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.

[1]  D. Kwiatkowski,et al.  Haplotype Analyses of Haemoglobin C and Haemoglobin S and the Dynamics of the Evolutionary Response to Malaria in Kassena-Nankana District of Ghana , 2012, PloS one.

[2]  J. Tappero,et al.  The association between malnutrition and the incidence of malaria among young HIV-infected and -uninfected Ugandan children: a prospective study , 2012, Malaria Journal.

[3]  Kevin Marsh,et al.  Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study , 2011, The Lancet.

[4]  Dylan S. Small,et al.  Building a Stronger Instrument in an Observational Study of Perinatal Care for Premature Infants , 2010 .

[5]  S. Adjei,et al.  Differing effects of HbS and HbC traits on uncomplicated falciparum malaria, anemia, and child growth. , 2010, Blood.

[6]  K. Deribe,et al.  Malaria and Under-Nutrition: A Community Based Study Among Under-Five Children at Risk of Malaria, South-West Ethiopia , 2010, PloS one.

[7]  J. Stanford,et al.  Exploring the relationship between chronic undernutrition and asymptomatic malaria in Ghanaian children , 2010, Malaria Journal.

[8]  P. Rosenbaum,et al.  Amplification of Sensitivity Analysis in Matched Observational Studies , 2009, Journal of the American Statistical Association.

[9]  B. Cissé,et al.  Impact of child malnutrition on the specific anti-Plasmodium falciparum antibody response , 2009, Malaria Journal.

[10]  S. Adjei,et al.  Sickle cell trait (HbAS) and stunting in children below two years of age in an area of high malaria transmission , 2009, Malaria Journal.

[11]  Dylan S. Small,et al.  War and Wages , 2008 .

[12]  M. Tobin,et al.  Mendelian Randomisation and Causal Inference in Observational Epidemiology , 2008, PLoS medicine.

[13]  George Davey Smith,et al.  Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology , 2008, Statistics in medicine.

[14]  S. Ebrahim,et al.  Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? , 2008, Human Genetics.

[15]  O. Doumbo,et al.  Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin , 2008, Proceedings of the National Academy of Sciences.

[16]  S. Adjei,et al.  A randomized controlled trial of extended intermittent preventive antimalarial treatment in infants. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[17]  T. Agbenyega,et al.  Hemoglobin variants and disease manifestations in severe falciparum malaria. , 2007, JAMA.

[18]  F. Mockenhaupt,et al.  Malaria, anemia, and malnutrition in african children--defining intervention priorities. , 2006, The Journal of infectious diseases.

[19]  Mercedes Onis,et al.  WHO Child Growth Standards based on length/height, weight and age , 2006, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[20]  Sammy Wambua,et al.  An Immune Basis for Malaria Protection by the Sickle Cell Trait , 2005, PLoS medicine.

[21]  K. Marsh,et al.  Malaria and nutritional status in children living on the coast of Kenya. , 2004, The American journal of clinical nutrition.

[22]  R. Snow,et al.  Impact of malaria control on childhood anaemia in Africa – a quantitative review , 2004, Tropical medicine & international health : TM & IH.

[23]  S. Ebrahim,et al.  Mendelian randomization: prospects, potentials, and limitations. , 2004, International journal of epidemiology.

[24]  Jeffrey M. Wooldridge,et al.  Solutions Manual and Supplementary Materials for Econometric Analysis of Cross Section and Panel Data , 2003 .

[25]  T. Shakespeare,et al.  Observational Studies , 2003 .

[26]  M. Kolczak,et al.  Impact of permethrin-treated bed nets on malaria, anemia, and growth in infants in an area of intense perennial malaria transmission in western Kenya. , 2003, The American journal of tropical medicine and hygiene.

[27]  S. Ebrahim,et al.  'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? , 2003, International journal of epidemiology.

[28]  Dianne J Terlouw,et al.  Protective effects of the sickle cell gene against malaria morbidity and mortality , 2002, The Lancet.

[29]  L. Seidlein,et al.  Increased risk for malaria in chronically malnourished children under 5 years of age in rural Gambia. , 2002, Journal of tropical pediatrics.

[30]  Guido W. Imbens,et al.  The Interpretation of Instrumental Variables Estimators in Simultaneous Equations Models with an Application to the Demand for Fish , 2000 .

[31]  M. Alpers,et al.  Relation of anthropometry to malaria morbidity and immunity in Papua New Guinean children. , 1998, The American journal of clinical nutrition.

[32]  Joshua D. Angrist,et al.  Identification of Causal Effects Using Instrumental Variables , 1993 .

[33]  R. Snow,et al.  The relationship between anthropometric measurements and measurements of iron status and susceptibility to malaria in Gambian children. , 1991, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[34]  Andrew J. McMichael,et al.  Common West African HLA antigens are associated with protection from severe malaria , 1991, Nature.

[35]  B. Kirkwood,et al.  Malaria chemoprophylaxis with chloroquine in young Nigerian children. III. Its effect on nutrition. , 1985, Annals of tropical medicine and parasitology.

[36]  B. Kirkwood,et al.  Malaria chemoprophylaxis with chloroquine in young Nigerian children. IV. Its effect on haematological measurements. , 1985, Annals of tropical medicine and parasitology.

[37]  L. Rombo,et al.  A case-control study in northern Liberia of Plasmodium falciparum malaria in haemoglobin S and beta-thalassaemia traits. , 1983, Annals of tropical medicine and parasitology.

[38]  Naghma-e-Rehan.  Growth Status of Children with and without Sickle Cell Trait , 1981 .

[39]  W. Trager,et al.  The biochemistry of resistance to malaria. , 1981, Scientific American.

[40]  M. Kramer,et al.  Growth and development in children with sickle-cell trait. A prospective study of matched pairs. , 1978, The New England journal of medicine.

[41]  G. Serjeant,et al.  Heights and weights of West Indian children with the sickle cell trait. , 1978, Archives of disease in childhood.

[42]  M. Friedman.  Erythrocytic mechanism of sickle cell resistance to malaria. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Serjeant,et al.  Growth, behaviour, and educational achievement of Jamaican children with sickle-cell trait. , 1976, British medical journal.

[44]  Sir Ronald A. Fisher.  POLYMORPHISM AND NATURAL SELECTION , 1958 .

[45]  I. McGregor,et al.  Effects of Heavy and Repeated Malarial Infections on Gambian Infants and Children , 1956, British medical journal.

[46]  Organização Mundial de Saúde,et al.  World malaria report 2011 , 2011 .

[47]  S. Ebrahim,et al.  Education and debate , 2005 .

[48]  Jeffrey M. Woodbridge.  Econometric Analysis of Cross Section and Panel Data , 2002 .

[49]  A. Hyder,et al.  Malnutrition as an underlying cause of childhood deaths associated with infectious diseases in developing countries. , 2000, Bulletin of the World Health Organization.

[50]  N. Rehan.  Growth status of children with and without sickle cell trait. , 1981, Clinical pediatrics.

[51]  A. Allison.  POLYMORPHISM AND NATURAL SELECTION IN HUMAN POPULATIONS. , 1964, Cold Spring Harbor symposia on quantitative biology.

[52]  J. Robins,et al.  American Journal of Epidemiology Practice of Epidemiology Credible Mendelian Randomization Studies: Approaches for Evaluating the Instrumental Variable Assumptions , 2022 .