Regional weight-for-age growth references for malaria endemic areas in Africa, Asia and Latin America to improve age-based dosing

INTRODUCTION Regulatory development of drug regimens is based on dosing by weight. In practice however, in developing countries treatment is often based on age for drugs that are available at primary health care level. The lack of standardized procedures to devise age-based proxies for weight-based recommendations contributes to considerable variability in existing anti-malarial age-based dose regimens, resulting in some poor, but widely-used regimens. Creation of safe and effective age-based regimens requires knowledge of the weight-for-age distribution of the target populations. We developed growth references for malaria endemic regions that reflect the actual attained anthro-pometric status of populations in Asia, Africa, and Latin America, and explored age-dependent differences between regional and global weight-distributions. METHODS Existing weight-for-age data from malaria endemic countries was used to compile a reference dataset with > 800,000 records. Using a new and innovative two-step modelling method allowing the use of compiled data with widely varying age ranges and sample sizes we produced references at both country and regional levels. The first step modelled country-specific centile curves through an expanded LMS method taking into account data mean, spread, skewedness and possible kurtosis while allowing individual countries to vary in median weight and spread. The second step defined the regional reference as a mixed distribution of these country curves, weighted by their population size. RESULTS We will present the development process and resulting smoothed weight-for-age growth references for the malaria endemic regions of Africa, Asia and Latin America. The regional references deviate substantially from the recently updated 2006 WHO global growth standard and CDC 2000 US growth reference, with relative age-dependent regional median weights 20-65% below the 2000 US reference. This reflects the difference between actual attained growth of assessed populations compared to their estimated global growth potential. Age-dependent weight-distributions also differ considerably between regions, with observed variations in median weight from <10% in infancy to > 40% during adolescence, particularly between malaria endemic regions in Latin America and Asia. These references and the associated regimen development tool are currently used to review age-based dose recommendations for anti-malarials, but can apply to other drugs.