Confounding in Studies of Adverse Reactions to Vaccines

Abstract

Several social and medical attributes are associated with both avoidance or delay of vaccination and an increased risk of adverse events such as sudden infant death syndrome or childhood encephalopathy. Studies that fail to control adequately for such confounding factors are likely to underestimate the risks of adverse events attributable to vaccination. This paper reviews the literature on studies of severe adverse events after the administration of pertussis antigen-containing vaccines, with particular attention to the measures taken by different investigators to avoid this problem. Most published studies have reported a deficit of sudden infant death syndrome among vaccinees, which may reflect confounding in their study designs. An expression is derived to explore the extent of underestimation that may be introduced in such studies, under different sets of conditions. Confounding of this sort is a general problem for studies of adverse reactions to prophylactic interventions, as they may be withheld from some individuals precisely because they are already at high risk of the adverse event.

Day-to-Day Reactogenicity and the Healthy Vaccinee Effect of Measles-Mumps-Rubella Vaccination

“…Regarding systemic reactions, fever was the sign most uniformly caused by MMR vaccination (Table 2; Figs 1 and 2), although conditional logistic regression analysis showed the same trend for rash, arthralgia, conjunctivitis, staying in bed, drowsiness, and irritability. In contrast, respiratory symptoms and signs (and diarrhea, nausea, and vomiting; Figs 1 and 2) were clearly not attributable to MMR vaccination but to other concurrent factors, 21,22 probably commonplace infections. The presence of these symptoms also understandably increased the probability of fever, arthralgia, conjunctivitis, staying in bed, and irritability.…”

“…Because vaccinations were given in a relatively symptom-free state, both populations only returned to the usual frequency of trivial symptoms and signs within a week or so postinjection (Fig 1). This healthy vaccinee effect 13,21 has never been so indisputably documented before. Were this phenomenon fully understood-and explained to parents before vaccination-many misunderstandings (and lawsuits) would be avoided.…”

International collaboration to assess the risk of Guillain Barré Syndrome following Influenza A (H1N1) 2009 monovalent vaccines

“…While the pooled analysis provides more power, the meta-analytic approach is more conservative in its estimation as it weighs results from sites with less variability more heavily, thus providing greater assurance that outlying observations or sites with highly variable data will not bias the overall RI estimate. All analyses using the standard SCCS approach excluded the two weeks preceding vaccination from the background period to account for a possible healthy vaccinee effect [17], and controlled for seasonality as defined by periods of circulating influenza.…”

The Early Benefits of Human Papillomavirus Vaccination on Cervical Dysplasia and Anogenital Warts

“…[31][32][33][34] To address this methodological challenge, we used the regression discontinuity design (RDD), a quasi-experimental approach for evaluating the causal effects of interventions in a way that accounts for this type of observed and unobserved confounding, thus facilitating reliable causal inference. [35][36][37] The RDD has been used extensively in fields like health economics, [37][38][39] and is becoming increasingly popular in epidemiology, given the advantages it offers over standard regression adjustment.…”