Indexing disease progression at study entry with individuals at‐risk for Huntington disease

Abstract

The identification of clinical and biological markers of disease in persons at risk for Huntington Disease (HD) has increased in efforts to better quantify and characterize the epoch of prodrome prior to clinical diagnosis. Such efforts are critical in the design and implementation of clinical trials for HD so that interventions can occur at a time most likely to increase neuronal survival and maximize daily functioning. A prime consideration in the examination of prodromal individuals is their proximity to diagnosis. It is necessary to quantify proximity so that individual differences in key marker variables can be properly interpreted. We take a data-driven approach to develop an index that can be viewed as a proxy for time to HD diagnosis known as the CAG-Age Product Scaled or CAPS. CAPS is an observed utility variable computed for all genetically at-risk individuals based on age at study entry and CAG repeat length. Results of a longitudinal receiver operating characteristic (ROC) analysis showed that CAPS had a relatively strong ability to predict individuals who became diagnosed, especially in the first 2 years. Bootstrap validation provided evidence that CAPS computed on a new sample from the same population could have similar discriminatory power. Cutoffs for the empirical CAPS distribution can be used to create a classification for mutation-positive individuals (Low-Med-High) that is useful for comparison with the naturally occurring mutation-negative Control group. The classification is an improvement over the one currently in use as it is based on observed data rather than model-based estimated values.

Predicting clinical diagnosis in Huntington's disease: An imaging polymarker

“…The hypoconnectivity measure showed a strong positive correlation with estimated years to clinical diagnosis4 (r = 0.581; p = 0.009, 95% confidence interval [CI; 0.391 0.723]) and a strong negative correlation with the CAG‐Age Product Scaled (CAPs) 18 score (r = –0.526; p  = 0.01; 95% CI [–0.682 –0.322]). A Steiger z‐test demonstrated that estimated years to clinical diagnosis explained a significantly larger amount of variance in hypoconnectivity scores than did the CAPs measure (z = 2.568; p  = 0.01) and was therefore not used going forward.…”

Unawareness of motor phenoconversion in Huntington disease

“…CAP scores can be converted to a scaled CAP score (CAP S ) based on a 5-year probability of diagnosis from study entry. 25 While group D's CAP score was significantly higher than that in other groups, the CAP score for the other diagnosed group (group C) was significantly higher than for groups A and B, indicating that these undiagnosed groups were further from estimated diagnosis. Table 3 shows the frequency and percentage of responses to UHDRS item 79 by awareness groups.…”

“…Age difference was not statistically significant between the mutation carrier groups (groups A-D). Baseline progression was indexed by the CAG-Age Product or CAP score, 25 which is computed as CAP 5 (Age at entry) 3 (CAG 2 33.66). CAP scores can be converted to a scaled CAP score (CAP S ) based on a 5-year probability of diagnosis from study entry.…”

Cognitive domains that predict time to diagnosis in prodromal Huntington disease

“…A prHD individual's genetic signature at the time of study entry was based on the CAG–age product (CAP) score 18. CAP is computed by multiplying age at study entry (Age 0 ) by a scaling of the CAG repeat length (CAP=Age 0 × (CAG–33.66)/432.3326).…”

“…Note, stratification of the prodromal Huntington's disease participants into low, medium, and high groups was based on the CAG–age product (CAP) score 18. The p values are from comparisons between prodromal Huntington's disease participants who did and did not receive a diagnosis, adjusting for CAP group.…”