Healthcare resource utilization and cost among individuals with late-onset versus adult-onset Huntington’s disease: a claims‑based retrospective cohort study

Abstract

Aims

Quantify healthcare resource utilization (HRU) and costs for individuals with late-onset Huntington’s disease (LoHD) and compare these with adult-onset HD (AoHD) and non-HD controls.

Methods

This retrospective cohort study used US healthcare claims data from the IBM MarketScan Commercial and Medicare Supplemental Databases. Individuals newly diagnosed with HD between 1/1/2009 and 12/31/2017 were selected (index date was first HD claim). Individuals ≥60 years of age at the index date were categorized as having LoHD while individuals 21–59 years of age were categorized as having AoHD. Non‑HD controls were exact matched 2:1 to LoHD and AoHD cohorts. Individuals were required to have continuous enrollment for ≥12 months pre- and post-index. Twelve-month all-cause HRU and healthcare costs were assessed for each cohort.

Results

In total, 763 individuals with LoHD and 1,073 individuals with AoHD were matched with 3,762 non-HD controls. Unadjusted all-cause HRU in the 12 months post-index was higher for individuals with LoHD and AoHD compared with non-HD controls across most service categories. Adjusted all-cause HRU for the LoHD cohort was significantly higher compared with non-HD controls across all service categories. In the 12 months post-index, mean total costs for the LoHD cohort ($29,055) were significantly higher than for non-HD controls (≥60 years old: $17,286; 21–59 years old: $12,688; p <.001) and similar to total costs in the AoHD cohort ($31,701; p =.47).

Limitations

It was not possible to control for differences in HD stage but regression models were adjusted for baseline HRU. Evaluations of costs did not include indirect costs, which are known to be significant components of the wider HD burden.

Conclusions

This study provides the first analysis of HRU and costs in LoHD, demonstrating that individuals with LoHD experience a significantly higher healthcare burden compared with non-HD controls and a similarly high burden compared with individuals with AoHD.

PLAIN LANGUAGE SUMMARY

Huntington’s disease (HD) usually develops between the ages of 30–50 but can develop earlier/later. This study looked at healthcare use in people who developed HD at age 60 or later in the United States. Researchers found that people who develop HD at age 60 or later have similar health needs to people with adult-onset HD. Furthermore, they have much greater health needs than people of a similar age who do not have HD.

Keywords:

• Huntington’s disease
• burden of illness
• healthcare resource utilization
• healthcare costs
• MarketScan

JEL CLASSIFICATION CODES:

• I1
• I10
• I11
• I12

Introduction

Huntington’s disease (HD) is a rare, genetic and neurodegenerative disease that typically manifests between the ages of 30 and 50 years^1,2, although onset can also occur during childhood³, or in later life⁴. HD is characterized by the development of a triad of behavioral, functional/motor and cognitive symptoms^2,5. HD leads to increasing levels of disability, loss of independence, and is characterized by a median survival time of 15 years after the initial onset of definitive motor symptoms⁶. The disability resulting from HD causes significant impacts on health-related quality of life, particularly emotional/physical health and social wellbeing⁷, with worsening social health problems linked to increased disease burden⁸.

Late-onset HD (LoHD), wherein disease onset occurs later in life, is most typically defined by an age of onset of ≥60 years⁹, although some earlier studies use a definition of LoHD as occurring after 50 years of age^10,11. The proportion of individuals with LoHD within the HD population has been reported as 11.5% in a study in Greece¹² to as high as 25.2% in cohorts analyzed in Italy¹³ and 25.4% in Finland¹⁴. A recent study using data from the Enroll-HD database found that LoHD represented 11% of cases in a global HD cohort¹⁵. Data from the Finnish study demonstrated an increase in the proportion of LoHD cases (out of all new HD diagnoses), from 21% (1991–2000) to 33% (2001–2010)¹⁴. Another study, conducted in the USA, suggested an increase in the number of HD diagnoses in individuals ≥60 years of age following the introduction of genetic testing⁴.

There is currently a paucity of literature describing the LoHD population, and only a few previously published studies focused on the clinical characteristics of LoHD. Individuals diagnosed with HD at an older age are often thought to have slower disease progression with fewer behavioral symptoms than individuals diagnosed at a younger age^16,17. Although LoHD has previously been thought to be a milder form of HD, some recent studies suggest that individuals with LoHD may have similar disease progression to individuals with a typical age onset of HD (referred to as adult-onset HD [AoHD] from hereon)^18–20. Furthermore, individuals with LoHD often experience a high burden of illness resulting from manifestations of HD in combination with increasing age^12,18. In fact, individuals with LoHD present more often with gait and balance problems compared with individuals with AoHD^12,18.

HD is associated with a high burden of disease, reduced quality of life and high healthcare costs^21–24. Management of HD requires a multidisciplinary care approach and in the absence of disease-modifying therapies that can alter disease progression, treatment is focused on the relief of symptoms and improvement of quality of life²⁵.

Previous studies using claims databases have reported that individuals with HD have significant healthcare costs that are much greater than for individuals without HD. Average total annual US healthcare costs in 2013 for patients with early- to late-stage HD were estimated to be between $4,947–$22,582 (2011 US dollars [USD]) for commercial patients and $3,257–$37,495 (2011 USD) for those with Medicaid coverage²⁴. A more recent study of Medicare beneficiaries found that mean total healthcare costs for beneficiaries with HD were $41,631 (standard deviation [SD] = $57,393) compared with $17,222 (SD = $31,218) for beneficiaries without HD²⁶. Mean costs per patient per month for patients with HD have been found to be more than double than for patients without HD ($2,260 [SD = $4,682] vs $1,056 [SD = $3,078], 2018 USD)²⁷. Mean total healthcare costs per month were: $3,726 for early-stage HD; $7,988 for middle-stage HD; and $5,125 for late-stage HD²⁸. However, to our knowledge, no studies to date have examined the disease burden specifically in the LoHD population, and little is known about the relative burden of LoHD compared with AoHD.

The objectives of this study were to quantify healthcare resource utilization (HRU) and costs for individuals with LoHD and compare these with individuals with AoHD and individuals without HD, using administrative healthcare claims data from IBM MarketScan databases.

Methods

Study design and data source

This retrospective cohort study used the IBM MarketScan Commercial and Medicare Supplemental Databases from January 1, 2008–December 31, 2018 (study period). The IBM MarketScan databases contain records for over 273 million unique individuals from the USA, including healthcare data from >39.7 million covered people in the most recent year of full data²⁹.

The IBM MarketScan Commercial database contains employer and health plan medical and pharmacy claims data for >40 million commercial plan members annually. Enrollees include employees, their spouses and their dependents who are covered by employer-sponsored private health insurance. A variety of fee-for-service, fully capitated and partially capitated health plans are represented, including point of service, exclusive provider organizations, preferred provider organization plans, indemnity plans, health maintenance organizations, consumer-driven health plans and high-deductible health plans. The IBM MarketScan Medicare Supplemental database contains data on the Medicare-covered portion of payment (i.e., coordination of benefits amount) and employer expenses and out-of-pocket patient expenses for healthcare services provided in inpatient (IP) and outpatient (OP) settings for US Medicare beneficiaries.

Study population

HD cohorts

We identified individuals with newly diagnosed HD, defined as having ≥1 HD claim (International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification diagnosis codes; ICD‑9‑CM 333.4 – Huntington’s chorea, ICD-10-CM G10 – Huntington’s disease) between January 1, 2009 and December 31, 2017 (identification period), ≥21 years of age at first HD diagnosis (index date was the date of first HD claim) and had no HD claims for 12 months pre-index. Individuals aged ≥21 years at first HD diagnosis were selected, as an age of onset <21 years of age is typically defined as juvenile-onset HD³.

Individuals identified as newly diagnosed with HD were categorized into AoHD and LoHD groups based on their age at the index date. Individuals with HD who were 21–59 years of age at the index date were identified as having AoHD, whereas those ≥60 years of age at the index date were identified as having LoHD.

Matched non-HD controls

Non-HD controls for both the LoHD and AoHD cohorts were identified from a 5% random sample of individuals in the IBM MarketScan databases and were required to have no HD diagnosis throughout the study period. Non-HD controls were randomly assigned a proxy index date from the pool of index dates of the individuals with HD. Non-HD controls were matched 2:1 to the respective HD cohorts as follows: exact matched on age at index, sex, and insurance type (i.e., Commercial vs Medicare), and then propensity score matched using the greedy nearest neighbor approach with 0.25 caliper. Propensity scores were created based on: baseline modified Charlson Comorbidity Index (CCI; modified to exclude dementia as this is highly correlated with HD)³⁰; insurance plan type; geographic region; baseline HRU including inpatient, outpatient, and emergency room (ER) visits (number of visits by each HRU category).

All individuals in both HD cohorts, as well as the two non-HD control groups, were required to have ≥12 months of continuous enrollment in medical and pharmacy benefits pre- and post-index and have no evidence of switching insurance throughout the entire study period.

Study variables and outcomes

Demographic and clinical characteristics

Patient demographic characteristics were assessed at the index date. These baseline demographic characteristics included sex; geographic region; insurance type; insurance plan type; age; follow-up duration; baseline HRU; and baseline modified CCI. HD stage was determined using a previously published hierarchical algorithm that assigns stage based upon specific diagnostic and services claims during the 6-month post-index period²⁴. Selected HD-related comorbidities and medication use were described during the 12-month post-index period (listed in Supplemental Table 1).

All-cause HRU and costs

All-cause HRU (unadjusted and adjusted) and all-cause healthcare costs were assessed over 12 months post-index for individuals in each cohort. HRU categories included: IP (hospitalizations); OP (physician office, ER, radiology, physical/occupational therapy, speech therapy, durable medical equipment [DME]); long-term care (LTC)/nursing facility (NF)/skilled nursing facility (SNF) (both IP and OP claims); pharmacy.

Healthcare costs represented allowed payments made to providers by insurers (i.e., plan and coordination of benefits) and patients (i.e., copay, co-insurance, deductible), and were adjusted to 2020 USD using the medical component of the US Consumer Price Index³¹. Patients with capitated health plans (i.e., health maintenance organizations, point of service with capitation) were excluded from all cost analyses.

Statistical analysis

Patient demographics and baseline characteristics were summarized using descriptive statistics. Baseline characteristics of individuals with HD were descriptively compared with matched non-HD controls using standardized mean differences (SMDs). Unadjusted HRU was descriptively summarized using counts and percentages and compared across HD groups and non-HD control groups using chi-squared tests.

Two-part multivariable regression models were used to estimate predicted adjusted mean all-cause HRU and costs, to account for excess zeros in modeling HRU and costs³². For the two-part multivariable regression models for adjusted all-cause HRU, logistic regression was used for the binomial component and a generalized linear model with negative binomial distribution and log-link function was used for the continuous component. In the two-part multivariable regression models for adjusted 12-month all-cause healthcare costs, logistic regression was used for the binomial component and a generalized linear model with gamma distribution and log-link was used for the continuous component. Models with dummy variables created for each HD and control group (reference group: LoHD) and adjusted for sex, insurance type, modified CCI, and baseline HRU [IP, OP, ER] were used to derive the parameter estimates for all-cause HRU and predicted mean costs for individuals with LoHD, AoHD and both non-HD control groups during the 12-month post-index period. For estimating total healthcare costs (sum of IP, OP and pharmacy costs), a two-part model was not used since all individuals with HD had non-zero total healthcare costs. R v4.0.0 and STATA v15 were used for all statistical analyses, and all p values <.05 or SMD >0.1 were considered statistically significant.

Results

Demographic and clinical characteristics

A total of 1,836 individuals meeting the study criteria of newly diagnosed with HD were included in this analysis and were matched with 3,762 non-HD controls. Of the individuals with HD, 42% (n = 763) were categorized as having LoHD and 58% (n = 1,073) as having AoHD (Figure 1). Baseline characteristics were well balanced across all HD and respective non-HD control cohorts (SMD <0.1; Table 1).

Figure 1. Identification of study population with LoHD and AoHD in the IBM MarketScan database. Abbreviations. AoHD, adult-onset HD; HD, Huntington’s disease; LoHD, late-onset HD.

Table 1. Demographic and clinical characteristics.

		LoHD n = 763	Non-HD controls (≥ 60 years) n = 1,526	SMD	AoHD n = 1,073	Non-HD controls (<60 years) n = 2,146	SMD
Sex, n (%)	Female	431 (56.5)	862 (56.5)	<0.001	591 (55.1)	1,182 (55.1)	<0.001
Region, n (%)	North central	286 (37.5)	574 (37.6)	0.044	296 (27.6)	576 (26.8)	0.019
	Northeast	149 (19.5)	307 (20.1)		185 (17.2)	377 (17.6)
	South	194 (25.4)	384 (25.2)		378 (35.2)	767 (35.7)
	West	130 (17.0)	257 (16.8)		207 (19.3)	412 (19.2)
Plan type, n (%)	CDHP/HDHP	24 (3.1)	43 (2.8)	0.069	122 (11.4)	235 (11.0)	0.023
	HMO/POS with capitation	81 (10.6)	192 (12.6)		163 (15.2)	328 (15.3)
	POS	36 (4.7)	70 (4.6)		77 (7.2)	145 (6.8)
	PPO/EPO	342 (44.8)	653 (42.8)		633 (59.0)	1,278 (59.6)
Insurance type, n (%)	Commercial	251 (32.9)	502 (32.9)	<0.001	1,060 (98.8)	2,120 (98.8)	<0.001
	Medicare	512 (67.1)	1,024 (67.1)		13 (1.2)	26 (1.2)
Age at index, median (IQR)		70.0 (63.0–77.0)	70.0 (63.0–77.0)	<0.001	50.0 (42.0–55.0)	50.0 (42.0–55.0)	<0.001
Age at index, n (%)	<30	0 (0.0)	0 (0.0)	<0.001	74 (6.9)	148 (6.9)	<0.001
	30–39	0 (0.0)	0 (0.0)		149 (13.9)	298 (13.9)
	40–49	0 (0.0)	0 (0.0)		294 (27.4)	588 (27.4)
	50–59	0 (0.0)	0 (0.0)		556 (51.8)	1,112 (51.8)
	60–69	379 (49.7)	758 (49.7)		0 (0.0)	0 (0.0)
	≥70	384 (50.3)	768 (50.3)		0 (0.0)	0 (0.0)
Follow-up, months [end of enrollment – index date] (mean [SD])		38.25 (22.0)	34.70 (21.1)	0.165	42.56 (26.1)	33.90 (23.7)	0.348
Baseline HRU	ER visits (mean [SD])	1.3 (0.9)	1.3 (0.9)	0.009	1.0 (0.8)	1.0 (0.8)	0.002
	OP visits (mean [SD])	1.3 (0.5)	1.4 (0.5)	0.026	1.2 (0.4)	1.2 (0.4)	0.016
	IP visits (mean [SD])	0.5 (0.8)	0.4 (0.8)	0.097	0.2 (0.6)	0.2 (0.6)	0.023
Baseline CCI, mean (SD)		1.5 (2.1)	1.4 (1.9)	0.061	0.6 (1.4)	0.5 (1.1)	0.066
HD‑related comorbidities^a, n (%)	Depression	214 (28.0)	163 (10.7)	<0.001	331 (30.8)	295 (13.7)	<0.001
	Anxiety	132 (17.3)	124 (8.1)	<0.001	231 (21.5)	214 (10.0)	<0.001
	Dementia	95 (12.5)	47 (3.1)	<0.001	27 (2.5)	3 (0.1)	<0.001
	Gait/Balance Problems	175 (22.9)	85 (5.6)	<0.001	122 (11.4)	35 (1.6)	<0.001
	Falls	66 (8.7)	45 (2.9)	<0.001	34 (3.2)	21 (1.0)	<0.001
HD stage^b, n (%)	Early	249 (32.6)			539 (50.2)
	Middle	262 (34.3)			375 (34.9)
	Late	252 (33.0)			159 (14.8)

Unknown/missing values are not reported in this table.

Abbreviations. AoHD, adult-onset HD; CCI, Charlson Comorbidity Index; CDHP, consumer-driven health plan; EPO, exclusive provider organization; ER, emergency room; HD, Huntington’s disease; HDHP, high-deductible health plan; HMO, health maintenance organization; HRU, healthcare resource utilization; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modification; IP, inpatient; IQR, interquartile range; LoHD, late-onset HD; OP, outpatient; POS, point of service; PPO, preferred provider organization; SD, standard deviation; SMD, standardized mean difference.

^aComorbidities were measured during the 12-month post-index period. All ICD-9-CM and ICD-10-CM codes for comorbidities are listed in Supplemental Table 2.

^bHD stage was determined based on the presence of disease markers (i.e., diagnoses and services) in claims during the 6-month post-index period [22].

The median (interquartile range) age at the index for individuals in the LoHD cohort was 70 (63–77) years and 50 (42–55) years for the AoHD cohort (Table 1). Overall, 56.5% and 55.1% of the LoHD and AoHD cohorts were female, respectively. The mean (SD) CCI score at baseline for individuals with LoHD was 1.5 (2.1) and 0.6 (1.4) for individuals with AoHD. Most individuals in the LoHD cohort had Medicare Supplemental insurance (67.1%), whereas nearly all individuals with AoHD had commercial insurance coverage (98.8%).

In the LoHD cohort, there was a similar number of individuals with early- (249 [32.6%]), middle- (262 [34.3%]) and late-stage HD (252 [33.0%]). In the AoHD cohort, most individuals had early-stage HD (539 [50.2%]), followed by middle-stage HD (375 [34.9%]) and late-stage HD (159 [14.8%]) (Table 1). The most common comorbidities in individuals with LoHD and AoHD were depression (28.0% vs 30.8%), anxiety (17.3% vs 21.5%) and gait/balance problems (22.9% vs 11.4%), respectively, which were all more common in individuals with HD than the matched non-HD controls. Psychiatric comorbidities, including depression and anxiety, were most common in individuals with AoHD, while motor and cognitive symptoms, including gait/balance problems, dementia and falls were more common among those with LoHD.

Unadjusted all-cause HRU

The percentage of individuals with unadjusted all-cause HRU in the 12 months post-index was higher for individuals with LoHD and AoHD compared with the respective non-HD controls across most service categories, and this difference was statistically significant for all categories except physician office visits and the pharmacy fills between the LoHD cohort and non-HD controls (Table 2). The most common HRU service categories for individuals with LoHD and AoHD were any pharmacy fills, physician office visits, ER visits and PT/OT visits (Table 2).

Table 2. Unadjusted all-cause HRU in the 12-month post-index period.

HRU category	LoHD n = 763	Non-HD controls (≥60 years) n = 1,526	p value*	AoHD n = 1,073	Non-HD controls (<60 years) n = 2,146	p value*
	n (%)	n (%)		n (%)	n (%)
IP
Hospitalizations	236 (30.9)	303 (19.9)	<.001	188 (17.5)	205 (9.6)	<.001
OP
Physician office visits	687 (90.0)	1357 (88.9)	.4	1007 (93.8)	1804 (84.1)	<.001
ER visits	305 (40.0)	485 (31.8)	<.001	317 (29.5)	544 (25.3)	.011
Radiology visits	234 (30.7)	190 (12.5)	<.001	227 (21.2)	132 (6.2)	<.001
PT/OT visits	308 (40.4)	366 (24.0)	<.001	316 (29.5)	355 (16.5)	<.001
Speech therapy visits	135 (17.7)	53 (3.5)	<.001	111 (10.3)	10 (0.5)	<.001
DME	289 (37.9)	458 (30.0)	<.001	254 (23.7)	354 (16.5)	<.001
LTC/NF/SNF^a	156 (20.4)	95 (6.2)	<.001	58 (5.4)	12 (0.6)	<.001
Pharmacy fills	707 (92.7)	1425 (93.4)	0.5	988 (92.1)	1877 (87.5)	<.001
Selected medication use^b
Antidepressants	388 (50.9)	380 (24.9)	<.001	581 (54.1)	486 (22.6)	<.001
Antiepileptics	182 (23.9)	171 (11.2)	<.001	239 (22.3)	175 (8.2)	<.001
Antipsychotics	225 (29.5)	60 (3.9)	<.001	272 (25.3)	41 (1.9)	<.001
Benzodiazepines	247 (32.4)	262 (17.2)	<.001	362 (33.7)	299 (13.9)	<.001
Chorea medications	61 (8.0)	0 (0.0)	<.001	107 (10.0)	0 (0.0)	<.001
Cognitive medications	96 (12.6)	57 (3.7)	<.001	48 (4.5)	3 (0.1)	<.001
Antispasticity medications	44 (5.8)	55 (3.6)	.017	106 (9.9)	89 (4.1)	<.001
Non-benzodiazepine anxiolytics	35 (4.6)	49 (3.2)	.1	62 (5.8)	69 (3.2)	<.001

Abbreviations. AoHD, adult-onset HD; DME, durable medical equipment; ER, emergency room; HD, Huntington’s disease; HRU, healthcare resource utilization; IP, inpatient; LoHD, late-onset HD; LTC, long-term care; NF, nursing facility; OP, outpatient; OT, occupational therapy; PT, physical therapy; SNF, skilled nursing facility.

*p values represent comparison of LoHD vs non-HD controls (≥60 years of age) or AoHD vs non-HD controls (<60 years of age).

^aIncludes both IP and OP claims.

^bFull list of medications listed in Supplemental Table 2.

Selected medication use

Medication use, particularly the use of psychiatric medications, was higher among individuals with LoHD and AoHD compared with the respective non-HD controls across all HD-related drug classes included in this analysis (Table 2). In both the HD cohorts (LoHD, AoHD), the most common medications were antidepressants (50.9% vs 54.1%), benzodiazepines (32.4% vs 33.7%) and antipsychotics (29.5% vs 25.3%), respectively (Table 2).

Predicted adjusted mean all-cause HRU

Predicted adjusted mean all-cause HRU was significantly higher in individuals with LoHD compared with non-HD controls for all service categories (p <.05 for all, Table 3). Directly comparing HRU between the LoHD and AoHD cohorts across the various service categories showed some non-statistically significant differences in adjusted healthcare utilization between the two patient populations. The AoHD cohort had higher mean inpatient use (2.35 vs 1.92), including hospitalizations (2.26 vs 1.87), as well as slightly higher mean radiology visits (0.51 vs 0.39), DME claims (1.65 vs 1.48) and LTC/NF/SNF use (2.23 vs 1.83), respectively, but none of these comparisons were statistically significant. Adjusted mean ER visits were significantly lower among individuals with LoHD compared with those with AoHD (0.71 vs 0.96, p = .029).

Table 3. Predicted adjusted mean all-cause HRU in the 12-month post-index period.

HRU category	LoHD (reference group) n = 763	Non-HD controls (≥60 years) n = 1,526	AoHD n = 1,073	Non-HD controls (<60 years) n = 2,146
IP visits	1.92	1.03*	2.35	0.76*
Hospitalizations	1.87	1.01*	2.26	0.75*
OP visits	25.97	16.47*	24.07	13.73*
Physician office visits	7.64	6.46*	7.64	5.09*
ER visits	0.71	0.45*	0.96*	0.59
Radiology visits	0.39	0.14*	0.51	0.14*
PT/OT visits	3.68	1.83*	3.65	1.74*
Speech therapy visits	0.54	0.1*	0.38	0.02*
DME claims	1.48	1.03*	1.65	0.84*
LTC/NF/SNF^a	1.83	0.35*	2.23	0.21*
Pharmacy fills	22.49	17.48*	22.88	13.74*

Predicted mean HRU was estimated using two-part multivariable models adjusted for sex, insurance type, modified CCI, and baseline IP, OP and ER visits.

Abbreviations. AoHD, adult-onset HD; CCI, Charlson Comorbidity Index; DME, durable medical equipment; ER, emergency room; HD, Huntington’s disease; HRU, healthcare resource utilization; IP, inpatient; LoHD, late-onset HD; LTC, long-term care; NF, nursing facility; OP, outpatient; OT, occupational therapy; PT, physical therapy; SNF, skilled nursing facility.

*Indicates a p value <.05 vs the LoHD cohort.

^aIncludes IP and OP claims.

Predicted adjusted mean all-cause healthcare costs

During the study period, adjusted healthcare costs were higher across all measured service categories for individuals with LoHD compared with all non-HD controls, and this difference was statistically significant for all categories (p <.05) except for inpatient visits, hospitalizations and DME use (Table 4). Adjusted healthcare costs among individuals with LoHD were similar to those of individuals with AoHD across all service categories. Total annual all-cause healthcare costs for individuals with LoHD were $29,055, which were significantly higher than non-HD controls ($17,286, p <.001), and similar to individuals with AoHD ($31,701, p = .47) (Table 4).

Table 4. Predicted adjusted mean all-cause healthcare costs in the 12-month post-index period (2020 USD).

Cost category	LoHD (reference group) n = 682	Non-HD controls (≥60 years) n = 1,334	AoHD n = 910	Non-HD controls (<60 years) n = 1,818
Total^a	$29,055	$17,286*	$31,701	$12,688*
IP visits	$6,071	$4,781	$7,151	$4,142
Hospitalizations	$5,948	$4,727	$6,497	$4,108
OP visits	$12,143	$8,335*	$13,657	$7,373*
Physician office visits	$942	$751*	$981	$597*
ER visits	$882	$629*	$1,193	$913
Radiology visits	$226	$97*	$262	$115
PT/OT visits	$701	$345*	$634	$277*
Speech therapy visits	$85	$14*	$120	$3*
DME	$469	$296	$396	$281
LTC/NF/SNF^b	$1,639	$304*	$1,699	$139*
Pharmacy claims	$7,835	$3,455*	$9,694	$2,026*

Predicted mean costs were estimated using multivariable two-part models or generalized linear models with log-link and gamma distribution, adjusted for sex, insurance type, modified CCI, and baseline IP, OP and ER visits. Patients with capitated health plans (i.e., HMO, POS with capitation) were excluded from cost analyses.

Abbreviations. AoHD, adult-onset HD; CCI, Charlson Comorbidity Index; DME, durable medical equipment; ER, emergency room; HD, Huntington’s disease; HMO, health maintenance organization; IP, inpatient; LoHD, late-onset HD; LTC, long-term care; NF, nursing facility; OP, outpatient; OT, occupational therapy; POS, point of service; PT, physical therapy; SNF, skilled nursing facility; USD, US dollars.

*Indicates a p value <.05 vs the LoHD cohort.

^aTotal costs represented the sum of IP, OP and pharmacy costs and were estimated using generalized linear models with log-link and gamma distribution. All other costs were estimated using two-part models.

^bIncludes IP and OP claims.

Among individuals with HD, the highest costs were attributable to OP services ($12,143 for LoHD and $13,657 for AoHD), followed by pharmacy fills ($7,835 for LoHD and $9,694 for AoHD) and IP visits ($6,071 for LoHD and $7,151 for AoHD) (Table 4).

Discussion

To our knowledge, this is the first study to investigate the real-world HRU and healthcare costs among individuals newly diagnosed with LoHD compared with non-HD controls and individuals newly diagnosed with AoHD. In this study we address this research gap using a large retrospective claims data analysis, which demonstrates the significant HRU and cost burden among individuals newly diagnosed with LoHD.

The most common symptoms in individuals newly diagnosed with LoHD were motor and cognitive impairments, whereas behavioral comorbidities were most common among individuals with AoHD. These findings are consistent with previous studies describing differences in clinical characteristics of individuals with LoHD versus individuals with AoHD. Similar to our study, previous studies have reported that individuals with LoHD more often present with gait and balance symptoms compared with individuals with AoHD^12,18. This may be attributed to balance and gait problems associated with the increased age at diagnosis in combination with age-related disorders such as arthritis¹⁸. Furthermore, a lower burden of behavioral symptoms in LoHD compared with AoHD could be due to the higher prevalence of severe behavioral symptoms, such as depression and substance abuse, observed in early-stage disease and in individuals diagnosed at a younger age^15,16. However, the differences in the predominant symptoms between the LoHD and AoHD cohorts in this claims analysis could indicate differences in disease presentation between the two patient populations that could be explored by future research.

A high proportion of patients newly diagnosed with LoHD were classified as having middle- or late-stage HD, which might indicate late diagnoses in this patient population. This may be due to the perception that there is a low likelihood of HD in patients >60 years of age⁹. Additionally, heterogeneity in symptoms at disease presentation, as well as a negative family history of HD which is common among individuals with LoHD, may further contribute to under-awareness of the condition and delayed diagnosis in this population¹⁸.

Our study demonstrated that the HRU burden in individuals with LoHD was significant and comparable to the burden among individuals with AoHD. The high HRU burden in LoHD supports the findings of previous HD studies which have demonstrated similar disease progression in LoHD compared with AoHD^12,13. Koustis et al. reported that the prognosis of LoHD was no better than that of AoHD and may even be worse¹², while Volpi et al. have recently demonstrated similar clinical performance between individuals with LoHD and AoHD at baseline and during follow-up visits¹³.

For both HD cohorts, the unadjusted all-cause HRU burden was higher compared with matched non-HD controls. For all services categories, adjusted HRU in the LoHD cohort was significantly higher than in non-HD controls, and similar to those with AoHD except for ER visits. The adjusted mean number of ER visits in the LoHD cohort was significantly lower than in the AoHD cohort, although still significantly higher compared with the respective matched control group. The exact reasons for the lower adjusted mean number of ER visits in the LoHD cohort compared with the AoHD cohort are unclear, but it is worth noting that the ER usage in non-HD controls ≥60 years of age was lower than in non-HD controls <60 years of age. One possible explanation for this unexpected reduction of ER visits in older individuals could be due to the increased likelihood of hospitalization in these cohorts.

There is a significant cost burden of HD on individuals and the US healthcare system. The adjusted mean annual direct healthcare costs in this study of ∼$30,000 per year for AoHD and LoHD are comparable with previous studies, such as Divino et al. which reported costs ranging from $3,257–$37,495 depending on disease stage and insurance type in 2011 USD ($4,278–$49,244 in 2020 USD)²⁴. However, Divino et al. limited their analysis to individuals with commercial and Medicaid insurance (mean age: 48–49 years) thus including individuals with typical onset HD with higher disability which may explain the higher costs reported in their study.

Two newer studies using more recent claims data reported similar healthcare costs to those recorded in this study. A recent study comparing costs between HD and non-HD populations reported per patient monthly costs of $2,260 (2018 USD, equivalent to an annual cost of $28,927 in 2020 USD)²⁷, while an analysis of healthcare costs in different stages of HD reported mean monthly costs across HD cohorts of $2,889 (2018 USD, $36,978 annualized in 2020 USD)²⁸.

In our study, adjusted healthcare costs were significantly higher in the LoHD cohort compared with both non-HD cohorts. Healthcare costs for patients with LoHD were comparable to patients with AoHD, with no significant differences observed in overall costs or for any of the healthcare categories analyzed. Total costs were significantly higher (∼2-fold higher) in the LoHD cohort compared with non-HD controls, and higher across all service categories, with significant differences for most categories. The majority of costs were attributed to OP visits ($12,143 [42% of the total costs] in LoHD and $13,657 [43% of the total costs] in AoHD), followed by pharmacy fills ($7,835 [27%] and $9,694 [31%], respectively). No previous studies have examined HRU and cost differences between LoHD and AoHD; however, a few prior analyses have examined the differences in HRU and costs by service categories among those with HD and without HD^24,33. The proportion of costs attributable to outpatient services is similar to previous studies^24,27,28. Higher adjusted outpatient costs among those with HD are a reflection of the multidisciplinary nature of care required in the management of HD³⁴.

Limitations

This study has limitations that should be considered when assessing these findings. First, there are several limitations that are inherent in claims-based analyses. Data recorded in claims databases are primarily intended for billing purposes and may be subject to coding errors that may impact the validity of the findings³⁵. Second, these results may not be generalizable beyond the study population, as data used in this analysis were limited to individuals covered with a US Commercial insurance plan or Medicare supplemental insurance plan in MarketScan databases and did not include individuals with other types of insurance such as Medicaid. These data are limited to the US healthcare system, and thus may not translate directly to other parts of the world where community-based care is more common, but the direction of the result is expected to be the same. Thirdly, only a single HD claim was required for patients to be included in this study. Although this approach has been used by prior studies of HRU in HD^24,36,37, and the rate of misdiagnosis is expected to be low due the availability of genetic testing and health insurance implications, the final cohort may contain beneficiaries with a misdiagnosis of HD which could potentially result in underestimating the disease burden and costs to the healthcare system. In addition, individuals were identified as newly diagnosed with HD based upon no HD claims in the 12 months pre-index, so it is possible some individuals may have been included in the final study cohort who were not truly new diagnoses. Limited follow-up times are characteristic of claims database analyses, and these may be a particular limitation in studies of HD, since the progressive nature of the disease may mean that patients drop off their insurance plan before the full extent of HRU and cost burden are captured.

We were unable to control for differences in HD disease stage between individuals with LoHD and AoHD in multivariable models for adjusted HRU and costs. As our study examined individuals with newly diagnosed HD, the HD stage was measured in the post‑index period, and multivariable adjustment on post-index variables following exposure may result in bias³⁸. Multivariable models were adjusted for baseline HRU, which was used as a proxy for baseline health status and may not fully measure the true health status. Non-HD controls were matched to the HD cohorts on baseline CCI and HRU. This matching approach may have selected for a non-HD cohort that may be sicker than the general population and this may have resulted in an underestimation of the true burden of HD.

Approximately 50% of individuals with AoHD were 50–59 years of age at the index date of HD diagnosis, who may have similar characteristics to individuals with LoHD. It is not clear why the age characteristics of the AoHD cohort in this study tend towards the older end of the typical age of HD onset, but the costs and HRU in this group of individuals 50–59 years of age at onset may mask differences between the AoHD and LoHD cohorts.

Indirect costs due to loss of productivity or caregiving costs were not estimated, which are known to be a significant component of the burden of HD on a wider level, especially in terms of informal care costs³³. If indirect costs were measured, there might be a greater burden of AoHD which typically impacts individuals during the peak of their career when earning potential is highest (35–54 years of age)³⁹.

Finally, LTC, NF and SNF care may not be fully captured in claims data since these types of services are generally excluded from commercial insurance coverage and Medicare does not cover SNF care beyond 100 d⁴⁰. As a result, HRU and the cost burden reported here may be underestimated due to not fully capturing care costs, particularly among individuals with late-stage disease or the institutionalized LoHD population.

Conclusions

To the best of our knowledge, this is the first study to investigate the differences in HRU and costs in individuals with LoHD compared with individuals without HD and to further contextualize these differences by comparison with individuals with AoHD. We found that individuals with LoHD had a similar HRU and cost burden to individuals with AoHD, which was significantly higher than those without HD. These findings further establish the disease burden in HD and highlight a significant unmet medical need in the LoHD population.

Transparency

Author contributions

TMT: Research project conception and organization; statistical analysis design and review/critique; and manuscript review/critique; final approval of the version to be published; and agree to be accountable for all aspects of the work.

JTT: Review/interpretation of study findings, drafting of paper or revising it critically for intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work.

AMP: Involved in the interpretation of the data; the drafting of the paper or revising it critically for intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work.

SA: Involved in the interpretation of the data; the drafting of the paper or revising it critically for intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work.

IMA: Study conception, design; and interpretation of the results; final approval of the version to be published; and agree to be accountable for all aspects of the work.

RG: Involved in the interpretation of the data; the drafting of the paper or revising it critically for intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they receive funding for their research and meeting attendance as well as sponsorship by pharmaceutical companies, however, none of it is relevant to this article review. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Acknowledgements

The authors thank Jack Curran, PhD, of Chrysalis Medical Communications, for providing medical writing support, which was funded by F. Hoffmann-La Roche Ltd, in accordance with Good Publication Practice (GPP 2022) guidelines (http://www.ismpp.org/gpp-2022).

Some of the results from this study have previously been presented as a poster at MDS (2021) 25th International Congress of Parkinson’s Disease and Movement Disorders; 17–22 September 2021.

Declaration of funding

This study was funded by Genentech Inc. Medical writing support was funded by F. Hoffmann-La Roche Ltd, in accordance with Good Publication Practice (GPP 2022) guidelines (http://www.ismpp.org/gpp-2022). The study sponsor was involved with the study design, analysis, and interpretation of data; writing of the manuscript; and the decision to publish the article.

Declaration of financial/other interests

TMT: Employment and stock options with Genentech.

JTT: Employment with Genentech (at time of study) and stock options with Roche.

AMP: Employment and stock options with Roche/Genentech.

SA: Employment with Genesis Research (at time of study) who? received consulting fees from Genentech/Roche.

IMA: Employment and stock options with Genentech.

RG: Employment and stock options with Genentech.

When this work was conducted, TMT, JTT, AMP, IMA and RG were employees of Genentech Inc, and SA was an employee of Genesis Research.