Understanding the relationship between patient-reported outcome measures,clinician-rated assessments,and performance-based measures (cognitive tests and device-based estimates) of symptoms and functioning in people with Huntington's disease

Abstract

Background

Given the progressive cognitive decline in Huntington's disease (HD), most research in this population relies solely on objective assessments of symptoms and function, rather than on patient-reported outcome (PRO) measures.

Objective

The purpose of this paper is to understand how PRO measures relate to clinician-rated assessments and performance-based measures (cognitive tests and device-based estimates) of symptoms and functioning in people with HD.

Methods

We enrolled N = 52 participants with HD in this study. Participants completed several self-reported PROs as well as clinician-administered assessments and performance-based measures (cognitive tests and device-based estimates) of related concepts. Pearson correlations and linear regression models were used to examine the concordance among PROs, clinician-rated assessments, and performance-based measures.

Results

There were strong relationships among PROs that assessed related concepts. There were also strong relationships between PROs and associated clinician-rated assessments of physical functioning (chorea, sleep/fatigue) and mental health, and slightly less robust relationships between the PROs and associated clinician-rated assessments for speech/swallowing and cognition. Relationships between PROs and associated performance-based measures were moderate for chorea/motor functioning, but negligible for sleep/fatigue and cognition.

Conclusions

Findings from this study support the construct validity of PROs that assess motor functioning and mental health among individuals with HD and indicate that PROs and clinician-rated assessments of these constructs (i.e., motor functioning and mental health) provide complementary information. On the other hand, the negligible relationships between PROs and associated performance-based cognitive tests and between PROs and associated wearable device-based estimates of sleep and physical activity indicate that reliance solely on HD patients’ self-report for these concepts might be misleading.

Keywords

Huntington's disease ecological momentary assessment daily diaries health-related quality of life

Introduction

Huntington's disease (HD) is an inherited neurodegenerative disease affecting three primary brain functions: motor control (causing chorea, dystonia, dysarthria, dysphagia, and gait impairment); cognition (impairing attention, judgment, and executive function), and behavior (causing depression, anxiety, apathy, irritability and anger).^1–6 Symptoms often begin in the fourth or fifth decade and progress steadily, leading to death about 20 years thereafter. While there is an extensive body of literature related to the genetic, neuronal, and biological aspects of HD, there is limited formal understanding of the patients’ perspectives of day-to-day experiences of functioning (including physical activity and social participation) and behavioral symptoms (including sleep, fatigue, and anxiety). In part, this is due to progressive cognitive decline and associated concerns about the patients’ subjective self-reports.^7–19 Given this, most HD research relies solely on more objective assessments of symptoms and function via clinicians’ ratings or performance-based measures (the latter administered by clinicians or measured through an instrument or device).

While such assessments are invaluable in guiding care, treatment, and research, their limitations may affect research validity. For example, clinicians may fail to identify patients’ subjective symptoms when they have fewer “visible” clinical signs.²⁰ Disease stage may affect the concordance between clinician-rated and self-reported symptoms and function (i.e., PROs).^21,22 Involuntary choreic movements—a hallmark of HD—may confound the accuracy and analysis of data from wearables with accelerometers, even as such devices promise to revolutionize our objective understanding of physical activity and sleep states. Cognitive impairment and anosognosia (lack of awareness of deficits) may influence the validity of self-reported symptoms and function.^21,22 Because modern clinical trials increasingly query both objective (clinician-rated assessments, performance-based measures) and subjective (patient-reported) data elements, it is critical to understand their interrelationships. Doing so could help streamline future trial design, thus reducing the burden of clinician-rated assessments on study teams (including cost and time) as well as on HD participants (including time, travel, and arduous in-person visits) without sacrificing our ability to understand the patient experience.

Prior research by our team examining the concordance between objective and subjective measures of symptoms and functioning in HD concluded that differences between these types of measures are small enough to consider the sole use of patient-reported outcome measures (PROs) when clinician-rated assessments are impractical.²² Results from studies in other disease states offer mixed conclusions. A study of cancer found high concordance between patient- and clinician-reported symptoms for most symptoms, but more so for symptoms that had observable signs as opposed to those that were more subjective (e.g., fatigue, dyspnea), and that patients reported greater symptom severity than clinicians.²³ Analyses in other clinical populations report similar relationships among objective data sources and PROs.^24,25 In general, concordance between objective and subjective reports is lower when patients’ disease stage is more advanced, the severity of symptoms is worse, and the symptoms are less “obvious” (i.e., not visible).^26–28

For this study, we compared several clinician-rated, performance-based, and patient self-reported assessments to further understand the interrelationships between objective and subjective reports of symptoms and functioning in people with HD. We used data previously collected from 52 participants who enrolled in a prior study to assess the feasibility and acceptability of an intensive study design to capture HD symptoms and functioning. In that study, participants completed a baseline assessment that included several self-reported measures and clinician-rated assessments of mood and functioning, as well as performance-based measures of cognition and motor function. We expected to see the strongest relationships between self-reported (i.e., PROs) and clinician-rated assessments of observable symptoms and functional status indicators (e.g., movement disorder), and less robust relationships between PROs and clinician-rated assessments for symptoms that were subjective (e.g., depression and anxiety). We also expected low to moderate correlations between PROs and performance-based measures (i.e., cognitive tests and device-based estimates of physical activity and sleep) of associated concepts (e.g., mental health PROs with clinician-rated assessments of mental health); for these, we expected relationships to be moderated by measures of disease severity (total functional capacity and motor symptoms), as well as by symptoms of anxiety and depression (both subjective reports and clinicians’ ratings of these concepts).

Methods

Participants

To enroll in this study, participants had to: (1) have a medically documented clinical diagnosis of HD and/or documentation of a positive gene test; (2) be at least 18 years of age; (3) be able to read, speak, and understand English; and (4) have the cognitive capacity to provide informed consent and complete study assessments (i.e., scores ≥25 on the Orientation Log if there were cognitive capacity concerns). Participants also needed to be able to use the study technology independently or with assistance (e.g., turning the PRO-Diary device on/off, silencing alerts). Participants were ineligible for this study if they reported neurological insult (epilepsy, multiple sclerosis, Parkinson disease, Alzheimer or other non-HD dementia, stroke, traumatic brain injury, or brain tumor), or anything that would preclude safe or meaningful participation in the study. Recruitment occurred through an existing research registry, through established HD clinics or medical record data capture systems,²⁹ or via community outreach. Data were collected in accordance with the local Institutional Review Board. Participants provided informed consent via the REDCap consent platform prior to their engagement in any study-specific activities.

Study procedures

The study consisted of a baseline visit followed by seven days of home monitoring. In this paper, we report on the baseline data from this study. Details for the broader study are provided elsewhere.³⁰

Study assessments

Clinician-rated assessments (objective)

Clinicians completed the Unified Huntington's Disease Rating [UHDRS]^31,32 measures based on a clinical assessment of the patient, including the UHDRS Motor Assessment³¹ (we examined the Total Motor Score [TMS]—a sum score of 15 clinician-rated motor functioning items; the Total Chorea Score—a sum score of the 7 items from the TMS that evaluate chorea, and the single-item rating for clinician-rated dysarthria) and the UHDRS Total Functional Capacity Scale (TFC; scores range from 0–13, with higher scores reflecting greater clinician-rated functional capacity).³¹ Clinicians also completed the Problem Behaviors Assessment—short (PBAs),³³ a clinician-rated assessment of behavioral status based on participant interviews (scores reflect the product of the total frequency and the total severity for each of the items—Anxiety, Depression, Anger, Irritability, Disoriented Behavior, Perseverative Thinking—that we examined).

Performance-based measures (objective)

We also examined scores from several performance-based measures. Performance-based cognitive tests included the three measures from the UHDRS Cognitive Assessment: (1) the Symbol-Digit Modalities Test (SDMT),³⁴ which provides a measure of processing speed, psychomotor functioning, and working memory (scores reflect the total correct in 90 s; standardized scores that adjust for age and education were examined)³⁴; (2) the Letter Fluency Test, which provides a measure of executive function and language (scores reflect the number of words produced for three different letters; standardized scores that adjust for age and education were used in analyses)³⁵; and (3) the Stroop Color Word Interference Test, which provides a measure of psychomotor speed and executive function (scores reflect the number of correct responses in each 45-s trial for Word Reading, Color Naming, and Color/Word Interference standardized scores that adjust for age, sex, race, and education were used in analyses).^36,37 Performance-based measures also included a six-minute walk test, which assesses endurance (scores reflect the amount of distance traveled during a 6-min time frame),³⁸ as well as device-based estimates of physical activity (summary data for sedentary behavior, light, moderate, and intense activity) and sleep (total sleep duration).^39,40 Device-based estimates were derived from a wrist-worn device ([PRO-Diary [CamNTech, Cambridge, UK]).

PROs (subjective)

Participants self-reported demographic data and completed several PRO measures, including physical health PROs (Neuro-QoL HDQLIFE Chorea SF,^41–43 PROMIS Sleep-Related Impairment SF,⁴⁴ Neuro-QoL Fatigue SF,^45,46 Neuro-QoL HDQLIFE Speech Difficulties SF,^47–49 Neuro-QoL HDQLIFE Swallowing Difficulties SF,^47–49 Neuro-QoL Lower Extremity Functioning,^45,46 Neuro-QOL Upper Extremity Functioning),^45,46 mental health PROs (PROMIS Anger SF,^50,51 Neuro-QoL Depression SF,^45,46 Neuro-QoL Anxiety SF,^45,46 Neuro-QoL Emotional & Behavioral Dyscontrol SF),^45,46 and a cognitive health PRO (Neuro-QoL Cognitive Function SF).^45,46 Scores on these measures are on a t metric (M = 50, SD = 10), with higher scores indicating more of the named construct.

Data analyses

Descriptive statistics were calculated. Participants were classified according to the HD Integrated Staging System.⁵² Correlations among the PROs, clinician-rated assessments, and performance-based measures were examined using Pearson correlation coefficients. To assess if the relationships among PROs and either clinician-rated or performance-based measures differed by the functional severity of HD (i.e., TFC scores), HD motor severity (i.e., TMS scores), anxiety (self-reported: Neuro-QoL Anxiety and clinician-rated: PBAs Anxiety), or depression (self-reported: Neuro-QoL Depression and clinician-rated: PBAs Depression), linear regression models were performed with either clinician-rated or performance-based scores as the outcome, main effects for the self-reported measure and the effect-modifier variable being tested (i.e., TFC scores), and an interaction term (for performance-based or clinician-rated measures) and the effect-modifier (i.e., TFC scores). Given the large number of comparisons being conducted (i.e., 25), we employed a Bonferroni correction to aid in interpretation (i.e., 25/.05 = .0019). Analyses were performed in SAS v9.4.

Results

A total of 52 individuals participated in this study (13% stage 0–1, 23% stage 2, and 63% stage 4 HD).⁵² On average, participants were 53.9 years of age (SD = 15.0; range = 23 to 84), 50% were female, 94% were non-Hispanic, 94% were White, and 82% had greater than a high school education. Summary data for the baseline assessments are reported in Table 1.

Table 1.

Descriptive data.

Variable	Total sample (N = 52)
PROs – t score M(SD)
NQ HDQLIFE Chorea	52.1 (8.9)
NQ Fatigue	48.0 (10.2)
NQ Lower Extremity Function	47.9 (9.9)
NQ Upper Extremity Function	44.1 (10.0)
NQ HDQLIFE Speech Difficulties	50.1 (8.8)
NQ HDQLIFE Swallowing Difficulties	51.2 (9.0)
NQ Fatigue	48.0 (10.2)
PROMIS Sleep-Related Impairment	52.8 (11.1)
PROMIS Anger	52.2 (9.5)
NQ Anxiety	50.8 (9.0)
NQ Depression	47.2 (8.5)
NQ Cognitive Function	43.4 (10.2)
Clinical-Rated Assessments – M(SD)
UHDRS Exam
Total Chorea Score	5.1 (3.8)
Total Motor Scale Score	22.9 (15.6)
Dysarthria	0.3 (0.5)
Total Functional Capacity	11.0 (2.3)
PBAs
Anxiety	2.7 (3.9)
Depression	1.9 (3.0)
Anger	1.0 (2.1)
Irritability	2.7 (2.9)
Perseverative Thinking	1.6 (2.3)
Disorganized Behavior	0.6 (1.0)
Performance-Based Cognitive Tests – M(SD)
Symbol Digit Modalities Test (z score)	1.4 (1.31)
Verbal Fluency (t score)	39.3 (12.2)
Stroop Color Naming (t score)	31.5 (12.7)
Stroop Word Reading (t score)	29.1 (12.5)
Stroop Interference (t score)	41.7 (10.9)
Performance-Based Device-Based Estimates – M(SD)
6-min Walk Test (distance)	339.5 (91.2)
Device-Based Physical Activity	15,077.6 (9297.3)
Sleep Duration (minutes)	411.9 (136.1)

PROs: patient-reported outcome measures; NQ: Neuro-QoL; PROMIS: Patient-reported Outcome Measurement Information System; UHDRS: Unified Huntington's Disease Rating Scales; PBAs: Problem Behaviors Assessment—short.

Table 2 shows the interrelationships among the PROs and other associated measures (i.e., other PROs, clinician-rated assessments and performance-based measures of associated constructs). In general, relationships among PROs that were assessing similar constructs were strong. The relationships between the PROs and their associated clinician-rated assessment(s) were also strong for chorea and mental health, and moderate for the speech/swallowing and cognition measures. There were moderate relationships between physical health PROs and their associated performance-based measures of chorea/motor functioning, but these relationships were negligible for the PROs and the performance-based measures. Specifically, negligible relationships were found between the cognitive health PRO and the cognitive tests, as well as between the sleep/fatigue PROs and the device-based estimates of sleep.

Table 2.

Relationships between patient-reported outcome measures (PROs) and their associated comparators (other PROs, clinician-administered assessments, or performance-based measures of related constructs).

PRO measure	PRO measurer	Clinician-administered assessmentr	Performance-based measurer
NQ HDQLIFE Chorea	NQ Upper Extremity Fx−0.62NQ Lower Extremity Fx−0.70	UHDRS Motor Exam: TMS0.72UHDRS Total Chorea Score0.67	6-min Walk Test−0.40PRO-Diary Physical Activity−0.30
NQ HDQLIFE Speech Difficulties	NQ HDQLIFE Swallowing Difficulties0.71	UHDRS Dysarthria0.48	N/A
NQ HDQLIFE Swallowing Difficulties	NQ HDQLIFE Speech Difficulties0.71	UHDRS Dysarthria0.41	N/A
NQ Fatigue	PROMIS Sleep-Related Impairment0.85	N/A	PRO-Diary Sleep Duration*−0.04^
PROMIS Sleep-Related Impairment	NQ Fatigue0.85	N/A	PRO-Diary Sleep Duration*−0.09^
NQ Depression	NQ Anxiety0.70	PBAs Depression0.62	N/A
NQ Anxiety	NQ Depression0.70	PBAs Anxiety0.72	N/A
NQ Emotional & Behavioral Dyscontrol	PROMIS Anger0.86	PBAs Irritability0.70PBAs Anger0.56	N/A
NQ Cognitive Function*	NQ Anxiety−0.59NQ Depression−0.57	PBAs Perseverative Thinking−0.47PBAs Disoriented Behavior−0.50	SDMT0.23^Verbal Fluency0.20^Stroop Color Naming0.10^Stroop Word Reading0.10^Stroop Interference0.21^

Higher scores indicate worse HRQOL/function except for those denoted by an *; All p < 0.05 except when indicated by ^; PRO: patient-reported outcome measure; NQ: Neuro-QoL; PROMIS: Patient-reported Outcome Measurement Information System; UHDRS: Unified Huntington's Disease Rating Scales; PBAs: Problem Behaviors Assessment—short; SDMT: Symbol Digit Modalities Test.

Table 3 shows that, in general, neither the total functional capacity of HD, clinician-rated total motor scale, anxiety (self-reported and clinician-rated), nor depression (self-reported and clinician-rated) moderated the relationship between the subjective self-report measures (i.e., the PROs) and the objective measures (neither the clinician-rated assessments nor the performance-based measures). The total functional capacity of the person with HD and clinician-rated total motor scale did not moderate relationships between objective and subjective assessments (the sole exception was that the TMS moderated the relationship between self-reported cognition and clinician-rated disoriented behavior).

Table 3.

Moderation effects for Total Functional Capacity, Total Motor Score, Anxiety (clinician-rated and self-reported) and Depression (clinician-rated and self-reported).

PRO measure	PRO measurep	Clinician-administered assessmentp	Performance-based measurep
(A) Moderation effects for Total Functional Capacity
NQ HDQLIFE Chorea 6a	NQ Upper Extremity Fx0.55NQ Lower Extremity Fx0.005	UHDRS Motor Exam: TMS0.27UHDRS Total Chorea Score0.09	6-min Walk Test0.40PRO-Diary Physical Activity0.43
NQ HDQLIFE Speech Difficulties	NQ HDQLIFE Swallowing Difficulties0.77	UHDRS Dysarthria0.23	N/A
NQ HDQLIFE Swallowing Difficulties	NQ HDQLIFE Speech Difficulties0.34	UHDRS Dysarthria0.41	N/A
NQ Fatigue	PROMIS Sleep-Related Impairment0.18	N/A	PRO-Diary Sleep Duration0.41
PROMIS Sleep-Related Impairment	NQ Fatigue0.68	N/A	PRO-Diary Sleep Duration0.45
NQ Depression	NQ Anxiety0.99	PBAs Depression0.37	N/A
NQ Anxiety	NQ Depression0.98	PBAs Anxiety0.25	N/A
NQ Emotional & Behavioral Dyscontrol	PROMIS Anger0.55	PBAs Irritability0.68PBAs Anger0.91	N/A
NQ Cognitive Function	NQ Anxiety0.37NQ Depression0.54	PBAs Perseverative Thinking0.04PBAs Disoriented Behavior0.08	SDMT0.28Verbal Fluency0.60Stroop Color Naming0.37Stroop Word Reading0.23Stroop Interference0.31

(B) Moderation effects for Total Motor Scale
NQ HDQLIFE Chorea 6a	NQ Upper Extremity Fx0.08NQ Lower Extremity Fx0.54	N/A	6-min Walk Test0.67PRO-Diary Physical Activity0.10
NQ HDQLIFE Speech Difficulties	NQ HDQLIFE Swallowing Difficulties0.60	UHDRS Dysarthria0.02	N/A
NQ HDQLIFE Swallowing Difficulties	NQ HDQLIFE Speech Difficulties0.14	UHDRS Dysarthria0.02	N/A
NQ Fatigue	PROMIS Sleep-Related Impairment0.26	N/A	PRO-Diary Sleep Duration0.20
PROMIS Sleep-Related Impairment	NQ Fatigue0.93	N/A	PRO-Diary Sleep Duration0.10
NQ Depression	NQ Anxiety0.30	PBAs Depression0.10	N/A
NQ Anxiety	NQ Depression0.53	PBAs Anxiety0.17	N/A
NQ Emotional & Behavioral Dyscontrol	PROMIS Anger0.93	PBAs Irritability0.75PBAs Anger0.62	N/A
NQ Cognitive Function	NQ Anxiety0.45NQ Depression0.69	PBAs Perseverative Thinking0.49PBAs Disoriented Behavior0.005	SDMT0.81Verbal Fluency0.16Stroop Color Naming0.64Stroop Word Reading0.41Stroop Interference0.51

(C) Moderation effects for self-reported anxiety (NQ Anxiety)
NQ HDQLIFE Chorea 6a	NQ Upper Extremity Fx0.917NQ Lower Extremity Fx0.29	UHDRS Motor Exam: TMS0.13UHDRS Total Chorea Score0.29	6-min Walk Test0.11PRO-Diary Physical Activity0.52
NQ HDQLIFE Speech Difficulties	NQ HDQLIFE Swallowing Difficulties0.81	UHDRS Dysarthria0.15	N/A
NQ HDQLIFE Swallowing Difficulties	NQ HDQLIFE Speech Difficulties0.17	UHDRS Dysarthria0.06	N/A
NQ Fatigue	PROMIS Sleep-Related Impairment0.92	N/A	PRO-Diary Sleep Duration0.54
PROMIS Sleep-Related Impairment	NQ Fatigue0.32	N/A	PRO-Diary Sleep Duration0.22
NQ Depression	N/A	PBAs Depression<0.0001	N/A
NQ Emotional & Behavioral Dyscontrol	PROMIS Anger0.11	PBAs Irritability0.0005PBAs Anger0.003	N/A
NQ Cognitive Function	NQ Depression0.83	PBAs Perseverative Thinking0.35PBAs Disoriented Behavior0.19	SDMT0.69Verbal Fluency0.63Stroop Color Naming0.36Stroop Word Reading0.27Stroop Interference0.29

(D) Moderation effects for clinician-rated anxiety (PBAs Anxiety)
NQ HDQLIFE Chorea 6a	NQ Upper Extremity Fx0.34NQ Lower Extremity Fx0.57	UHDRS Motor Exam: TMS0.49UHDRS Total Chorea Score0.78	6-min Walk Test0.72PRO-Diary Physical Activity0.64
NQ HDQLIFE Speech Difficulties	NQ HDQLIFE Swallowing Difficulties0.29	UHDRS Dysarthria0.94	N/A
NQ HDQLIFE Swallowing Difficulties	NQ HDQLIFE Speech Difficulties0.03	UHDRS Dysarthria0.53	N/A
NQ Fatigue	PROMIS Sleep-Related Impairment0.43	N/A	PRO-Diary Sleep Duration0.34
PROMIS Sleep-Related Impairment	NQ Fatigue0.44	N/A	PRO-Diary Sleep Duration0.13
NQ Depression	NQ Anxiety0.02	PBAs Depression0.04	N/A
NQ Anxiety	NQ Depression0.10	N/A	N/A
NQ Emotional & Behavioral Dyscontrol	PROMIS Anger0.48	PBAs Irritability0.10PBAs Anger0.04	N/A
NQ Cognitive Function	NQ Anxiety0.48NQ Depression0.17	PBAs Perseverative Thinking0.72PBAs Disoriented Behavior0.46	SDMT0.42Verbal Fluency0.64Stroop Color Naming0.73Stroop Word Reading0.78Stroop Interference0.54

(E) Moderation effects for self-reported depression (NQ Depression)
NQ HDQLIFE Chorea 6a	NQ Upper Extremity Fx0.88NQ Lower Extremity Fx0.31	UHDRS Motor Exam: TMS0.21UHDRS Total Chorea Score0.42	6-min Walk Test0.11PRO-Diary Physical Activity0.24
NQ HDQLIFE Speech Difficulties	NQ HDQLIFE Swallowing Difficulties0.73	UHDRS Dysarthria0.17	N/A
NQ HDQLIFE Swallowing Difficulties	NQ HDQLIFE Speech Difficulties0.50	UHDRS Dysarthria0.16	N/A
NQ Fatigue	PROMIS Sleep-Related Impairment0.70	N/A	PRO-Diary Sleep Duration0.60
PROMIS Sleep-Related Impairment	NQ Fatigue0.28	N/A	PRO-Diary Sleep Duration0.13
NQ Depression	N/A	N/A	N/A
NQ Anxiety	N/A	PBAs Anxiety<0.0001	N/A
NQ Emotional & Behavioral Dyscontrol	PROMIS Anger0.22	PBAs Irritability0.002PBAs Anger0.003	N/A
NQ Cognitive Function	NQ Anxiety0.59	PBAs Perseverative Thinking0.07PBAs Disoriented Behavior0.38	SDMT0.23Verbal Fluency0.91Stroop Color Naming0.55Stroop Word Reading0.24Stroop Interference0.42

(F) Moderation effects for clinician-rated depression (PBAs Depression)
NQ HDQLIFE Chorea 6a	NQ Upper Extremity Fx0.34NQ Lower Extremity Fx0.03	UHDRS Motor Exam: TMS0.73UHDRS Total Chorea Score0.68	6-min Walk Test0.97PRO-Diary Physical Activity0.94
NQ HDQLIFE Speech Difficulties	NQ HDQLIFE Swallowing Difficulties0.93	UHDRS Dysarthria0.63	N/A
NQ HDQLIFE Swallowing Difficulties	NQ HDQLIFE Speech Difficulties0.02	UHDRS Dysarthria0.08	N/A
NQ Fatigue	PROMIS Sleep-Related Impairment0.60	N/A	PRO-Diary Sleep Duration0.14
PROMIS Sleep-Related Impairment	NQ Fatigue0.56	N/A	PRO-Diary Sleep Duration0.01
NQ Depression	NQ Anxiety0.39	N/A	N/A
NQ Anxiety	NQ Depression0.09	PBAs Anxiety0.12	N/A
NQ Emotional & Behavioral Dyscontrol	PROMIS Anger0.99	PBAs Irritability0.94PBAs Anger0.10	N/A
NQ Cognitive Function	NQ Anxiety0.76NQ Depression0.47	PBAs Perseverative Thinking0.19PBAs Disoriented Behavior0.99	SDMT0.18Verbal Fluency0.40Stroop Color Naming0.08Stroop Word Reading0.03Stroop Interference0.01

This table reports the p values for Moderation Models; significant values that survive the Bonferroni correction (i.e., p < 0.0019) are indicated by bolding. PROs: patient-reported outcome measures; NQ: Neuro-QoL; Fx: Function; TMS: Total Motor Scale Score; PROMIS: Patient-reported Outcome Measurement Information System; UHDRS: Unified Huntington's Disease Rating Scales; PBAs: Problem Behaviors Assessment—short; SDMT: Symbol Digit Modalities Test.

In addition, although there were some trends for depression and anxiety to moderate one another (for both subjective and objective ratings), correlations between subjective and objective levels of depression tended to be stronger among those with higher levels of objective depression and vice versa—anxiety correlations were stronger among those with high depression. Also, subjective and objective ratings of depression and anxiety were generally associated with stronger correlations between subjective and objective measures of emotional behavior dyscontrol and objective measures of irritability and anger. The only relationships that remained significant after the Bonferroni correction were: (1) self-reported anxiety moderated the relationship between self-reported depression and clinician-rated depression; (2) self-reported anxiety moderated the relationship between self-reported emotional and behavioral dyscontrol and clinician-rated irritability; and (3) self-reported depression moderated the relationship between self-reported anxiety and clinician-rated anxiety.

Discussion

Findings from these analyses partially supported the proposed hypotheses. As expected, we saw moderate to strong relationships between the physical health PROs and clinician-rated assessments of similar constructs for observable symptoms (i.e., chorea, sleep/fatigue, and speech/swallowing). Interestingly, we also saw moderate to strong relationships between the mental health PROs and the clinician-rated assessments for subjective mental health comparators (anxiety, depression, irritability, and anger) even though we had anticipated less robust correlations for these measures.

Unexpectedly, the relationship between the sleep and fatigue PROs and performance-based estimates for sleep was negligible, even accounting for total functional capacity and total motor scale scores. The actigraphy measure here was total sleep time, so the lack of correlation suggests that subjective sleep problems in Huntington disease may be due to a different parameter (such as sleep fragmentation). The highly variable findings between self-report and other more objective assessments of sleep and physical activity have long been debated in the literature even outside of HD.^53–58 As such, studies examining sleep and physical activity in HD should consider using multiple assessments for these constructs in order to ensure that the data are valid.

We also found negligible correlations between the cognitive PRO and performance-based cognitive tests. Most other studies in HD have reported at least a small to moderate relationship^59,60 and, in cases of people with premanifest HD, moderate to strong relationships have been reported.⁵⁹ Furthermore, most research (in HD and other populations) has reported that the relationship between perceived cognitive problems and actual cognitive performance is weaker for people experiencing symptoms of depression and anxiety.^61–64

The various relationships between the PROs and associated objective (clinician-rated and performance-based) measures were not consistently moderated by the total functional capacity of HD, clinician-rated total motor scale, anxiety, and depression. Taken together, these findings are consistent with other studies in HD^22,65 and should help to mitigate concerns about the clinical utility of PROs. While not identical to objective readouts, these PROs do provide complementary data valuable in understanding the needs of people living with HD so that care outcomes can be aligned accordingly.

Study limitations

While this study illustrates the complementary nature of different assessment modalities, it is also important to acknowledge the following weaknesses. First, this sample was confined to people with the cognitive capacity to provide informed consent; as such, findings are not representative of individuals with later-stage HD. Second, our sample was mostly White and highly educated, which may limit generalizability of the results. Finally, the premorbid abilities of the participants are unknown; as such, more work is needed to understand how disease onset and progression intersects with different assessment modalities.

Conclusions

Findings from this study indicate concordance between mental health PROs and clinician-rated assessment of HD mental health symptoms, as well as between self-reported PROs and clinician-rated assessments of physical function. These relationships are moderate to strong, supporting the complementary use of both types of assessments in clinical research, or the use of PROs alone if there are practical limitations to the inclusion of clinician ratings. On the contrary, findings also suggest negligible relationships between a PRO that assesses cognition and performance-based cognitive tests, as well as between physical health PROs and device-based estimates of sleep and physical activity. As such, reliance solely on HD patients’ self-report for these concepts might be misleading. More work is needed to understand the absence of a relationship between the PRO for cognition and the performance-based cognitive tests, as well as the absence of a relationship between physical health PROs and device-based estimates of sleep and physical activity. Regardless, understanding the advantages and disadvantages of these different types of assessment approaches and the data they provide can help clinicians and researchers better interpret clinical data and balance the cost/benefit of using these different types of assessments across different research and clinical settings.

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

ORCID iDs

Noelle E Carlozzi

Jonathan P Troost

Jennifer A Miner

Praveen Dayalu

Ethical considerations

This study was approved by the University of Michigan Institutional Review Board (HUM00195774).

Consent to participate

All participants provided written informed consent prior to their participation in any study-related activities.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported as an investigator-sponsored study by Teva Branded Pharmaceutical Products, R&D, Inc., who provided a courtesy medical review of the manuscript.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Carlozzi has been a consultant to Teva Pharmaceuticals Industries, Ltd, and received salary support for this project from Teva. Dr Carlozzi also receives compensation for her CHDI Foundation scientific advisory board role. She has no other potential conflicts to report. Dr Troost received salary support for this proposal from Teva Pharmaceuticals Industries, Ltd. He has no potential conflicts to report. Ms. Lombard has no potential conflicts to report. Ms. Miner received salary support for this proposal from Teva Pharmaceuticals Industries, Ltd. She has no potential conflicts to report. Dr Dayalu received salary support for this proposal from Teva Pharmaceuticals Industries, Ltd. He has no potential conflicts to report. In the past 12 months, Dr Carlozzi has received funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, the Patient-Centered Outcomes Research Institute, the Craig H. Neilsen Foundation, the Alzheimer's Association, the CHDI Foundation, and Teva Pharmaceutical Industries, as well as Health and Human Services, the Department of Centers for Medicare and Medicaid Services, and the Department of Food and Drug Administration. She has also served as a consultant for Teva Pharmaceutical Industries. In the past 12 months, Dr Troost has received funding from the National Institutes of Health, the Craig H. Neilsen Foundation, the Alzheimer's Association, Teva Pharmaceutical Industries, and the Gerber Foundation. In the past 12 months, Ms. Lombard has received funding from the National Institutes of Health. In the past 12 months, Ms. Miner has received funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Alzheimer's Association, the Craig H. Neilsen Foundation, Teva Pharmaceutical Industries, the Centers for Medicare and Medicaid Services, and the Department of Food and Drug Administration. In the past 12 months, Dr Dayalu has received funding from the CHDI Foundation, Teva Pharmaceutical Industries, uniQure Biopharmaceuticals, and Neurocrine Biosciences funding through the Huntington Study Group.

Data availability statement

The data supporting the findings of this study are available upon request from the corresponding author. These data are not publicly available due to privacy or ethical restrictions.

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