A digital motor score for sensitive detection of progression in Huntington's disease

Abstract

Remote digital monitoring of Huntington's disease (HD) has potential to enhance the development of therapeutics, but no data-driven digital motor score exists to quantify the diversity of disease manifestations and track their progression. The HD Digital Motor Score (HDDMS), co-designed with people with HD and neurologists, is a composite score for measuring motor progression of HD in clinical research. It is derived from smartphone sensor-based motor tests included in a remote HD digital monitoring platform. Developing the HDDMS involved selecting features that quantify test performance according to desired measurement properties and combining these features in a weighted composite score using factor analysis. It was developed and subsequently validated using data from four separate studies [HD Natural History Study (NCT03664804), open-label extension (OLE) of the tominersen phase I/IIa study (NCT03342053), GENERATION HD1 (NCT03761849) and Digital-HD]. Based on data from 1048 (the total number of individuals whose data contributed to the construction of the score includes the 40 gene-negative volunteers) individuals, the HDDMS encompasses balance, chorea, speeded tapping and gait. It has favourable characteristics, including reliability (intraclass correlation coefficient > 0.95), correlation with the composite Unified Huntington's Disease Rating Scale (cUHDRS) (r = -0.5), and better sensitivity to change (STC) than the cUHDRS. In a post hoc analysis of GENERATION HD1, the STC of HDDMS at Week 20 was comparable to that of the cUHDRS at Week 68. The HDDMS promises substantial reduction in sample size in clinical trials.

Keywords: digital health; digital health technology; disease progression; motor dysfunction; motor function; smartphone.

Figure 1

The HDDMS and analysis plan flow chart. (A) The HDDMS is a weighted composite score derived from smartphone sensor-based motor tests included in our digital remote monitoring platform. Highlighted in bold-face are the tests that are included in the final HDDMS. (B) The HDDMS was derived in two steps: (i) feature ranking and selection; and (ii) score building and validation. (C) Data collected from the different studies were divided into a development dataset (i.e. data from HD Natural History and OLE of the tominersen phase I/IIa study) and validation dataset (slice of GENERATION HD1). Data collected in Digital-HD was kept separate to assess feature validity (i.e. to ensure that only features that show worsening in response to disease progression are kept in the analysis). The timeline (arrows) indicates the order in which the development, validation and final analysis steps were conducted. BAL = Balance Test; CHO = Chorea Test; DAS = Draw a Shape Test; FRP = feature ranking process; Gen HD1 = GENERATION HD1; HDDMS = Huntington’s Disease Digital Motor Score; HD NHS = Huntington’s Disease Natural History Study; OLE = open-label extension; STT = Speeded Tapping Test; TWM = Two-Minute Walk Test; UTT = U-Turn Test.

Figure 2

HDDMS properties. (A) Cross-sectional correlations between HDDMS (x-axis) and cUHDRS (y-axis) across clinical visits using data from GENERATION HD1. Spearman’s correlation coefficient is provided in the top-right corner of each panel. The linear regression is indicated by the grey line. (B) Spearman rank correlation at baseline between the HDDMS or digital features and various HD clinical anchors. The legend on the right indicates the Spearman’s correlation coefficient. Correlations for different study periods are reported in Supplementary Fig. 4. (C) The mean change from baseline (±SEM) in HDDMS is shown for the placebo arm of the GENERATION HD1 study (red) and the HD Natural History Study (blue). (D) In the total dataset, test-retest reliability [ICC (±95% CI)] remained high across all study weeks. (E) This Quantile–Quantile plot compares the HDDMS quantiles obtained for the placebo arm of the GENERATION HD1 study (left panel) and for the HD Natural History Study (right panel) at baseline against a normal distribution. (F) Known-groups validity of the HDDMS are presented for gene-negative control volunteers, people with HD before CMD, and people with HD after CMD enrolled in the Digital-HD study. The notch represents the 95% CI of the median (middle horizontal line). (G) The yearly change and 95% CI of the HDDMS, the cUHDRS and its components per CAP 100 quartile in the placebo arm of GENERATION HD1. *P < 0.001. BAL = Balance Test; CHO = Chorea Test; CI = confidence interval; cUHDRS = composite Unified Huntington’s Disease Rating Scale; EQ-5D-5L = EuroQol 5-dimension 5-level; Gen HD1 = GENERATION HD1; HDDMS = Huntington’s Disease Digital Motor Score; HD NHS = Huntington’s Disease Natural History Study; ICC = intraclass correlation coefficient; r = Spearman rank correlation coefficient; SDMT = Symbol Digit Modalities Test; SEM = standard error of mean; STT = Speeded Tapping Test; SWRT = Stroop Word Reading Test; TFC = Total Functional Capacity; TMS = Total Motor Score (31 items); TMS-4 = short version of the Total Motor Score; TMW = Two-Minute Walk; UHDRS = Unified Huntington’s Disease Rating Scale.

Figure 3

Sensitivity to change estimated by a mixed model for repeated measures. (A and B) compare the sensitivity to change between HDDMS and HD clinical anchors in people with HD-ISS Stage 2 and HD-ISS Stage 3 disease, respectively (cUHDRS, SDMT, SWRT, and TFC were multiplied by −1 so that an increase on the y-axis corresponds to a worsening of the disease status. (C and D) compare the sensitivity of change between HDDMS and top features selected by the feature ranking process instead. BAL = Balance Test; CHO = Chorea Test; cUHDRS = composite Unified Huntington’s Disease Rating Scale; HD = Huntington’s disease; HDDMS = Huntington’s Disease Digital Motor Score; HD-ISS = Huntington’s Disease Integrated Staging System; SDMT = Symbol Digit Modalities Test; STT = Speeded Tapping Test; SWRT = Stroop Word Reading Test; TFC = Total Functional Capacity; TMS = Total Motor Score (31 items); TMS-4 = short version of the Total Motor Score; TMW = Two-Minute Walk; UHDRS = Unified Huntington’s Disease Rating Scale.

Figure 4

Estimated number of subjects per arm. Estimated number of subjects per arm (on a log 10 scale) required to detect a 40% effect size difference with a power of 0.8 and an alpha of 0.2, 0.1 or 0.05 when using the HDDMS or the cUHDRS for a study duration of 36, 52 or 68 weeks in HD-ISS Stage 2 (left) or Stage 3 disease (right). cUHDRS = composite Unified Huntington’s Disease Rating Scale; HD-ISS = Huntington’s Disease Integrated Staging Scale; HDDMS = Huntington’s Disease Digital Motor Score.