The causal effect of malaria on stunting: a Mendelian randomization and matching approach.
BACKGROUND
Previous studies on the association of malaria and stunted growth delivered inconsistent results. These conflicting results may be due to different levels of confounding and to considerable difficulties in elucidating a causal relationship. Randomized experiments are impractical and previous observational studies have not fully controlled for potential confounding including nutritional deficiencies, breastfeeding habits, other infectious diseases and socioeconomic status.


METHODS
This study aims to estimate the causal effect between malaria episodes and stunted growth by applying a combination of Mendelian randomization, using the sickle cell trait, and matching. We demonstrate the method on a cohort of children in the Ashanti Region, Ghana.


RESULTS
We found that the risk of stunting increases by 0.32 (P-value: 0.004, 95% CI: 0.09, 1.0) for every malaria episode. The risk estimate based on Mendelian randomization substantially differs from the multiple regression estimate of 0.02 (P-value: 0.02, 95% CI: 0.003, 0.03). In addition, based on the sensitivity analysis, our results were reasonably insensitive to unmeasured confounders.


CONCLUSIONS
The method applied in this study indicates a causal relationship between malaria and stunting in young children in an area of high endemicity and demonstrates the usefulness of the sickle cell trait as an instrument for the analysis of conditions that might be causally related to malaria.
Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA, Section for Tropical Medicine, I. Department of Internal Medicine, University Medical Center Eppendorf, Hamburg, Germany, Research Group Infectious Disease Epidemiology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany and Kumasi Center for Collaborative Research in Tropical Medicine, Kumasi, Ghana.
Hyunseung
H
Kang
Benno
B
Kreuels
Ohene
O
Adjei
Ralf
R
Krumkamp
Jürgen
J
May
Dylan S
DS
Small
D000962:Antimalarials / Q000627:therapeutic use; D016022:Case-Control Studies; D015984:Causality; D002657:Child Development; D002675:Child, Preschool; D015331:Cohort Studies; D004338:Drug Combinations; D005260:Female; D020022:Genetic Predisposition to Disease; D005869:Ghana / Q000453:epidemiology; D006130:Growth Disorders / Q000453:epidemiology*; D006441:Hemoglobin A / Q000235:genetics; D006451:Hemoglobin, Sickle / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008288:Malaria / Q000453:epidemiology* / Q000235:genetics / Q000517:prevention & control; D008297:Male; D057182:Mendelian Randomization Analysis; D015999:Multivariate Analysis; D016012:Poisson Distribution; D011739:Pyrimethamine / Q000627:therapeutic use; D012044:Regression Analysis; D012805:Sickle Cell Trait / Q000453:epidemiology* / Q000235:genetics; D013413:Sulfadoxine / Q000627:therapeutic use
D000962:Antimalarials; D004338:Drug Combinations; D006451:Hemoglobin, Sickle; C028672:hemoglobin AA; C001205:fanasil, pyrimethamine drug combination; C028671:hemoglobin AS; D013413:Sulfadoxine; D006441:Hemoglobin A; D011739:Pyrimethamine
Malaria; Mendelian randomization; children; matching; stunting