A sensitivity analysis of a randomized controlled trial of zinc in treatment of falciparum malaria in children.
BACKGROUND
The randomized trial has long been recognized as a means to assess the efficacy of new interventions, because the investigator can reduce or eliminate many sources of error. As such, clinical trials often do not include quantitative assessments of the extent that systematic error could affect their results. We examined the impact of different sources of bias on a randomized controlled trial of the efficacy of zinc as an adjuvant to malaria therapy in reducing time to total parasite clearance.


METHODS
Using data from a previously published study, we identified two sources of bias and used the sensitivity analysis technique developed by Lash and Fink to assess the impact of each source of bias on the outcome.


RESULTS
After correcting for each source of bias and reincorporating random error into our results, the point estimate of effect comparing those who received placebo to those who received zinc changed slightly (SMR changed from 0.92 to 0.90) but the 95% interval increased 22% (changing from 0.73-1.16 in the conventional analysis to 0.65-1.26 in the sensitivity analysis).


CONCLUSIONS
The findings of this sensitivity analysis serve as a reminder that the frequentist confidence interval underestimates the total error, even in a randomized controlled trial. Authors of randomized controlled trial investigations ought to conduct a complete assessment of the impact of potential sources of bias in their studies. CONSORT guidelines for reporting trial results should be updated to encourage authors to assess the impact of non-random errors on their studies.
Fox
Matthew P
MP
Center for International Health and Development, Boston University School of Public Health, 85 East Concord St., 5th Floor, Boston, MA 02118, USA. mfox@bu.edu
Lash
Timothy L
TL
Hamer
Davidson H
DH
D000962:Antimalarials / Q000627:therapeutic use*; D015982:Bias; D017024:Chemotherapy, Adjuvant; D002675:Child, Preschool; D016001:Confidence Intervals; D019587:Dietary Supplements; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D012680:Sensitivity and Specificity; D015032:Zinc / Q000627:therapeutic use*
D000962:Antimalarials; D015032:Zinc