Risk prediction measures for case-cohort and nested case-control designs: an application to cardiovascular disease

Abstract

Case-cohort and nested case-control designs are often used to select an appropriate subsample of individuals from prospective cohort studies. Despite the great attention that has been given to the calculation of association estimators, no formal methods have been described for estimating risk prediction measures from these 2 sampling designs. Using real data from the Swedish Twin Registry (2004-2009), the authors sampled unstratified and stratified (matched) case-cohort and nested case-control subsamples and compared them with the full cohort (as "gold standard"). The real biomarker (high density lipoprotein cholesterol) and simulated biomarkers (BIO1 and BIO2) were studied in terms of association with cardiovascular disease, individual risk of cardiovascular disease at 3 years, and main prediction metrics. Overall, stratification improved efficiency, with stratified case-cohort designs being comparable to matched nested case-control designs. Individual risks and prediction measures calculated by using case-cohort and nested case-control designs after appropriate reweighting could be assessed with good efficiency, except for the finely matched nested case-control design, where matching variables could not be included in the individual risk estimation. In conclusion, the authors have shown that case-cohort and nested case-control designs can be used in settings where the research aim is to evaluate the prediction ability of new markers and that matching strategies for nested case-control designs may lead to biased prediction measures.

Figure 1.

Individual risk (plotted on the logarithmic scale) from sampling designs compared with the realizations (“gold standard”) for simulated biomarker 1 (BIO1) and a 1:1 sampling ratio, TwinGene, 2004–2009. Values on the bisector indicate perfect agreement between individual risk calculated in the sampling design and in the realization. Cases are represented by a black “X” and controls by gray hollow circles. A, realizations versus unstratified case-cohort design; B, realization versus unmatched nested case-control design; C, realizations versus stratified case-cohort design; D, realizations versus matched nested case-control study design.