Abstract
BackgroundIn case control studies disease risk not explained by the significant risk factors is the unexplained risk. Considering unexplained risk for specific populations, places and times can reveal the signature of unidentified risk factors and risk factors not fully accounted for in the case-control study. This potentially can lead to new hypotheses regarding disease causation.MethodsGlobal, local and focused Q-statistics are applied to data from a population-based case-control study of 11 southeast Michigan counties. Analyses were conducted using both year- and age-based measures of time. The analyses were adjusted for arsenic exposure, education, smoking, family history of bladder cancer, occupational exposure to bladder cancer carcinogens, age, gender, and race.ResultsSignificant global clustering of cases was not found. Such a finding would indicate large-scale clustering of cases relative to controls through time. However, highly significant local clusters were found in Ingham County near Lansing, in Oakland County, and in the City of Jackson, Michigan. The Jackson City cluster was observed in working-ages and is thus consistent with occupational causes. The Ingham County cluster persists over time, suggesting a broad-based geographically defined exposure. Focused clusters were found for 20 industrial sites engaged in manufacturing activities associated with known or suspected bladder cancer carcinogens. Set-based tests that adjusted for multiple testing were not significant, although local clusters persisted through time and temporal trends in probability of local tests were observed.ConclusionQ analyses provide a powerful tool for unpacking unexplained disease risk from case-control studies. This is particularly useful when the effect of risk factors varies spatially, through time, or through both space and time. For bladder cancer in Michigan, the next step is to investigate causal hypotheses that may explain the excess bladder cancer risk localized to areas of Oakland and Ingham counties, and to the City of Jackson.
Highlights
With over 350,000 new cases each year, bladder cancer ranks ninth globally in incidence among all cancers [1]
Considering unexplained risk for specific populations, places and times can reveal the signature of unidentified risk factors and risk factors not fully accounted for in the case-control study
For bladder cancer in Michigan, the step is to investigate causal hypotheses that may explain the excess bladder cancer risk localized to areas of Oakland and Ingham counties, and to the City of Jackson
Summary
With over 350,000 new cases each year, bladder cancer ranks ninth globally in incidence among all cancers [1]. Allocating that risk to specific local populations, places and times can reveal excesses that may be the signature of unidentified risk factors or risk factors that were not fully accounted for in the original study design This may reveal localized exposures and behaviors, potentially leading to new hypotheses regarding disease causation. Considering unexplained risk for specific populations, places and times can reveal the signature of unidentified risk factors and risk factors not fully accounted for in the case-control study. This potentially can lead to new hypotheses regarding disease causation
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