title: Analysis of an ordinal outcome in a multicentric randomized controlled trial: application to a 3- arm anti- malarial drug trial in Cameroon.
abstract: BACKGROUND
  Malaria remains a burden in Sub-Saharan Countries. The strategy proposed by the World Health Organization (WHO) is to systematically compare the therapeutic efficacy of antimalarial drugs using as primary outcome for efficacy, a four-category ordered criterion. The objective of the present work was to analyze the treatment effects on this primary outcome taking into account both a center-effect and individual covariates. A three-arm, three-centre trial of Amodiaquine (AQ), sulfadoxine-pyrimethamine (SP) and their combination (AQ + SP), conducted by OCEAC-IRD in 2003, in 538 children with uncomplicated Plasmodium falciparum malaria, is used as an illustration.
  
  
  METHODS
  Analyses were based on ordinal regression methods, assuming an underlying continuous latent variable, using either the proportional odds (PO) or the proportional hazards (PH) models. Different algorithms, corresponding to both frequentist- and bayesian-approaches, were implemented using the freely available softwares R and Winbugs, respectively. The performances of the different methods were evaluated on a simulated data set, and then they were applied on the trial data set.
  
  
  RESULTS
  Good coverage probability and type-1 error for the treatment effect were achieved. When the methods were applied on the trial data set, results highlighted a significance decrease of SP efficacy when compared to AQ (PO, odds ratio [OR] 0.14, 95% confidence interval [CI] 0.04-0.57; hazard ratio [HR] 0.605, 95% CI 0.42-0.82), and an equal effectiveness between AQ + SP and AQ (PO, odds ratio [OR] 1.70, 95% confidence interval [CI] 0.25-11.44; hazard ratio [HR] 1.40, 95% CI 0.88-2.18). The body temperature was significantly related to the responses. The patient weights were marginally associated to the clinical response.
  
  
  CONCLUSIONS
  The proposed analyses, based on usual statistical packages, appeared adapted to take into account the full information contained in the four categorical outcome in malaria trials, as defined by WHO, with the possibility of adjusting on individual and global covariates.
authors.affiliation: Département de Mathématiques et Sciences Physiques, Université de Yaoundé I, Ecole Nationale Supérieure Polytechnique, Yaounde, Cameroon. solange.whegang@math-info.univ-paris5.fr
authors.forename: Solange Youdom
authors.initials: SY
authors.lastname: Whegang
authors.forename: Leonardo K
authors.initials: LK
authors.lastname: Basco
authors.forename: Henri
authors.initials: H
authors.lastname: Gwét
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Thalabard
mesh_terms: D000655:Amodiaquine / Q000627:therapeutic use*; D000962:Antimalarials / Q000627:therapeutic use*; D002163:Cameroon; D002675:Child, Preschool; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004812:Epidemiologic Methods; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D015233:Models, Statistical; D015337:Multicenter Studies as Topic; D016016:Proportional Hazards Models; D011739:Pyrimethamine / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D013413:Sulfadoxine / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine