Acknowledgements

1. Deworming and adjuvant interventions for children in low and middle income countries: systematic review and network meta-analysis Vivian Welch, Chris Cameron, Shally Awasthi, Chisa Cumberbatch, Robert Fletcher, Jessie McGowan, Shari Krishnaratne, Salim Sohani, Peter Tugwell, George Wells

2. Acknowledgements • Canadian Institutes of Health Research Knowledge Synthesis

3. Geohelminths and schistosomiasis Necator americanus and Ancylostoma duodenale (hookworm) Ascaris lumbricoides (roundworm) Schistosomiasis Trichuris Trichiura (whipworm)

7. The greatest burden of STH occurs in Sub-Saharan Africa (SSA). This map shows the predicted distribution of STHs in SSA with AscarisLumbricoides. Source: Global Atlas of Helminth Infections

8. WHO Guidelines for Deworming, 2011 • For soil-transmitted helminths, annual treatment in areas where prevalence rate of soil-transmitted helminthiases is between 20% and 50%, and, a bi-annual treatment in areas with prevalence rates of over 50%. • For schistosomiasis, annual treatment with praziquantel in high risk communities (>50%), once every two years in medium risk (>10% and <50%), twice during primary school in low risk communities (<10%)

9. What do we know about effects of deworming?

10. Deworm the World • School-based deworming identified as one of the most efficient and cost-effective solutions to the global challenges facing us today (Copenhagen Consensus Meeting) • School-based deworming proven to reduce school absenteeism by 25%, and can lead to an additional year of attendance for only $3.50. • Children regularly dewormed are shown to earn over 20% more and work 12% more hours as adults • Children less than one year old at the time of school-based deworming in their communities are shown to have large cognitive improvements equivalent to half a year of schooling. • Source: www.Dewormtheworld.org; Kremer and Miguel 2004, Ozier 2011, Baird 2011

12. Taylor-Robinson et al 2012, Cochrane • Aimed to summarize the effects of deworming to children to treat soil-transmitted intestinal worms (nematode geohelminths) on weight, haemoglobin, and cognition; and the evidence of impact on physical well being, school attendance, school performance, and mortality • 42 randomized and quasi-randomized trials satisfied eligibility criteria • Author’s conclusion: “it is probably misleading to justify contemporary deworming programmes based on evidence of consistent benefit on nutrition, haemoglobin, school attendance or school performance as there is simply insufficient reliable information to know whether this is so”

13. DEVTA- “largest trial ever” • 1 million children in India, aged 1-6 years • No difference in mortality (deaths per child-care centre at ages 1·0–6·0 years during the 5-year study were 3·00 (SE 0·07) albendazole versus 3·16 (SE 0·09) control, difference 0·16 (SE 0·11, mortality ratio 0·95, 95% CI 0·89 to 1·02, p=0·16))

14. Why such discordant conclusions?

15. Possible reasons for discordance… • Spillover effects/positive externalities • All intestinal worms are not the same • Not all intestinal worms respond to the same deworming medication. • Only moderate and heavy intestinal helminth infections typically cause measurable disease. • Reinfection • Underlying host and environment factors • Non-standard measures of school attendance and cognitive performance • Heterogeneity within and between studies

16. Mechanism of action of selected drugs

17. Campbell review on deworming: a network meta-analysis IDCG review

18. Research questions • Effect of deworming according to the WHO guidelines compared to placebo (or control)? • Effect of deworming for STH vs. schistosomiasis vs. combined approaches? • Effect of adding hygiene education, sanitation, micronutrients or feeding programs compared to deworming alone • What factors contribute to heterogeneity of effect (e.g. endemicity, child age, baseline nutritional status, infection intensity)?

19. Hygiene promotion and/or sanitation LEGEND Intermediary outcomes Final outcomes Interventions/ co-interventions Causal pathway Cyclical effect • Vectors: • soil • drinking water • washing water Reduced reinfection • feces • hands • food Reduced symptoms 3 (eg. diarrhoea, abdominal pain, general malaise, weakness, intestinal blood loss, anemia, fever, dysuria, intestinal obstruction, haematuria, and organ damage) • Improved longer • term outcomes • Reduced • proportion • of wasted children • Improved weight • and height • Improved social, • physical, • emotional and • cognitive • functioning • Effects of improved • health outcomes • Improved • overall well-being • Increased • school • attendance • and achievement • Improved labour • market outcomes Target Population Children (1-16 yrs) in wormendemic areas[AscarislumbricoidesTrichuristrichuraAncylostomaduodenale,Necatoramericanus, and Schistosoma] Deworming (STH treatment +/ or schistoso-miasis treatment) Decreased worm burden in treated children1 • Improved short term outcomes • Improved • nutrient absorption • Improved • nutritional status Spillover decreased worm burden in control children 2 Decreases the gap between the poor and least poor Improves health equity Nutritional therapy (eg. micronutrient, feeding, iron) Risk factors/conditions for implementation and up-take: Individual anaemia, undernutrition, low socioeconomic status Environment high worm burden, high endemicity of other infectious disease, poor sanitation, poor hygiene, poverty Intervention supervision, dosage, time of day, place of administration

20. Mixed treatment comparisons • Assessment of heterogeneity due to multiple components (i.e. hygiene, sanitation, micronutrients, feeding and type of deworming); • Identification of areas where evidence is limited • Meta-regression allows more complete consideration of covariates (such as age, study duration, nutritional status and intensity of worm infection)

21. What is a network meta-analysis?

22. Methods • Bayesian Mixed Treatment Comparison Network Meta-analysis using WinBUGSsoftware • Normal likelihood model which allows for the use of multi-arm trials • Both fixed and random-effects Bayesian network meta-analyses were conducted • Choice of model was based on assessment of the Deviance Information Criterion (DIC) and comparison of residual deviance to number of unconstrained data points • Compared deviance and DIC statistics in fitted consistency and inconsistency models • Vague or flat priors were assigned for basic parameters throughout Bayesian analyses

23. PICO • Population: 6 months- 16 years of age • Intervention: Mass drug administration for chemoprevention of STH or schistosomiasis, alone or in combination with cointerventions • Comparison: placebo, control, active • Outcomes: anthropometry, educational status, cognition, well-being, adverse events

24. Eligible studies • Randomized and quasi-randomized controlled trials • Quasi-experimental studies which use statistical methods to account for confounding and sample selection bias

25. Search strategy

26. PRISMA Flow diagram 9,790 identified through database searching Impact evaluation databases remain to be searched 9790 screened for eligibility 9,619 Excluded Studies retrieved in full text (n=171) 143 Excluded 7 awaiting data from authors RCTs included in quantitative synthesis (n=21)

27. Characteristics of studies • # arms: 14 two arm, 5 three arm, 2 four arm • Age range: < 6 months: 1; 12-60 month: 9; >60 month: 11 • Endemicity: low: 8; moderate: 5; high: 8 • Size of study: <100: 3; 100-500: 7; >500: 7; >1000: 4 • Study duration: <6 months: 3; 6 months-1 year: 11; > 1 year: 7 • # cluster RCTs: 7 out of 21

28. Evidence Network – Deworming-Weight gain (Kg) 21 RCTs 16 Treatments N=42,197

29. Results vs. Placebo – Weight gain in Kg FE: Resdev=161 vs 51; DIC=60.65 RE: Resdev=52.7 vs 51; DIC=-35.9

30. Results vs. Placebo, RE Model– Weight gain in Kg Deworming 0.29 (0.13, 0.45) Overall I2=92%

31. Next steps • Hand searching reference lists, impact evaluation databases, contacting authors • Educational outcomes • Quasi-experimental studies • Risk of bias • Causal pathway analysis • Covariate analysis to explore heterogeneity and improve consistency of model

32. Questions? • Vivian.welch@uottawa.ca