For the assessment of clinical validity, studies of DNA tests conducted in northern European Caucasians with iron overload suggesting HHC compared to a control population were eligible for inclusion in the review. Studies had to report or allow for the calculation of sensitivity (the proportion of at-risk people who tested positively for C282Y homozygosity) and specificity (the probability of a negative test in people without the disease).
For the assessment of clinical utility, studies incorporating DNA tests conducted in the broader Caucasian population (including relatives of suspected cases) with iron overload suggesting HHC compared with cases identified without DNA testing were eligible for inclusion. Patient-based measures (for example, morbidity and mortality) were the utility outcomes of interest. There were no studies assessing clinical utility.
There was substantial variation within the included studies assessing clinical validity (for example, in terms of definitions of HHC and patient-relative status). The extent to which control groups were phenotypically negative or representative of the target population was unclear. Two independent reviewers selected the studies for inclusion. Differences were resolved through discussion.