Motion characteristics of subclinical tremors in Parkinson’s disease and normal subjects

The characteristics of the Parkinson’s disease tremor reported previously are not applicable to the full spectrum of severity. The characteristics of high- and low-amplitude tremors differ in signal regularity and frequency dispersion, a phenomenon that indicates characterisation should be studied separately based on the severity. The subclinical tremor of Parkinson’s disease is close to physiological tremor in terms of amplitude and frequency, and their distinctive features are still undetermined. We aimed to determine joint motion characteristics that are unique to subclinical Parkinson’s disease tremors. The tremors were characterised by four hand–arm motions based on displacement and peak frequencies. The rest and postural tremors of 63 patients with Parkinson’s disease and 62 normal subjects were measured with inertial sensors. The baseline was established from normal tremors, and the joint motions were compared within and between the two subject groups. Displacement analysis showed that pronation–supination and wrist abduction–adduction are the most and least predominant tremor motions for both Parkinson’s disease and normal tremors, respectively. However, the subclinical Parkinson’s disease tremor has significant greater amplitude and peak frequency in specific predominant motions compared with the normal tremor. The flexion–extension of normal postural tremor increases in frequency from the proximal to distal segment, a phenomenon that is explainable by mechanical oscillation. This characteristic is also observed in patients with Parkinson’s disease but with amplification in wrist and elbow joints. The contributed distinctive characteristics of subclinical tremors provide clues on the physiological manifestation that is a result of the neuromuscular mechanism of Parkinson’s disease.


Tremor measurement and postures
Supplementary Figure

Participation of the study subjects
Based on the previous study, the Parkinson's disease (PD) can occur as early as age 30-39 years 1 and the incidence rates for the 40-49-year age group for females and males are 3.26 and 3.57 per 100,000 person-years 2 . Therefore, healthy subjects in the 40-80-year age range were appropriate to be the controls for the study. Referring to Supplementary Figure 1, 82 patients recruited in previous study were assessed for eligibility. One patient was with dyskinesia and 18 more patients with predicted rating of more than 0.50 were excluded from the study. The reason for excluding patients with dyskinesia is that the measurement system has not tested under the condition with dyskinesia. The data of a total of 63 patients were available for the study. Apart from this, 62 normal subjects recruited in previous study were all included in this study.
Since some of the subjects did not perform all the rest, outstretching and wing actions, less than 63 sets of data per action are available. The number of missing of data is as tabulated in Supplementary Table 1. Manipulation was not done to replace the missing data.

Clinical characteristics of the subjects
The characteristics of the subjects involved in the study are reported in Supplementary Table   2. The median ages of the 63 PD and 62 normal subjects participated are 69 (interquartile range, IQR = 11.0) and 51 (IQR = 15.8), respectively. The percentage values of the male subjects in PD and control groups are 66.7% and 50.0% respectively. The durations from the last intake of medication to the first measurement differ among subjects. An estimated medication wearoff period of three hours was used as a reference to characterize the patients recruited. More subjects took the medicine for three or more hours (n = 45; 71.4%). Five (7.9%) subjects who could not report that duration were categorized as unknown for that criterion, and one subject was not on medication.

Holm's sequential Bonferroni correction
When performing multiple comparisons, some statistical tests may result in p values of less than 0.05 by chance, so Holm's sequential Bonferroni correction is one way to resolve the problem by adjusting the p values. Six sets of within-group comparisons are possible. The first to sixth most significant p values must be less than 0.008, 0.010, 0.013, 0.017, 0.025, and 0.050, respectively, to be considered to have significant difference.
The adjusted p values used sequentially for the n pair of comparisons are: Where is the alpha level.
In this study, six comparisons, namely EFE vs EPS, EPS vs WFE, EPS vs WAA, WAA vs WFE, EFE vs WFE and EFE vs WAA to evaluate the statistical significant difference between the readings in each comparison pair were performed. By using of 0.05, the first to sixth most significant p values has to be less than 0.008, 0.010, 0.013, 0.017, 0.025 and 0.050 respectively to be considered to have significant difference.

Effect size
Variability with statistical significance may not reflect the practical importance. The effect size is a means for assessing the practical importance of an effect. For the within-and between-group comparisons, the effect is the difference between the compared parameters.
Based on the guidelines provided by Cohen, the following interpretation of the effect size can be made: small effect η 2 = 0.01; medium effect η 2 = 0.06; large effect η 2 = 0.14. 4

Estimation of sample size based on previous literature
Since no previous study pertaining to the comparison of tremor motion among PD and normal subjects, the sample size of previous study was used as the reference. were determined as the sufficient number of subjects for the data to be statistically valid. The number of subject is determined based on the pre-study sample size calculation to achieve more than 90% confidence for the comparison. Since our work involves subject group comparison in tremor motion as well, 50 subjects per subject group was taken the approximated sample size in the clinical study.
Supplementary The median values are in ˚. n = number of sample.

Within-group comparison
The statistical results for within-group comparison using RMS ∆θ joint and peak frequency are tabulated in Supplementary Table 5

Summary of the tremor motion characteristics
Though all the tremors had no clinical sign, the characteristics that are unique to PD and normal tremors are found in the analysis (see Supplementary Table 10

Tremors involving patients with medication intake of within and greater than 3 h
Statistical analysis was performed to compare the difference between PD with medication intake of within three hours (subgroup I) and another subgroup with medication intake of within three hours removed   for degrees of freedom, d.f. = 1 is 3.841 (one-tailed). The Eta-squared, η 2 indicates the effect size. The significance of the difference is reported at * p < 0.05, ** p < 0.001 and *** p < 0.0001. The terms "subgroup II" and "subgroup I" refer to the PD subgroups without and with the last dose of medication taken within 3 h before the measurement. RMS∆θ joint was used to quantify the tremor severity.
Supplementary The median values are in ˚. n = number of sample. Supplementary