Abstract
Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. Herein we argue that selecting controls regardless of respiratory symptoms provides the least biased estimates of pneumonia etiology. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. We conclude that exclusion of controls with respiratory symptoms will result in biased estimates of etiology. Randomly selected community controls, with or without respiratory symptoms, as long as they do not meet the criteria for case-defining pneumonia, are most representative of the general population from which cases arose and the least subject to selection bias.
Highlights
One of the greatest challenges of case-control studies is identification of a suitable control group
Higdon et al as “If upper respiratory tract infection is on the causal chain or is an intermediate state on the path to severe or very severe pneumonia, should controls with respiratory symptoms be excluded?” The similar risk of later being enrolled as a Pneumonia Etiology Research for Child Health (PERCH) case observed for controls with vs without respiratory symptoms suggests that URTI is not on the causal pathway in pneumonia
A case-control study that enrolls all cases, but excludes controls with respiratory symptoms and enrolls a random sample of healthy controls, overestimates the odds ratio by 20%, the attributable fraction by 33%, and the population attributable fraction by 33%. This theoretical phenomenon is illustrated by real-world data from a case-control pneumonia etiology study in Kenya in which the adjusted odds ratio for respiratory syncytial virus A infection was 12.5 when the analysis was restricted to controls without respiratory symptoms, compared with 3.8 when all controls were included in the analysis [16]
Summary
Should Controls With Respiratory Symptoms Be Excluded From Case-Control Studies of Pneumonia Etiology? Reflections From the PERCH Study. Should Controls With Respiratory Symptoms Be Excluded From Case-Control Studies of Pneumonia Etiology? Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. When designing PERCH, we considered this question and decided that the optimal set of controls would include those without and with respiratory symptoms (excluding those with case-defining illnesses, namely severe and very severe pneumonia). There are several reasons why investigators might choose to exclude controls with respiratory symptoms in pneumonia etiology studies. We argue that these reasons do not justify the exclusion of controls with respiratory symptoms from pneumonia etiology studies such as PERCH. We present data from PERCH which support the decision to include all controls in the main PERCH etiology analysis
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