ) + covD ij + ] π k + [ C i C j + covD ij - ] ( 1 - π k ) The conditional correlations between two test outcomes for infected and non-infected individuals were calculated as ρ D + = covD + S i ( 1 - S i ) S j ( 1 - S j ) and ρ D - = covD - C i ( 1 - C i ) C j ( 1 - C j ) , respectively. Uninformative prior information was provided for the sensitivity and underlying true prevalence (using a beta distribution with the shape parameters alpha and beta equal to 1). For the covariance terms, a uniform prior distribution was assumed with limits as described in Dendukuri and Joseph (2001) and Branscum et al. (2005) to ensure that probabilities are confined to values between 0 and 1. Specificity was included as a fixed term based on the most parsimonious, best-fitting model (i.e. that with the lowest deviance information criterion (DIC) value) and was assumed to be the same for all compared methods. This was justified on the dual assumption that false positives are rarely obtained by any type of copro-microscopic technique (Knopp et al., 2011; Levecke et al., 2011) and the necessity to restrict the number of estimated parameters for the identifiability of the model. The models, built separately for A. lumbricoides, T. trichiura and hookworms, were computed using WinBUGS software version 14 (Spiegelhalter, D., Thomas, A., Best, N., Gilks, W., 1996. BUGS: Bayesian Inference Using Gibbs Sampling. MRC Biostatistics Unit, Cambridge). Models were also developed separately for low and high intensity settings. Stratification was based on reported arithmetic mean egg counts (in eggs per gram of faeces, epg). Empirical cut-offs of 2500 epg, 400 epg and 165 epg average infection intensity were used for A. lumbricoides, T. trichiura and hookworms, respectively. These cut-offs were established based on the overall average infection intensity of studies included in the meta-analysis. Data with only geometric means reported were excluded from this analysis unless the geometric mean, which is lower than the average egg count, exceeded the cut-off value. Further details of model parameterisation, including handling of multiple slides, are provided in Supplementary Data S2. 2.3 Comparison of quantitative performances To compare the various diagnostic tests in terms of their quantitative performance, we compared the arithmetic mean egg count obtained by various techniques. Statistical significance of differences was assessed using the non-parametric paired Wilcoxon signed-ranks test and the linearity of the relationship between counts was assessed by scatter plots of log-transformed (natural logarithm) average egg counts. Moreover, we evaluated the percentage of studies reporting egg counts of other techniques that were lower/higher than the Kato-Katz method, which currently forms the basis of the WHO defined intensity thresholds. To allow for a small variation in counts, egg counts were considered as lower or higher than the Kato-Katz method if these were lower or higher than the Kato-Katz egg count plus or minus 10%. Due to the limited availability of data and the fact that faecal egg counts do not vary significantly by the sampling effort for Kato-Katz analysis, all versions of Kato-Katz were combined (Levecke et al., 2014). 3 Results 3.1 Identification of diagnostic test comparisons The initial literature search identified 56 articles which were retrieved for full-text review. Of these, 32 studies fulfilled the inclusion criteria and 2 × 2 comparison data could be obtained for 20 studies (Table 1) (see Fig. 1 for an outline of literature selection steps). The number of extracted 2 × 2 comparisons by species and diagnostic methods is shown in Fig. 2. The included studies were published between 2003 and 2014 and conducted in 12 countries, primarily among school-aged children. The inclusion of only recent studies was somewhat surprising. Even though the original literature search had retrieved studies published since 1967, the non-availability of 2 × 2 data, the type of compared techniques and the evaluation of methods in laboratory or hospital samples led to their exclusion. The evaluation of diagnostic tests was mainly based on comparison with a combined reference-standard (14 of 20 studies); few studies used predicted estimates as a reference (1/20), an LCA approach (1/20) or a combination of the two (1/20). Three studies did not provide sensitivity estimates. The most widely applied method was the Kato-Katz method in 18 of 20 studies (mostly 1-slide or 2-slides on a single sample). The main characteristics of included studies are summarised in Table 1. 3.2 LCA of diagnostic test sensitivities (presence of infection) For all STH species, the models allowing for dependency between compared diagnostic tests showed a better fit, indicated by a lower DIC (not shown). Significant positive correlation between diagnostic test outcomes for infected individuals was observed, especially for comparisons of a 1-slide 1-sample Kato-Katz test with other diagnostic tests (details are provided in Supplementary Data S2). Taking this dependency into account, the sensitivities of selected diagnostic methods were estimated separately for A. lumbricoides, T. trichiura and hookworm and are provided in Table 2 and Fig. 3. Generally, sensitivities of all compared tests were higher for T. trichiuria (Fig. 3B) than for hookworm (Fig. 3C) and A. lumbricoides (Fig. 3A). The obtained sensitivities were highest overall for the FLOTAC method with 79.7% (95% Bayesian credible interval (BCI): 72.8–86.0%), 91.0% (95% BCI: 88.8–93.5%), and 92.4% (95% BCI: 87.6–96.2%) for A. lumbricoides, T. trichiura and hookworm, respectively (Table 2). The lowest sensitivity was observed for the direct microscopy method with 52.1% (95% BCI: 46.6–57.7%), 62.8% (95% BCI: 56.9–68.9%), and 42.8% (95% BCI: 38.3–48.4%), respectively. The estimated sensitivity of the 2-slide 1-sample Kato-Katz test for A. lumbricoides was 64.6% (95% BCI: 59.7–69.8%), for T. trichiura was 84.8% (95% BCI: 82.5–87.1%) and for hookworm was 63.0% (95% BCI: 59.8–66.4%). These estimates were only a slight improvement upon the sensitivities of a 1-slide 1-sample Kato-Katz test. However, increased sensitivities could be observed for 1-slide Kato-Katz performed on two consecutive samples. The sensitivity for Kato-Katz tests performed on three consecutive samples was only slightly further improved. Test specificities were not the main outcome and were fixed at 99.6% for A. lumbricoides, 97.5% for T. trichiura and 98.0% for hookworm, based upon model fit. 3.3 Effect of infection intensity on diagnostic test sensitivity The obtained sensitivity estimates by intensity group are presented in Table 3 and Fig. 4. For all tests and STH species evaluated in both intensity groups, sensitivity varied markedly and most strongly for the Kato-Katz method. For example, for A. lumbricoides the 1-slide Kato-Katz method had a sensitivity of 48.8% (95% BCI: 37.6–58.2%) in the low intensity group compared with 95.8% (95% BCI: 91.8–98.5%) in the high intensity group. Interestingly, in the low intensity group the sensitivity of Kato-Katz was improved markedly by performance of a second slide on the same sample. The sensitivity of the FLOTAC method was highest at 81.8% (95% BCI: 65.5–90.3%) at low intensity compared with 97.1% (95% BCI: 93.1–99.7%) at high intensity. 3.4 Comparison of quantitative test performances A total of 17, 16 and 27 comparisons of average Kato-Katz A. lumbricoides, T. trichiura and hookworm egg counts with other diagnostic methods were obtained from 11 articles (Table 1, analysis 2). The majority of comparisons were between versions of Kato-Katz and FLOTAC or McMaster techniques. Only a few studies compared egg counts between Kato-Katz and FEC or Mini-FLOTAC methods; none with direct microscopy. Table 4 shows that the FLOTAC method generally underestimates the average egg counts compared with Kato-Katz, even though the difference is not statistically significant for T. trichiura. The McMaster technique, however, resulted in a higher egg count for six of 11 comparisons (55%) for T. trichiura and four of 12 comparisons (33%) for hookworm whilst A. lumbricoides egg counts were significantly lower. The relationships between the logarithmic average measurements of Kato-Katz and FLOTAC or McMaster techniques followed a linear trend as shown by the scatter plots presented in Fig. 5. 4 Discussion A global assessment of STH diagnostic test sensitivities and their extent of variation is required to investigate the suitability of diagnostic tools for different transmission settings or stages of STH control programmes. Here we present, to our knowledge, the first meta-analysis of STH diagnostic method performance using a Bayesian LCA framework to overcome the absence of a true gold standard (Dendukuri and Joseph, 2001; Branscum et al., 2005). Our results demonstrate that sensitivities of evaluated diagnostic tests are low overall and cannot be generalised over different transmission settings. Sensitivity, overall and in both intensity groups, was highest for the FLOTAC method, but was comparable for Mini-FLOTAC and Kato-Katz methods. Test sensitivities are strongly influenced by intensity of infection and this variation needs to be taken into account for the choice of a diagnostic test in a specific setting. Moreover, reduced test sensitivity at low infection intensities is of increasing importance as ongoing control programmes reduce the prevalence and intensity of STH infections within endemic communities. The Kato-Katz method is the most widely used and reported diagnostic method, due to its simplicity and low cost (Katz et al., 1972), and is recommended by the WHO for the quantification of STH eggs in the human stool (WHO, 2002). Even though the overall sensitivity of the Kato-Katz method was low, the results of the stratified analysis suggest a high sensitivity of 74–95% when infection intensity is high, which is likely the case for mapping and baseline assessment. However, the test sensitivity dropped dramatically in low transmission settings, making the method a less valuable option in later stages of control programmes. This is likely a reflection of methodological problems specific to the Kato-Katz method, especially when diagnosing multiple STH species infections, as different helminth eggs have different clearing times (Bergquist et al., 2009). In high intensity settings, little value was added by performing a 2-slide test on the same sample, even though this is the currently recommended protocol; whereas in low intensity settings sensitivity was improved by performing a second slide. Sensitivity increased significantly when performing the Kato-Katz method on multiple consecutive samples, which is most likely explained by daily variations of egg excretions and the non-equal distribution of eggs in the faeces leading to substantial variation in egg numbers between stool samples from the same person (Booth et al., 2003; Krauth et al., 2012). For all investigated STH species, sensitivity was highest for the FLOTAC method, even when evaluated in low intensity settings, a finding which is consistent with previous evaluations (Utzinger et al., 2008; Knopp et al., 2009b; Glinz et al., 2010). However, despite its improved performance compared with other copro-microscopic methods, FLOTAC has several practical constraints including higher associated costs, necessity of a centrifuge and longer sample preparation time, decreasing its value as a universal diagnostic method (Knopp et al., 2009a). To enable its use in settings with limited facilities, the Mini-FLOTAC method, a simplified form of FLOTAC, was developed (Barda et al., 2013a). Our findings suggest that the sensitivity of Mini-FLOTAC is much lower than FLOTAC, and it does not outperform the less expensive Kato-Katz method according to a recent study in Kenya (Speich et al., 2010; Assefa et al., 2014). A recognised advantage of the Mini-FLOTAC method, however, is that it can be performed on fixed stools, enabling processing at a later date in a central laboratory. This can help to increase the quality control process and overcomes some of the logistical difficulties in examining fresh stool samples in the field on the day of collection (Barda et al., 2013a). The obtained Mini-FLOTAC sensitivity estimates have relatively high uncertainty, visible in the wide confidence intervals, probably due to the limited number of studies available for the analysis and their evaluation primarily in low transmission settings, where the number of positive individuals is very limited. The detection or failure of detection of a single individual therefore might have a large impact on the sensitivity estimate. In remote areas where microscopy is often unavailable, studies can also use FEC, which allows the fixation of stool samples for later examination (WHO, 1994); several authors have also suggested the use of the McMaster technique as it is easier to standardise than Kato-Katz (Levecke et al., 2011; Albonico et al., 2012). Overall, the observed relative performances of these diagnostic tests when compared with the Kato-Katz method are consistent with those presented in the literature: the performance of Kato-Katz and McMaster methods were comparable, although this did vary by setting (Levecke et al., 2011; Albonico et al., 2013). Similarly, even though FEC had predominantly lower sensitivity than Kato-Katz in included studies, the reported relative performance varies in the literature (Glinz et al., 2010; Speich et al., 2013). The sensitivity of direct microscopy was consistently lower than the Kato-Katz method. Other available methods which were not included in our meta-analysis due to limited data availability, such as the midi-Parasep, do not show any improved test performance in their previous evaluations (Funk et al., 2013). Although we present an improved approach for evaluating diagnostic test performances, accounting for the absence of a perfect gold standard by estimating the true unmeasured infection status and allowing for conditional dependency between the test outcomes, our analysis is subject to several limitations. The results presented here are limited by the low availability of comparable data for each diagnostic test, especially when performing the analysis stratified by intensity group. Direct microscopy was primarily evaluated in low intensity settings, which could have led to the lower observed sensitivity estimates, whereas the Kato-Katz method was evaluated in a full range of settings. The cut-off value to define high and low intensity groups of study populations was chosen based on the data included in the meta-analysis, but does not necessarily represent two main types of transmission settings. Nevertheless, the groupings demonstrate the substantial differences in test performance across varying infection intensities. As the investigated range of transmission settings was limited, further diagnostic test evaluations in specified transmission settings will be needed to provide concrete test performance estimates for each of the settings. To take into account the conditional dependency between compared diagnostic tests, we used a fixed effects model, assuming that conditional dependency is the same for all study settings. Different approaches allowing for varying correlations by using random effects to model sensitivities and specificities as a function of a latent subject-specific random variable could be explored further (Dendukuri and Joseph, 2001). Moreover, our findings might be biased towards results from studies comparing multiple diagnostic tests at the same time, as these are underpinned by a larger amount of data. Assumptions had to ensure identifiability of the model by limiting the number of parameters to be estimated. We focussed our analysis on the sensitivity of diagnostic tests, assuming that specificity of various methods do not differ largely, and therefore included the specificity of all single sample diagnostic tests as one fixed parameter. This assumption can be questioned, as for example Kato-Katz slides are more difficult to read than FLOTAC slides due to debris (Glinz et al., 2010); however, it is still an improvement on the assumption of 100% test specificity for all diagnostic tests as applied in previous publications (Booth et al., 2003; Knopp et al., 2011; Levecke et al., 2011). Using uninformative priors instead of fixed terms did not improve model fit and led to slightly wider BCIs. Importantly, the current model assumes that sensitivities are identical within all populations, which is not fulfilled if sensitivity varies by study setting (Toft et al., 2005). Indeed, the stratified analysis showed that sensitivity varied by infection intensity; however, there were not sufficient data to obtain good estimates for all tests in various transmission settings. Additionally, sensitivity in a specific study setting might be affected by other factors including stool consistency and diet, standardisation and adherence to protocols, equipment quality and human error (Bogoch et al., 2006; Bergquist et al., 2009; Levecke et al., 2011). To overcome the limited comparability of evaluations from different studies, purposeful evaluations of test sensitivity over a continuous range of infection intensities in comparable populations, for example before and after treatment rounds, are clearly necessary to better refine sensitivity estimates, and could be used to identify intensity categories within which sensitivity remains comparable. Results could then be transformed into recommendations for the use of diagnostic tests for different stages of disease control programmes. The performance of a diagnostic tool should not only be measured in terms of sensitivity, but also needs to consider the ability of the test to quantify faecal egg counts. Current infection and treatment effect indicators are based on the Kato-Katz method, and the question arises whether the increasing use of other methods will constitute a problem for standardised recommendations (WHO, 2002). The comparison of average egg counts obtained by Kato-Katz and FLOTAC methods shows a broad agreement with previous studies with generally higher Kato-Katz egg counts (Knopp et al., 2009b, 2011; Albonico et al., 2013). The quantitative performance of the McMaster technique, however, varied in comparison to the Kato-Katz method as higher McMaster average egg counts were observed in several studies, especially for T. trichiura and hookworms (Levecke et al., 2011; Albonico et al., 2012, 2013). The current analysis has focussed on copro-microscopic diagnostic tests, which are based on examination of stool samples. There is current interest in developing more sensitive assays that allow a high sample throughput for screening of large populations using other biological samples and the simultaneous detection of several parasite species in co-endemic settings (Bergquist et al., 2009; Knopp et al., 2014). Recently, assays based on PCR have been developed for the detection of STH (Verweij et al., 2007; Schar et al., 2013; Knopp et al., 2014); however, we did not include this method in our meta-analysis due to limited data availability from field settings. Nonetheless, a recent study showed that the sensitivity of PCR methods was comparable with the Kato-Katz method, especially in low endemicity settings (Knopp et al., 2014). In conclusion, we provide a first known meta-analysis of the sensitivity and quantitative performance of STH diagnostic methods most widely used in resource-limited settings. Our results show that the FLOTAC method had the highest sensitivity both overall and in low intensity settings; however this technique requires a centrifuge and has relatively low throughput. Our results further show that the sensitivities of the Kato-Katz and Mini-FLOTAC techniques were comparable and in high intensity settings both techniques provide a practical and reliable diagnostic method. A particular advantage of the Kato-Katz method is the ability to simultaneously detect STH and schistosome species at low cost; whereas the Mini-FLOTAC method has the advantage that it can be used on preserved samples. As control programmes reduce the intensity of infection, there is a need for diagnostic methods which are more sensitive than these currently used. In evaluating the performance of new diagnostic methods we recommend a standardised evaluation in multiple transmission settings, using the robust statistical methods presented here, as well as a consideration of the cost-effectiveness of alternative methods (Assefa et al., 2014).

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Assessment of the Anthelmintic Efficacy of Albendazole in School Children in Seven Countries Where Soil-Transmitted Helminths Are Endemic

Jozef Vercruysse, Jerzy Behnke, Marco Albonico … (2011)

Introduction The three major Soil-Transmitted Helminths (STH), Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and Necator americanus/Ancylostoma duodenale (the hookworms) are amongst the most widespread parasites worldwide. An estimated 4.5 billion individuals are at risk of STH infection and more than one billion individuals are thought to be infected, of whom 450 million suffer morbidity from their infection, the majority of who are children. An additional 44 million infected pregnant women suffer significant morbidity and mortality due to hookworm-associated anemia. Approximately 135,000 deaths occur per year, mainly due to infections with hookworms or A. lumbricoides [1]. The most widely implemented method of controlling STH infections is through periodic administration of anthelmintics. Rather than aiming to achieve eradication, current control programs are focused on reducing infection intensity and transmission potential, primarily to reduce morbidity and avoid mortality associated with the disease [2]. The benzimidazole (BZ) drugs, i.e. albendazole (ALB) and mebendazole, are the most widely used drugs for the control of STH. While both show broad-spectrum anthelmintic activity, for hookworms a single dose of ALB is more effective than mebendazole [3]. The scale up of chemotherapy programs that is underway in various parts of Africa, Asia and South America, particularly targeting school children, is likely to exert increasing drug pressure on parasite populations, a circumstance that is likely to favor parasite genotypes that can resist anthelmintic drugs. Given the paucity of suitable alternative anthelmintics it is imperative that monitoring programs are introduced, both to assess progress and to detect any changes in therapeutic efficacy that may arise from the selection of worms carrying genes responsible for drug resistance. The well documented occurrence of resistance to anthelmintics in nematode populations of livestock [4], highlights the potential for frequent treatments used in chemotherapy programs to select drug resistant worms. Such an eventuality threatens the success of treatment programs in humans, both at individual and community levels [5]. Although some small scale studies [6], [7], have suggested emerging drug resistance in human STH, these studies should be interpreted with some caution, since suboptimal efficacy could have been due to factors other than drug resistance. Moreover, although for the BZ drugs there are many published studies reporting the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR), the two most widely used indicators for assessing the efficacy of an anthelmintic in human medicine, comparison of such studies is difficult, largely because there is no widely accepted standard operating procedure for undertaking such trials [8]. Published studies are confounded by methodological variations including treatment regimens, poor quality of drugs, differing statistical analyses used to calculate therapeutic efficacy, as well as a range of other problems in study design, such as small sample size, diagnostic methods, variation in pre-intervention infection intensities and confounding factors related to geographical locations. Such variation among studies greatly complicates direct comparison [3]. A World Health Organization-World Bank (WHO-WB) meeting on “Monitoring of Drug Efficacy in Large Scale Treatment Programs for Human Helminthiasis”, held in Washington DC at the end of 2007, highlighted the need to closely monitor anthelmintic drug efficacy and to develop standard operating procedures for this purpose. In a systematic meta-analysis of published single-dose studies, Keiser and Utzinger [8], confirmed that there was a paucity of high quality trials, and that the majority of trials were carried out more than 20 years ago. They recommended that well-designed, adequately powered, and rigorously implemented trials should be undertaken to provide current data regarding the efficacy of anthelmintics against the main species of STH. These should be designed to establish benchmarks (including standard operating procedures) for subsequent monitoring of drug resistance. The objective of the present work was to validate a standard protocol that has been developed for monitoring efficacy of anthelmintics against STH. To give the study wide relevance, we conducted the trial in seven populations in different geographic locations in Brazil, Cameroon, Cambodia, Ethiopia, India, Tanzania and Vietnam. In each of the study sites, different epidemiologic patterns of infection prevail, including different combinations of STH. We assessed the efficacy of a single dose (400 mg) of ALB in terms of the CR and the FECR in school children between 14 and 30 days following treatment. The McMaster egg counting technique was used in a standardized fashion, with rigorous quality control. Levecke et al. [9] reported that the McMaster holds promise as a standardized method on account of its applicability for quantitative screening of large numbers of subjects. This method is the recommended method for measuring fecal egg counts (FEC) when performing FECR for the detection of anthelmintic resistance in veterinary medicine [10], [11]. Methods Study sites This study was carried out in seven different countries covering Africa (Cameroon, Ethiopia and Tanzania), Asia (Cambodia, India and Vietnam) and South-America (Brazil). However, it is important to note, that while we refer to individual countries to identify results from particular trials, we do not make any conclusions about any country as such. Here, names of countries are used only to distinguish between 7 separate trials that were conducted in 7 geographically disparate regions of the world. In total ten study sites with varying STH and treatment history were included. These seven STH endemic countries were selected because of the presence of investigator groups with previous extensive experience in the diagnosis and control of STH. Table 1 provides their specific locations (district/province/state) and treatment history. Both species of hookworms (N. americanus and A. duodenale) were present in all study sites in varying degree with the exception of Brazil where only N. americanus was present. 10.1371/journal.pntd.0000948.t001 Table 1 The location and treatment history of the ten study sites. Country District/Province/State Treatment history Brazil Minas Gerais LSAT since 2007 (ALB) Cambodia Kratie LSAT since 1997, last in 2007 (MBD) Cameroon Loum LSAT (MBD/ALB) since 1999, last in 2008 (MBD) Yoyo No LSAT Ethiopia Jimma No LSAT India Vellore LSAT, since 2001, last in 2008 (ALB) Thiruvanamalai No LSAT Tanzania (Zanzibar) Pemba Island LSAT since 1994, last in 2006 (PZQ, IVM, ALB) Vietnam Thái Nguyên LSAT since 2005 Tuyên Quang No LSAT LSAT: large scale anthelmintic treatment, MBD: mebendazole, PZQ: praziquantel, IVM: ivermectine, ALB: albendazole. Trial design During the pre-intervention survey, school children aged 4 to 18 years at the different study sites were asked to provide a stool sample. For the initial sampling the aim was to enroll at least 250 infected children with a minimum of 150 eggs per gram of feces (EPG) for at least one of the STH. This sample size was selected based on statistical analysis of study power, using random simulations of correlated over-dispersed FEC data reflecting the variance-covariance structure in a selection of real FEC data sets. This analysis suggested that a sample size of up to 200 individuals (α = 0.05, power = 80%) was required to detect a 10 percentage point drop from a null efficacy of ∼ 80% (mean percentage FEC Δ per individual) over a wide range of infection scenarios. Standard power analyses for proportions also indicated that the detection of a ∼10 percentage point drop from a null cure rate required sample sizes up to 200 (the largest samples being required to detect departures from null efficacies of around 50%). Given an anticipated non-compliance rate of 25%, a sample of 250 individuals with >150 EPG pre-treatment was therefore considered necessary at each study site. Fecal samples were processed using the McMaster technique (analytic sensitivity of 50 EPG) for the detection and the enumeration of infections with A. lumbricoides, T. trichiura and hookworms [9]. None of the samples were preserved. Samples which could not be processed within 24 hours were kept at 4°C. A single dose of 400 mg ALB (Zentel) from the same manufacturer (GlaxoSmithKline Pharmaceuticals Limited, India) and same lot (batch number: B.N°: L298) was used at all trial sites. No placebo control subjects were included in the trial for ethical and operational reasons. Between 14 to 30 days after the pre-intervention survey, stool samples were collected from the treated subjects and processed by the McMaster technique. All of the trials were carried out in a single calendar year (2009). Subjects who were unable to provide a stool sample at follow-up, or who were experiencing a severe concurrent medical condition or had diarrhea at time of the first sampling, were excluded from the study. The participation, the occurrence of STH and sample submission compliance for pre- and post-intervention surveys are summarized in Figure 1. 10.1371/journal.pntd.0000948.g001 Figure 1 The participation, occurrence of STH and sample submission compliance for pre- and post-intervention surveys. Subjects who were not able to provide a sample for the follow-up, or who were experiencing a severe current medical condition or had diarrhea at the time of the first sampling were excluded from the trial. The McMaster counting technique The McMaster counting technique (McMaster) was based on the modified McMaster described by the Ministry of Agriculture, Fisheries and Food (UK; 1986) [12]. Two grams of fresh stool samples were suspended in 30 ml of saturated salt solution (density = 1.2). The suspension was poured three times through a wire mesh to remove large debris. Then 0.15 ml aliquots were added to each of the 2 chambers of a McMaster slide. Both chambers were examined under a light microscope using a 100x magnification and the FEC for each helminth species was obtained by multiplying the total number of eggs by 50. Statistical analysis The efficacy of the treatment for each of the three STH was evaluated qualitatively based on the reduction in infected children (CR) and quantitatively based on the reduction in fecal egg counts (FECR). The outcome of the FECR was calculated using three formulae. The first two formulae were based on the mean (arithmetic/geometric) of the pre- and post-intervention fecal egg count (FEC) ignoring the individual variability, whereas the third formula represented the mean of the reduction in the FEC per subject. The latter is the only quantitative indicator of efficacy for which the importance of confounding factors can be assessed by statistical analysis. The CR and the FECR (1-3) outputs were calculated for the different trials, both sexes, age classes (A: 4–8 years; B: 9–13 years and C: 14–18 years) and for the level of egg excretion intensity at the pre-intervention survey. These levels corresponded to the low, moderate and high intensities of infection as described Montresor et al. [13] For A. lumbricoides these were 1–4,999 EPG, 5,000–49,999 EPG and >49,999 EPG; for T. trichiura these levels were 1–999 EPG, 1000–9,999 EPG and >9,999 EPG; and for hookworms these were 1–1,999 EPG, 2,000–3,999 EPG and >3,999 EPG, respectively. In addition, the robustness of the three FECR formulae was explored by comparing the FEC reduction rate obtained from all samples containing STH and those obtained from samples containing more than 150 EPG as recommended in the anthelmintic resistance guidelines of the World Association for the Advancement of Veterinary Parasitology [9]. Finally, putative factors affecting the CR and the FECR (3) were evaluated. For the CR, generalized linear models (binomial error) were built with the test result (infected /uninfected) as the outcome, ‘trial’ (7 levels: trials in Brazil, Cambodia, Cameroon, Ethiopia, India, Tanzania and Vietnam) and ‘sex’ (2 levels: female and male) as factors, and ‘age’ and the log transformed pre-intervention FEC as covariates. Full factorial models were evaluated by the backward selection procedure using the likelihood ratio test of χ2. Finally, the CR for each of the observed values of the covariate and factor was calculated based on these models (The R Foundation for Statistical Computing, version 2.10.0 [14]). For analysis of the data from FECR (3), non-parametric methods were used, because models based on parametric statistics, even with negative binomial error structures, or based on transformed data would not converge satisfactorily as a consequence of the high proportion of FEC with zero EPG. Hence, the impact of the factors ‘trial’ and ‘sex’ were assessed by the Kruskal-Wallis test (for more than 2 group comparisons) and the Mann-Whitney U test, respectively. The correlation between the outputs of FECR (3) and the covariates (age and pre-intervention FEC) was estimated by the Spearman rank order correlation coefficient (SAS 9.1.3, SAS Institute Inc.; Cary, NC, USA). Ethics statement The overall protocol of the study was approved by the Ethics committee of the Faculty of Medicine, Ghent University (Nr B67020084254) and was followed by a separate local ethical approval for each study site. For Brazil, approval was obtained from the Institutional Review Board from Centro de Pesquisas René Rachou (Nr 21/2008), for Cambodia from the National Ethic Commitee for Health Research, for Cameroon from the National Ethics Committee (Nr 072/CNE/DNM08), for Ethiopia from the Ethical Review Board of Jimma University, for India from the Institutional Review Board of the Christian Medical College (Nr 6541), for Tanzania (Nr 20) from the Zanzibar Health Research Council and the Ministry of Health and Social Welfare, for Vietnam by the Ministry of Health of Vietnam. An informed consent form was signed by the parents of all subjects included in the study. This clinical trial was registered under the ClinicalTrials.gov Identifier NCT01087099. Results The cure rate (CR) Overall, the highest CRs were observed for A. lumbricoides (98.2%), followed by hookworm (87.8%) and T. trichiura (46.6%). However, as shown in Table 2, the CRs varied across the different trials, age classes and pre-intervention FEC levels. The differences in CRs between trials were most pronounced for T. trichiura, ranging from 21.0 (Tanzania) to 88.9% (India). The T. trichiura CRs of 100% for the trials in Brazil and Cambodia are not considered here as they were based on only 1 and 2 individuals, respectively. For hookworms and A. lumbricoides, the CRs varied from 74.7 (India) to 100% (Vietnam) and from 96.4 (Tanzania) to 99.3% (Ethiopia and Cameroon), respectively. The CRs for A. lumbricoides in Cambodia (100%) and India (95.2%) are not considered here as they were based on fewer than 50 individuals. The CRs increased over the three age classes (A. lumbricoides: 95.8 to 100%; T. trichiura: 44.7 to 54.1%), except for hookworms where the CRs ranged from 86.1 to 88.3, and then to 87.5%. For each of the three STH, there was a decline in the CR with increasing levels of infection intensities at the pre-intervention survey. The largest drop was observed for T. trichiura, which decreased from 53.9 to 12.5%. For the two other STH, the drop in the CR was less pronounced, ranging from 88.6 to 76.9% for hookworms and only from 98.3 to 95% for A. lumbricoides. The observed differences between sexes were negligible for all three STH. 10.1371/journal.pntd.0000948.t002 Table 2 The cure rate (CR) for treatment with a single dose of albendazole against soil-transmitted helminths. A. lumbricoides T. trichiura Hookworms n CR (%) N CR (%) n CR (%) Country Brazil 50 98.0 1* 100 52 88.5 Cambodia 5* 100 2* 100 127 87.4 Cameroon 298 99.3 386 47.4 140 87.1 Ethiopia 151 99.3 105 85.7 91 98.9 India 21* 95.2 18* 88.9 95 74.7 Tanzania 279 96.4 396 21.0 349 86.8 Vietnam 148 98.6 138 81.2 58 100 Age class A (4–8) 215 95.8 219 44.7 173 86.1 B (9–13) 669 98.8 753 46.3 643 88.3 C (14–18) 68 100 74 54.1 96 87.5 Sex Female 462 98.1 503 48.5 393 89.1 Male 490 98.4 543 44.8 519 86.9 Pre-intervention infection intensity Low 662 98.3 823 53.9 859 88.6 Moderate 270 98.1 215 19.5 40 75.0 High 20 95.0 8 12.5 13 76.9 Total 952 98.2 1046 46.6 912 87.8 *Due to the low number of infected subjects ( 75%). The pre-intervention FEC was probably the most important as it had a considerable effect on the CR of A. lumbricoides (χ2 1 = 4.14, p 99.3%). The results of FECR (3) mostly yielded comparable or lower values than those from FECR (1). The low values (sometimes negative) can be explained by subjects for whom the post-intervention FEC exceeded the pre-intervention FEC. These subjects contributed to a negative FEC reduction rate which had a significant impact on the final FEC reduction rate calculated with FECR (3). This became apparent in the FEC reduction rate for A. lumbricoides, where a Cameroonian male subject of 7 years with a pre-intervention FEC of 100 and a post-intervention FEC of 22,050 EPG, contributed markedly to lowering the overall values for the data-set from the trial in Cameroon (FECR (1): 99.2%; FECR (3): 26.0%). This lowering of FECR (3) compared to FECR (1) for A. lumbricoides also occurred with age class A (FECR (1): 98.9%; FECR (3): −2.7%) and the low pre-intervention infection intensity level (FECR (1): 97.8%; FECR (3): 66.6%), but not for the remaining variables. The number of negative individual FEC reduction rates, and the magnitude of the difference between pre- and post-intervention FEC, both contributed to the discrepancies found for T. trichiura (176 subjects) and hookworms (10 subjects). Robustness of FECR formulae Table 5 summarizes the FEC reduction rates restricted to samples of more than 150 EPG indicating that the results of FECR (1) and FECR (2) remained roughly unchanged. The values from FECR (3) increased and were mostly comparable with those obtained by FECR (1). This change in the results of FECR (3) is due to the exclusion of negative individual FEC reduction rates which mostly occurred among the subjects with low pre-intervention FEC (see also Table 4). Differences of more than 5% between the results of FECR (3) and FECR (1) were limited to T. trichiura (country: Cameroon, India, Tanzania and Vietnam; age class: A and C). 10.1371/journal.pntd.0000948.t005 Table 5 Fecal egg count reduction for samples with a pre-intervention FEC of more than 150 EPG. A. lumbricoides T. trichiura Hookworms n FECR(1)(%) FECR(2)(%) FECR(3)(%) n FECR(1)(%) FECR(2)(%) FECR(3)(%) n FECR(1)(%) FECR(2)(%) FECR(3)(%) Country Brazil 47* 100.0 100.0 100.0 0* _ _ _ 46* 97.5 99.6 97.5 Cambodia 1* 100.0 100.0 100.0 1* 100.0 99.7 100.0 100 97.7 99.6 96.7 Cameroon 266 99.8 100.0 100.0 233 39.9 93.4 50.4 71 93.6 99.5 95.1 Ethiopia 145 100.0 99.9 100.0 72 92.3 99.2 92.6 66 99.6 99.7 99.8 India 17* 98.9 99.9 99.6 11* 72.0 99.1 87.0 83 87.8 99.3 84.2 Tanzania 266 100.0 100.0 99.9 325 58.3 86.6 36.4 281 95.4 99.7 93.1 Vietnam 130 100.0 99.9 99.9 71 93.1 99.2 88.0 19* 100.0 99.7 100.0 Age class A (4–8) 196 99.9 100.0 99.8 153 65.1 94.8 57.2 130 94.7 99.6 94.4 B (9–12) 613 99.8 100.0 99.9 515 48.4 94.1 51.8 460 94.9 99.6 93.2 C (13–18) 63 100.0 100.0 100.0 45 60.2 94.4 46.4 76 96.4 99.6 97.1 Sex Female 428 100.0 100.0 99.9 343 54.0 94.7 57.7 286 95.2 99.6 93.8 Male 444 99.7 100.0 99.9 370 53.0 93.8 48.0 380 94.8 99.6 94.0 Pre-intervention infection intensity Low 582 99.9 99.9 99.9 490 49.0 95.1 50.2 613 94.1 99.6 93.6 Moderate 270 100.0 100.0 100.0 215 58.7 92.2 58.7 40 97.6 99.9 97.1 High 20 99.5 100.0 99.6 8 40.0 88.6 40.1 13 95.9 99.9 96.4 Total 872 99.9 100.0 99.9 713 53.5 94.3 52.7 666 95.0 99.6 93.9 FECR(1): group based and arithmetic mean; FECR(2): group based and geometric mean; FECR(3): individual based and arithmetic. *Due to the low number of infected subjects ( 95% for A. lumbricoides and >90% for hookworms are appropriate thresholds, and that efficacy levels below this should raise concern. The great variability of the FECR for T. trichiura and the relatively low efficacy of ALB, confirmed in this present study, indicate that it is not possible to propose an efficacy threshold for this parasite based on our data. In conclusion, the present study is the first to evaluate drug efficacy of a single-oral dose of ALB on such a scale and across three continents. The results confirm the therapeutic efficacy of this treatment against A. lumbricoides and hookworms, and the low efficacy against T. trichiura. Efficacy varied widely across the seven different trials, particularly in the case of T. trichiura and it remains unclear which factors were principally responsible for this variation, although pre-intervention FEC and age played clear roles in this respect. The FEC reduction rate based on arithmetic means is the best available indicator of drug efficacy, and should be adopted in future monitoring and evaluation studies of large scale anthelmintic treatment programs. Finally, our findings emphasize the need to revise the WHO recommended efficacy threshold for single dose ALB treatments. Supporting Information Checklist S1 CONSORT Checklist (0.22 MB DOC) Click here for additional data file. Protocol S1 Trial Protocol (1.17 MB PDF) Click here for additional data file.

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Assessing the feasibility of interrupting the transmission of soil-transmitted helminths through mass drug administration: The DeWorm3 cluster randomized trial protocol

Kristjana Hrönn Ásbjörnsdóttir, Sitara S. Rao Ajjampur, Roy M. Anderson … (2018)

Current control strategies for soil-transmitted helminths (STH) emphasize morbidity control through mass drug administration (MDA) targeting preschool- and school-age children, women of childbearing age and adults in certain high-risk occupations such as agricultural laborers or miners. This strategy is effective at reducing morbidity in those treated but, without massive economic development, it is unlikely it will interrupt transmission. MDA will therefore need to continue indefinitely to maintain benefit. Mathematical models suggest that transmission interruption may be achievable through MDA alone, provided that all age groups are targeted with high coverage. The DeWorm3 Project will test the feasibility of interrupting STH transmission using biannual MDA targeting all age groups. Study sites (population ≥80,000) have been identified in Benin, Malawi and India. Each site will be divided into 40 clusters, to be randomized 1:1 to three years of twice-annual community-wide MDA or standard-of-care MDA, typically annual school-based deworming. Community-wide MDA will be delivered door-to-door, while standard-of-care MDA will be delivered according to national guidelines. The primary outcome is transmission interruption of the STH species present at each site, defined as weighted cluster-level prevalence ≤2% by quantitative polymerase chain reaction (qPCR), 24 months after the final round of MDA. Secondary outcomes include the endline prevalence of STH, overall and by species, and the endline prevalence of STH among children under five as an indicator of incident infections. Secondary analyses will identify cluster-level factors associated with transmission interruption. Prevalence will be assessed using qPCR of stool samples collected from a random sample of cluster residents at baseline, six months after the final round of MDA and 24 months post-MDA. A smaller number of individuals in each cluster will be followed with annual sampling to monitor trends in prevalence and reinfection throughout the trial. Trial registration ClinicalTrials.gov NCT03014167

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Piet Cools:

ORCID: http://orcid.org/0000-0003-2980-5307

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Johnny Vlaminck:

ORCID: http://orcid.org/0000-0002-3601-9825

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Marco Albonico: Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing

Shaali Ame: Role: InvestigationRole: Writing – review & editing

Mio Ayana: Role: InvestigationRole: Writing – review & editing

Barrios Perez José Antonio:

ORCID: http://orcid.org/0000-0002-6328-7497

Role: MethodologyRole: Writing – review & editing

Giuseppe Cringoli: Role: MethodologyRole: Writing – review & editing

Daniel Dana: Role: InvestigationRole: Writing – review & editing

Jennifer Keiser: Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing

Maria P. Maurelli: Role: MethodologyRole: Writing – review & editing

Catalina Maya: Role: Software

Leonardo F. Matoso: Role: InvestigationRole: Writing – review & editing

Antonio Montresor: Role: Writing – review & editing

Zeleke Mekonnen: Role: InvestigationRole: Writing – review & editing

Greg Mirams: Role: MethodologyRole: SoftwareRole: Writing – review & editing

Rodrigo Corrêa-Oliveira: Role: Writing – review & editing

Simone A. Pinto: Role: Writing – review & editing

Laura Rinaldi: Role: MethodologyRole: Writing – review & editing

Somphou Sayasone: Role: InvestigationRole: Writing – review & editing

Eurion Thomas: Role: MethodologyRole: SoftwareRole: Writing – review & editing

Jaco J. Verweij: Role: InvestigationRole: MethodologyRole: Writing – review & editing

Jozef Vercruysse: Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing

Bruno Levecke: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Matthew C. Freeman: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Negl Trop Dis

Journal ID (iso-abbrev): PLoS Negl Trop Dis

Journal ID (publisher-id): plos

Journal ID (pmc): plosntds

Title: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1935-2727

ISSN (Electronic): 1935-2735

Publication date (Electronic): 1 August 2019

Publication date Collection: August 2019

Volume: 13

Issue: 8

Electronic Location Identifier: e0007446

Affiliations

[1 ] Department of Virology, Parasitology and Immunology, Ghent University, Merelbeke, Belgium

[2 ] Center for Tropical Diseases, Sacro Cuore Don Calabria Hospital, Negrar, Italy

[3 ] Department of Life Sciences and Systems Biology, University of Turin, Italy

[4 ] Public Health Laboratory-Ivo de Carneri, Chake Chake, United Republic of Tanzania

[5 ] Jimma University Institute of Health, Jimma University, Jimma, Ethiopia

[6 ] Engineering Institute of National Autonomous University of Mexico, Mexico City, Mexico

[7 ] Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy

[8 ] Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

[9 ] University of Basel, Basel, Switzerland

[10 ] Laboratory of Molecular and Cellular Immunology, Research Center René Rachou—FIOCRUZ, Belo Horizonte, Brazil

[11 ] Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland

[12 ] Techion Group Ltd, Dunedin, New Zealand

[13 ] Lao Tropical and Public Health Institute, Ministry of Health, Vientiane, Lao People’s Democratic Republic

[14 ] Techion Group Ltd, Aberystwyth, United Kingdom

[15 ] Laboratory for Medical Microbiology and Immunology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands

Emory University, UNITED STATES

Author notes

The FECPAKG2 technology was produced and distributed by Techion Group Ltd, of which ET is an employee and GM is managing director. Both hold stocks in Techion Group Ltd. The Mini-FLOTAC device is a commercial product distributed by GC, LR and MPM through the University of Napoli Federico II. However, the affiliations of ET, GM, GC, LR and MPM did not play any role in the preparation and submission of this manuscript. All other authors declared that they have no competing interests.

* E-mail: bruno.levecke@ 123456ugent.be

Author information

Piet Cools http://orcid.org/0000-0003-2980-5307

Johnny Vlaminck http://orcid.org/0000-0002-3601-9825

Barrios Perez José Antonio http://orcid.org/0000-0002-6328-7497

Article

Publisher ID: PNTD-D-19-00233

DOI: 10.1371/journal.pntd.0007446

PMC ID: 6675048

PubMed ID: 31369558

SO-VID: fd484755-381d-44ba-a081-a83d227653ac

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 13 February 2019

Date accepted : 7 May 2019

Page count

Figures: 5, Tables: 5, Pages: 22

Funding

Funded by: funder-id http://data.crossref.org/fundingdata/funder/10.13039/100000865, Bill & Melinda Gates Foundation;

Award ID: OPP1120972

Award Recipient : Bruno Levecke

PC is financially supported through a grant from the Bill & Melinda Gates foundation (OPP1120972, principal investigator is BL; www.starworms.org). JV is financially supported through an International Coordination Action of the Flemish Research Foundation ( www.FWO.be). BL is a postdoctoral fellow of the Research Foundation ( www.FWO.be). The study was financially supported by a grant from the Bill & Melinda Gates foundation (OPP1120972, principal investigator is BL; www.starworms.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability The complete data set is found as S7 Info 'Data Set', an excel file with all raw data.

Diagnostic performance of a single and duplicate Kato-Katz, Mini-FLOTAC, FECPAK ^G2 and qPCR for the detection and quantification of soil-transmitted helminths in three endemic countries

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Sensitivity of diagnostic tests for human soil-transmitted helminth infections: a meta-analysis in the absence of a true gold standard

Assessment of the Anthelmintic Efficacy of Albendazole in School Children in Seven Countries Where Soil-Transmitted Helminths Are Endemic

Assessing the feasibility of interrupting the transmission of soil-transmitted helminths through mass drug administration: The DeWorm3 cluster randomized trial protocol

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