systematic reveiw huntingtons disease

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Lay Abstract

Huntington’s disease (HD) is a relatively rare genetic neurological condition.

Despite its relatively low occurrence in the general population, it has a

substantial impact on its victims. The effect of HD can easily be seen,

because suffers have difficulty with general cognitive functions and physical

actions such walking and eating food. These debilitating symptoms increase

emotional social and economic impact of HD.

Health state values help health economist to calculate the socioeconomic

impact of a disease on an individual. Little is known about the health state

values of HD. Health state values are needed to calculate the Quality

Adjusted live Years (QALYs). QALYs are used by organisations such as

National Institute of Clinical and Health Excellence (NICE) to measure the

cost and benefits of new and old innovations in healthcare. The QALY

combines the impact an innovation can have on a person’s quality of life, and

quantity of life into one numeric value. A systematic literature review, that

could easily be replicated (Systematic Review) was conducted to identify the

health state values for HD in the published literature.

Only two papers matched the inclusion and exclusion criteria that were set.

The two papers were Hocoaglu et al (2012) and Calvert et al (2012). They

reported and EQ-5D mean score of 0.3 and 0.53 respectively. The EQ-5D is a

generic measure used to gather health state values from the general public.

Hocoaglu et al (2012) reported a VAS score of 58.4. VAS (Visual Analogue

Scale) is a generic measure used to gather health state values from

individuals who have a particular condition. The ability of the EQ-5D to

measure the health state values of people with HD was also investigated.

Some weaknesses were found in the methods used to gather health state

values; this suggests a need for further research in this area.

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Abstract

Introduction: Huntington’s disease (HD) is a genetic

neurodegenerative condition. It is relatively rare, but its impact on a

person’s health related quality of life (HRQoL) can be substantial.

Health state values are used as weights to calculate the quality

adjusted life years (QALYs) and could be used by policy makers to

develop suitable policies for people living with HD. A systematic review

of published literature was conducted to identify the health state values

for people who have been diagnosed with HD.

Method: A systematic search was conducted in accordance with the

PRISMA guidelines to find the current literature on the health state

values of individuals with HD. The included articles were critically

appraised.

Results: Two articles were identified, at the end of the systematic

search, they were: Calvert et al (2012) and Hocaoglu et al (2012). The

authors used the EQ-5D to report health state values, for individuals

who were diagnosed with HD. They reported mean scores of 0.3 and

0.53 respectively. Hocaoglu et al (2012) reported a VAS score of 58.4.

A critical analysis was carried out on the methods used to gather the

health state values.

Conclusion: Two full articles matched the inclusion criteria. On the

basis of the critical analysis, recommendations were made to improve

the methods that researchers used to investigate the health state

values of individuals who had HD. The results suggest that EQ-5D

lacked content validity as a measure for the HRQoL in the lives of

people with HD. Additional research is needed to provide health state

values for each level of disease severity. The HDQoL could be

developed as a condition-specific preference-based measure.

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Background

According to Haskins et al (2000), the clinical features of Huntington's

disease (HD) were first described in the 19th century by George

Huntington. Fiedorowicz et al (2011) described HD as a fatal

neurodegenerative condition that affects many parts of the brain. It

occurs due to an excessive number of CAG repeats on chromosome

four. The prevalence of HD has been estimated by Pringsheim et al

(2012) to be 5.7 per 100,000 in North America, Europe and Australia.

Since HD follows an autosomal dominant pattern of inheritance,

individuals with the defect have a 50% chance of passing the disease

to their children. Cases of people with the disease are likely to increase

in the future (Walker et al 2007). Chisholm et al (2012) and Evans et al

(2010) have shown that characteristic of HD is that it is fully penetrant,

therefore people who test positive for HD in a genetic test would

definitely develop the disease in the future; even if they did not exhibit

the symptoms before testing. Disease onset usually occurs when

individuals are in their forties and the average life expectancy is 15 to

25 years after diagnosis (Walker 2007).

Studies have shown that HD causes an individual’s motor, cognitive

and behavioural functions to decline over time, until the individual

becomes fully dependent on care (Walker et al 2007; Fiedorowicz et al

2011 and Veenhuizen et al 2011). According to Carlozzi et al (2012);

Beglinger et al (2007) and Haskins et al (2000), patients may suffer

from psychological problems such as obsessive compulsive disorder,

aggression and irritability. These individuals are eight times more likely

to commit suicide than members of the general population (Haskins et

al 2000). Walker (2007) and Pulsen et al (2013) have reported that

people who have been diagnosed with HD display multiple physical

symptoms such as: dystonia, bradykinesia and involuntary movements.

Chorea is an example of an involuntary movement; it is seen as the

signature symptom of HD. Chisolm et al (2012) stated that people who

have HD encounter various cognitive issues, ranging from loss of short

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term memory to slurred speech. Sleep deprivation is also common in

people with HD (Morton et al 2012). It has been suggested that due to

the nature of the condition, many complex issues may arise that

impacts on the health-related quality of life (HRQoL) of people with HD

and their families (Williams et al 2011).

The way in which HD is treated has not changed in the last 20 years

according to Walker (2007). Haskins et al (2000) reported that, there

are still no therapies available to alter the progression of the disease or

the disease course. Therefore all current methods of treatment are

focused on managing the symptoms and supportive care (Haskins et al

2000). Thus, well informed decisions are needed to develop suitable

policies that may best alleviate the symptoms of HD in the lives of

those affected by the disease.

Given that resources are limited, every decision made in healthcare

has an opportunity cost, that is an alternative that is forgone (Posnet

1996). In light of this, economist has recommended that economic

evaluations of diseases can serve as a key tool to assist policy makers

to make more justifiable decisions (Drummond et al 2005; Drummond

1996; Drummond 1984 and Rutten 1996) (See Figure 1).There has

been increasing emphasis on economic evaluations across the world in

nations such as the UK, the Netherlands, Canada and Australia (NICE

2004; Commonwealth Department of Health and Ageing 2002; Ministry

of Health 1994 and Rutten 1996).

Drummond et al (1998) states that, many healthcare decision-making

organisations use the findings of cost-utility analysis which is a form of

economic evaluation to aid policy decisions. Torrance (1985) explains

that cost-utility analysis estimates the cost-per-QALY (quality-adjusted

life-year) of treatments or interventions. According Drummond et al

(1998), QALYs assess quality of life and quantity as a single health

outcome measure. Health state values or health utilities form

preference weights or ‘quality’ weights, and they are combined with

survival estimates to calculate QALYs (Brazier et al 2007). Longworth

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(2014) and Brazier et al (2007) reported that generic preference-based

measures such as the EQ-5D, HUI and SF-6D, are commonly used in

economic evaluations because they enable comparison between

different interventions and different groups of people. However, Brazier

et al (2007) also mentions that generic measures may fail to truly

capture how certain diseases can affect an individual’s HRQoL.

Condition specific preference-based measures reflect the impact that a

particular disease has on an individual’s HRQoL; however, it is more

difficult to compare across different conditions and interventions with

these measures (Brazier et al 2007 and Longworth et al 2014).

Health state values or QALY weights for HD health states derived from

good quality research are needed to inform decision-making regarding

interventions for this largely neglected condition (Figure 1). Therefore, a

systematic review was conducted of health state values for HD health

states.

Figure 1: The role of research in providing health state values for HD

have in decision making

The aims for this systematic review were as follows:

To identify health state values for HD in the published literature;

To describe these health state values that have been published

for HD health states;

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To summarise the methods that have been used in published

papers which estimated health state values of health states of

people with HD;

To comment on the methodological quality of the methods used

to estimate the health state values of health states of people with

HD;

To assess the content validity of the EQ-5D as a measure of

health-related quality of life for people with HD.

Methods

The methods and reporting framework used for this systematic review

followed the PRISMA (Preferred Reporting Items for Systematic

Reviews and Meta-analyses) guidance which has been adapted for a

methodological systematic reviews of health state values by Liberti et al

(2009).

Initially all of the original reports and published reports were identified,

these included, Health Technology Assessments and reports from

research institutions of empirically-derived health state values for any

HD health state.

Information sources

The following databases were searched on the 6/3/14: Medline in

process (Ovid); Embase (Ovid); PsycINFO (Ovid); Cochrane Library (all

databases); CINAHL (Ebsco) and EconLIT (Ebsco). In addition, the

references of all full text papers that were obtained were screened for

potential eligibility.

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Search strategy

The search strategy comprised two elements used in combination:

i) terms to identify papers relating to HD;

ii) terms to identify reports of health state values.

The HD search terms were devised in collaboration with a librarian at

the University of Exeter Medical School. The health state values search

terms were drawn from previous systematic reviews of health state

values and updated to include more recent methods of health state

valuation, for example, stated preference and discrete choice

experiments. These terms were drawn from different studies, Main et al

(2008); Thompson-Coon et al (2010); Shearer et al (2012) and Ryan

and Gerard (2003). The search terms were significantly adapted to be

appropriate to the particular database, and non-English papers, letters,

editorials and comments were specifically filtered out at this stage of

the review. The search strategies can be seen in Appendix 1.

Study Selection

The inclusion and the exclusion criteria were as follows:

Inclusion criteria

Study relates in part/full to adults with HD.

Health state values for HD health states are given.

Study presents empirically-derived health state values, given for

the first time. (Systematic reviews which presented new

empirical findings of health state values were eligible for

inclusion).

Published in English.

Exclusion criteria

Study does not relate to people with HD.

Study relates to carers of people with HD only.

Study relates to children only.

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Health state values are not given.

Study only uses or applies health state values that have been

previously reported. (If studies were applications of, or used,

previously published research reporting health state values,

these were excluded).

Screening

Two independent reviewers identified papers for potential inclusion in to

this review by reading titles and abstracts. At this stage, cost-utility

studies of treatments for people with HD were included as they should

provide references to original health state value data. Full text papers

of all potentially eligible studies were obtained in order to verify

inclusion or exclusion, and for subsequent data extraction. The reasons

for papers being excluded were documented.

Data extraction

A data extraction form (Appendix 2) was devised and used to extract

information from each of the included studies. An overview of the

extracted items is given in Table 1.

Table 1: Data items extracted from included studies

Study

details

Demographic and

clinical information

Health state value

data

Year of publication Age Descriptive system

Country Gender Method of health state

valuation

Study design HD stage Mean (sd) health state

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value

Sample size Disease duration Health state values by

disease severity

Description of included studies and findings

The studies were described and summarised according to the

characteristics detailed above.

Methodological quality of studies

The methods used to estimate the health state values of people with

HD in the included papers were assessed using the checklist given in

Appendix 3. This is based on two previously published checklists:

‘Check-list for judging the merits of preference-based measures of

health’ (Brazier 1999) and ‘Critical appraisal of a survey’

(Crombie1996). Two factors influenced this decision. Firstly the two

papers identified used cross-sectional survey methods and secondly

the discussion in the Brazier et al (2007) book which explains, in detail,

how to critically appraise different methods of gathering health state

values. Subsequently, the assessment criteria were divided to

separately assess:

i) the health state descriptive system and

ii) the valuation of health states.

The content validity of the EQ-5D

The HDQoL, according to a study carried out by Hocaoglu et al (2012),

is a recently developed measure designed to assess the HRQoL of

people with HD. In Hocoaoglu et al (2012) study, the HDQol was

developed based on a review of the literature, qualitative research and

face-to-face interviews with 31 people with HD living in the UK. The

interviews were audibly recorded and transcribed. 81 initial items were

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generated which were checked with 281 individuals, who had different

stages of disease severity, across 12 European countries. Participants

were asked how frequently they experienced each item, and the extent

to which each item impacted their HRQoL. This resulted in some items

being eliminated and the remaining items were further examined using

Rasch analys; this is a method used to analyse instruments that

measure an individual’s Quality life (Tennant et al 2004).

Due to the robust methods used in the development of the HDQoL, it

seemed fair to assume that HDQoL when this report was written, was

the best measure to fully capture the HRQoL of people with HD. Due to

this, the content validity of the EQ-5D, one of the most commonly used

generic preference-based measure, of HRQoL for people with HD was

carried out (Longworth et al 2014). The content validity of the EQ-5D

was investigated by comparing the EQ-5D dimensions with the HDQoL

scales. Here, as stated by Brazier et al (2007) content validity refers to

the extent to which the measures comprehensively cover the

dimensions of HRQoL affected by HD. This comparison was

undertaken to determine if there were key differences between the

coverage of measures. If the measures assess similar constructs, this

would be indicative of content validity of the EQ-5D for people with HD.

On the other hand, clear differences in coverage of the measures

would suggest that the EQ-5D lacks content validity for measuring the

HRQoL of people with HD.

Results

Article identification

Table 2 shows a breakdown of the number of articles that were

identified by each of the databases.

Table 2: Summary of results from the systematic search

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Study Selection

Figure 2 shows a flow diagram of the number of studies identified,

screened, eligible and included. The electronic database searches

identified 457 papers as potentially eligible. After duplicates were

removed this resulted in 384 potentially eligible papers. Each of these

studies were screened (based on title and abstract), resulting in the

exclusion of 372 papers. There were 12 titles and abstracts that met

the inclusion criteria. Of these 12, 10 titles and abstracts were

conference proceedings, these were: Clay et al (2011) a; Clay et al

(2011) b; Clay et al (2011) c; Clay et al (2010) d; Dorey et al (2011) a;

Dorey et al (2011) b; Dorey et al (2010) c; Dorey et al (2010) d;

Kehremiri et al (2012) and Urbernati et al (2012). Full text articles were

obtained of the two papers Calvert et al (2012) and Hocauglo et al

(2012).

Database Interface Date Hits

Medline OVID 06/03/2014 261

Embase OVID 06/03/2014 135

PsycINFO OVID 06/03/2014 11

CINAHL EBSCO 06/03/2014 23

EconLit EBSCO 06/03/2014 1

Cochrane Library Wiley 06/03/2014 26

Total hits 457

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Figure 2: Flow chart summarising the systematic search

Description of the studies

The two included papers were published in 2012 and were conducted

in the UK. The purpose of the Calvert et al (2012) study was to

examine the HRQoL of individuals who had different rare long-term

neurological conditions, and HD being one of these conditions. The

second paper, Hocaoglu et al (2012) compared how individuals, who

were at different stages of HD valued their own health state, with how

the carers valued the health states of the HD sufferers.

Demographic and clinical characteristics of study participants

The age of participants with HD in the Calvert et al (2012) paper was

57.1 (15.4) years (mean (standard deviation)), and of these participants

45.1% were male. The mean disease duration was 4.9 years, which

was calculated by subtracting the reported mean age in years from the

reported mean age of diagnosis. The disease severity of the

participants was not documented.

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Participants in the Hocaoglu et al (2012) study had a similar age of

56.42 (12.8) (mean (standard deviation)). 58% of the participants were

female, while 42% were male. The duration of disease was not

reported, however, participants were grouped by their HD stage. There

were seven stages. Participants were assigned to stage one if they

were seen to have slight changes in mood and motor control function.

Participants who were grouped in stage two could no longer work, and

needed help with daily activities. Participants, who were assigned to

stage 3, were described as being no longer able to carry out functions

independently. Participants, who needed assistance at home, were

allocated to stage 4. Stage 5 participants needed nursing care. There

was also a presymptomatic stage, which included participants that were

known to have the HD gene mutation but did not show any symptoms.

Finally, the at-risk group was made up of participants who had a family

member who was diagnosed with HD, but their own genetic status was

unknown.

Methods of included studies

Hocaoglu et al (2012) used a self-report postal method to gather data

via the UK HD Association (HDA). This cross-sectional survey

contained 105 individuals who were diagnosed HD. Participants could

ask for help with filling out the survey if required.

The study by Calvert et al (2012) was also cross-sectional in design.

The survey was completed either online or on paper, and participants

could ask for help to complete the survey. In total, 266 participants

were included in this study, and 53 of these participants were

diagnosed with HD. Participants were recruited via a number of

charities: MNDA, HD Association, MSA Trust, Ataxia UK, PSP Europe,

Polio Survey Network, CMT UK, specialist neurology clinics and via the

UK Clinical Research Networks (Dementias and Neurodegenerative

Disease Research Network and the Primary Care Network).

Researchers did not report the number of individuals that were

recruited from the various charities, and the condition that each

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participant had. Therefore it cannot be assumed that the 53 people with

HD were recruited from the HDA.

Sampling and response rate

The two studies recruited participants solely from charities and

associations. It is therefore unlikely that the samples were

representative of the general UK HD population, creating the potential

for selection bias (Berk 1983). People from associations such as the

HAD, could have been from particular subgroups of the HD population.

Thus they may have had certain characteristics. This could mean that

these individuals may have reported their health status in particular

ways which were not comparable with the rest of the HD population.

Both studies failed to mention the response rate; i.e. how many people

the questionnaire was sent to and how many replied. Therefore, it is

only possible to speculate on the type and size of bias that could have

arisen in the two studies.

Health State Values

Brazier et al (2007) explains that to produce a health state value, a

measure needs a descriptive system to describe health states, and a

valuation system to provide values for individuals’ health states.

Health state descriptive systems

Both studies used the EQ-5D, which was Euro Qol group (1996).

Longworth (2014) reported that the EQ-5D is one of the most

commonly used generic, preference-based measure to assess the

HRQoL of individual; and the EQ-5D is recommended by NICE in the

UK in Health Technology Assessment. This measure has five domains

which are: mobility, self-care, usual activities; pain and discomfort;

anxiety and depression according to Robin et al (2001). Robin et al

(2001) also explains that, the five domains are equally weighted in this

measure.

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Health state valuation

In the Hocaoglu et al (2012) study, health state values were derived

from the general population. Given the range of possible values

described, it is assumed that the UK value set suggested by Dolan

(1997) was used, but this is not stated in the paper. Health state values

were also collected from people with HD themselves using the EQ-5D

VAS (Brazier et al 2007).

The general population UK value set was also used in the Calvert et al

(2012) study. Health state values elicited directly from people with HD

were not collected in this research.

The scale for the EQ-5D starts with 0 which is equivalent to death and

ends with 1 which is equivalent to full health. The VAS scale ranges

from 0 (death) to 100 full health.

Health state values of HD health states

Hocaoglu et al (2012) reported a mean (sd) score of EQ-5D of 0.56

(0.35) for people with HD. They also reported a mean (sd) EQ-5D VAS

score of 58.4. The mean EQ-5D score described by Calvert et al (2012)

was 0.3 (no standard deviation was given). Table 3 provides a

summary of the results.

Table 3: Summary of included studies

Authors Calvert, Pall, Hoppitt,

Eaton, Savil and Sackley

Hocaoglu, Gaffan and Ho

Health State Value

instrument

EQ-5D EQ-5D

Mean Score 0.3 0.56

Standard Deviation Not given 0.35

Mean VAS Score Not givenhyyytt Not given 58.4

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Standard Deviation VAS

Score

Not given 23.2

Sample Size 53 105

Disease severity Not given

Mean disease duration 4.9

years

Range from ‘At risk’ to

stage 5 (individual needs

nursing care)

Content Validity

To assess the content validity of the EQ-5D for measuring the

HRQoLof people with HD, a table was created. The dimensions of the

EQ-5D formed the columns and the HQoL scales formed the rows (see

Table 3). Information given in Table 3 was obtained, firstly, by

considering the descriptive systems of the two measures (See

Appendix 4 and Appendix 5), and secondly, by referring to the studies

carried out by Hocoaglu et al (2012) and Robin et al (2002). Where the

measure captured similar aspects of an individual’s HRQoL, the box

was green. For example, the square that represented where the

mobility column intercepted the cognitive row, (a, 1) was green; this is

because, mobility is part dependent on an individual’s cognitive ability.

When the measure did not overlap, the square was red. For example

the square where Physical and Function met with Anxiety and

depression (e, 4) was red; this is because, anxiety and depression

considers a person’s psychological state rather than physical state

Of the possible 30 squares only 9 were green indicating similarity

between the two measures.

Table 3: Content validity of EQ-5D for assessing the HRQoL of HD

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EQ-5D dimensions

HDQoL scales Mobility

(a)

Self-care

(b)

Usual

activities

(c)

Pain/

Discomfort

(d)

Anxiety/

Depression

(e)

Cognitive (1)

Hopes & Worries (2)

Services (3)

Physical and

Functional (4)

Mood state (5)

Self and Vitality (6)

Key

Content areas where the EQ-5D and

the HDQoL overlap

Content areas where the EQ-5D and

HDQoL do not overlapped

Discussion

Summary of findings

A systematic review was conducted to identify health state values for

HD health states. Two papers matched the inclusion and exclusion

criteria. Calvert et al (2012) reported an EQ-5D mean score of 0.3 and

Hocaoglu et al (2012) reported an EQ-5D mean score of 0.56.

Hocaoglu et al (2012) also described an EQ-5D VAS score of 58.4.

Strengths and weaknesses of the systematic review

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Six databases were searched for the systematic review, along with

numerous search terms to ensure the thoroughness of the systematic

search (Appendix 1). The systematic search followed the PRISMA

guidance adapted for methodological reviews outlined by Liberti et al

(2009). However, the fact that the ISI Web of Science was not one of

these databases, which may have limited the search in terms of

obtaining, published grey literature.

One of the strengths of this systematic review is that it was the first

conducted regarding the health state values literature for HD. However,

there is a limited amount of extant literature in this field. 10 conference

titles and abstracts were identified from the systematic search. These

studies were Clay et al (2011) a; Clay et al (2011) b; Clay et al (2011)

c; Clay et al (2010) d; Dorey et al (2011) a; Dorey et al (2011) b; Dorey

et al (2010) c; Dorey et al (2010) d; Kehremiri et al (2012) and

Urbernati et al (2012 ). Full text articles were obtained of the two

papers (Calvert et al 2012 and Hocauglo et al 2012).

Analysis of the included articles

The Calvert et al (2012) paper reported that the mean score for people

with HD was 0.3 (no standard deviation were given). Walker (2007)

shown that HD affects a person’s HRQoL differently depending on

disease severity. However, Calvert et al (2012) failed to describe the

disease severity of their participants. Therefore, it is uncertain what the

mean health state value score represents, as it is not known whether

people within the sample had severe, moderate or mild HD.

In contrast, Hocaoglu et al (2012) did describe the disease severity of

participants in their study. The stages spanned the spectrum of the

disease from ‘At risk’ (people that were related to individuals who were

diagnosed with HD), to stage 5 (people with HD that need nursing

care). Despite the spread of disease severity, the paper only stated one

mean EQ-5D score and one mean EQ-5D VAS score, 0.56 and 58.4.

The standard deviations were 0.35, and 23.2 which re-emphasises the

magnitude of variation in the data. For this reason, the relevance of the

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average was limited. A useful addition to the data described would

have been, mean EQ-5D scores for each disease stage. Nevertheless,

because some of the stages included as few as eight people, such

reporting may have had limited validity.

Reported limitations

The Calvert et al (2012) study did not report the disease severity of

study participants. But, researchers did report that the health state

values are generally, more representative of those with advancing

disease. Authors also suggested that, due to this, people with HD may

have wanted to participate in the study as a result of having a lower

perceived view of their own HRQoL.

Calvert et al (2012) described the selection process used in the study

as non-random. They also stated that it was possible that people with

severe limitations were unable to participate in the study.

Hocaoglu et al (2012) did not describe any limitations in their study.

However, it is plausible that people that had severe limitations were

unable to take part in the study

Content Validity

In Table 3, 30% of the squares were green. These findings, coupled

with the nature of HD as described in the Background, imply that the

EQ-5D may be unable to assess the full impact that HD has on a

person’s HRQoL. Ma et al (2001), and Pulsen (2013) have come to

similar conclusions. This raises concerns about the content validity of

the EQ-5D as a measure of HRQoL for people with HD.

Recommendations to improve the methods used to collect health state

values for HD health states

On the basis of this review, there are a few key recommendations on

how the methods used to collect health state values for people with HD

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can be improved that can be made. It is important to present health

state values for each stage of HD according to the widely used HD

measure for disease severity, the Unified Huntington’s Disease Rating

Scale (UHDRS) which is described by, Phillips et al (2008) and Ho et al

(2009). This is because, the way in which HD affects a person’s

HRQoL when they are at risk of the condition, is significantly different to

how HD would affect a person’s HRQoL when they are at Stage 5 (in

need of a nursing home) of the disease according to Walker (2007). It

is therefore crucial that researchers take this into account when

reporting health state values for people with HD.

Furthermore, larger sample sizes are needed for each stage of the

disease to ensure that the health state values are accurate. Hocoaglu

et al (2012) separated their sample into different stages of HD and

reported a single EQ-5D mean score. The number of participants at

one stage comprised only eight; therefore it would have been

inappropriate to report a mean score for each stage.

Finally, it is recommended that researchers should endeavour to make

their samples as representative as possible and therefore, should not

rely solely on associations and charities recruit participants. In an

attempt to reduce recruitment bias, participants who have been

diagnosed with HD could be recruited via GP surgeries.

Future Research

Other studies use different instruments such as the SF 36, as a

descriptive system for the HRQoL for HD according to Ho et al (2009;

and Ho et al 2004). As previously mentioned, the two studies included

in this systematic review use the EQ-5D to provide health state values

for people living with HD. There are other methods available that would

enable researchers to gather health state values for individuals with

HD, such as the SF-6D (SF-6D converts data from the SF 36 into

health state value). However, to date, research has not been carried

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out using the SF-6D to provide health state values of health states for

individuals living with HD. Once such work has been conducted,

researchers will be able to determine which generic preference-based

measure may best capture the HRQoL of people with HD by comparing

the EQ-5D with the SF-6D.

The two included studies used a cross-sectional method, to gather

health state values of individuals with HD. Longitudinal methods should

be considered to explore how the health state values of health states

experienced by people with HD change over time.

Finally, Carlozzi et al (2013) has recommended that future research

should focus on developing the HDQoL into a condition-specific

preference-based measure, which may lead to more accurate health

state values for people with HD in the future.

If all of these recommendations are followed through, it is hoped that

more accurate measures would be used to collect information about the

health state values of individuals that have HD. This may possibly lead

to more accurate methods of measuring the HRQOL for people living

with HD; thus increasing the likelihood of more precise economic

evaluations for HD interventions, which may aid policy makers,

resulting in better policies for people with HD in the future.

References

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Appendix 1

Search strategy for Medline

1. Huntington$.ti,ab.

2. (Chorea adj4 progressive).ti,ab.

3. (chorea adj4 hereditary).ti,ab.

4. (chorea adj4 chronic).ti,ab.

5. (Westphal and (variant or dis$)).ti,ab.

6. exp Huntington Disease/

7. 1 or 2 or 3 or 4 or 5 or 6

8. "quality adjusted life".tw.

9. (qaly$ or qald$ or qale$ or qtime$).tw.

10. "disability adjusted life".tw.

11. daly$.tw.

12. "health state valu$".ti,ab.

13. "health status".tw.

14. "health related quality of life".tw.

of 43

15. (sf36 or sf 36 or short form 36 or shortform 36 or sf thirtysix or sf thirty six or

shortform thirtysix or shortform thirty six or short form thirty six or short form thirtysix

or short form thirty six).tw.

16. (sf6 or sf 6 or short form 6 or shortform 6 or sf six or sfsix or shortform six or

short form six).tw.

17. (sf12 or sf 12 or short form 12 or shortform 12 or sf twelve or sftwelve or

shortform twelve or short form twelve).tw.

18. (sf16 or sf 16 or short form 16 or shortform 16 or sf sixteen or sfsixteen or

shortform sixteen or short form sixteen).tw.

19. (sf20 or sf 20 or short form 20 or shortform 20 or sf twenty or sftwenty or

shortform twenty or short form twenty).tw.

20. (euroqol or euro qol or eq5d or eq 5d or eq-5d).tw.

21. (hql or hqol or h qol or hrqol or hr qol).tw.

22. (hye or hyes).tw.

23. "health$ year$ equivalent$".tw.

24. "health utilit$".tw.

25. (hui or hui1 or hui2 or hui3).tw.

26. disutil$.tw.

27. rosser.tw.

28. "quality of wellbeing".tw.

29. "quality of well being".tw.

30. qwb.tw.

31. "willingness to pay".tw.

32. "standard gamble$".tw.

33. "time trade off".tw.

34. "time tradeoff".tw.

35. tto.tw.

36. (index adj2 wellbeing).ti,ab,kw.

37. (index adj2 well being).ti,ab,kw.

38. (quality adj2 well being).ti,ab,kw.

39. (quality adj2 wellbeing).ti,ab,kw.

40. (health adj3 utilit$ ind$).ti,ab,kw.

41. ((multiattribute$ or multi attribute$) adj3 (health ind$ or theor$ or health state$ or

utilit$ or analys$)).ti,ab,kw.

42. "stated preference".ti,ab,kw.

43. "discrete choice".ti,ab,kw.

44. HDQOL.tw.

45. exp Value of Life/

of 43

46. exp Health Status Indicators/

47. exp quality adjusted life year/

48. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22

or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or

37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47

49. 7 and 48

Search strategy for Psyc Info


2. (Chorea adj4 hereditary).ti,ab.

3. (Chorea adj4 progressive).ti,ab.

4. (Chorea adj4 chronic).ti,ab.


6. exp Huntingtons Disease/

7. 1 or 2 or 3 or 4 or 5 or 6




11. daly$.tw.


13. "health status".tw.






short form six).tw.











of 43



26. disutil$.tw.

27. rosser.tw.



30. qwb.tw.





35. tto.tw.










44. HDQOL.tw.



37 or 38 or 39 or 40 or 41 or 42 or 43 or 44

46. 7 and 45

Search Strategy for Embase


2. (Chronic adj4 Chorea).ti,ab.

3. (hereditary adj4 Chorea).ti,ab.

4. (progressive adj4 Chorea).ti,ab.


6. exp Huntington disease/

7. 1 or 2 or 3 or 4 or 5 or 6



of 43


11. daly$.tw.


13. "health status".ti,ab.






short form six).tw.













26. disutil$.tw.

27. rosser.tw.



30. qwb.tw.





35. tto.tw.






of 43





44. HDQOL.tw.

45. exp quality adjusted life year/

46. exp socioeconomics/

47. exp health status indicator/




49. 7 and 48

Econ Lit

1. TI Huntington* OR AB Huntington*

2. TI (Chorea N4 hereditary) OR AB (Chorea N4 hereditary)

3. TI (Chorea N4 Chronic) OR AB (Chorea N4 chronic)

4. TI (Chorea N4 progressive) OR AB (Chorea N4 progressive)

5. TI (Westphal AND variant) OR AB (Westphal AND variant)

6. TI (Westphal AND dis*) OR AB (Westphal AND dis*)

7. (MH "Huntington's Disease")

8. TI "quality adjusted life" OR AB "quality adjusted life"

9. TI (qaly* or qald* or qale* or qtime*) OR AB (qaly* or qald* or qale* or qtime*)

10. TI "disability adjusted life" OR AB "disability adjusted life"

11. TI daly* OR AB daly*

12. TI "health state valu*" OR AB "health state valu*"

13. TI "health status" OR AB "health status"

14. TI "health related quality of life" OR AB "health related quality of life"

15. TI (sf36 or "sf 36" or "short form 36" or "shortform 36" or "sf thirtysix" or "sf

thirty six" or "shortform thirtysix" or "shortform thirty six" or "short form thirty

six" or "short form thirtysix" or "short form thirty six" or "36-item short*") OR AB

(sf36 or "sf 36" or "short form 36" or "shortform 36" or "sf thirtysix" or "sf thirty

six" or "shortform thirtysix" or "shortform thirty six" or "short form thirty six" or

"short form thirtysix" or "short form thirty six" or "36-item short*")

16. TI ("sf6" or "sf 6" or "short form 6" or "shortform 6" or "sf six" or "sfsix" or

"shortform six" or "short form six" or "6 item short*") OR AB ("sf6" or "sf 6" or

"short form 6" or "shortform 6" or "sf six or sfsix" or "shortform six" or "short

form six" or "6 item short*")

17. TI (sf12 or "sf 12" or "short form 12" or "shortform 12" or "sf twelve or

sftwelve" or "shortform twelve" or "short form twelve" or "12-item short*") OR

of 43

AB (sf12 or "sf 12" or "short form 12" or "shortform 12" or "sf twelve or

sftwelve" or "shortform twelve" or "short form twelve" or "12-item short*")

18. TI (sf16 or "sf 16" or "short form 16" or "shortform 16" or "sf sixteen" or

sfsixteen or "shortform sixteen" or "short form sixteen" or "16-item short*") OR

AB (sf16 or "sf 16" or "short form 16" or "shortform 16" or "sf sixteen" or

sfsixteen or "shortform sixteen" or "short form sixteen" or "16-item short*") -

19. TI (sf20 or "sf 20" or "short form 20" or "shortform 20" or "sf twenty or sftwenty

or "shortform twenty of short form twenty" "20-item short*") OR AB(sf20 or "sf

20" or "short form 20" or "shortform 20" or "sf twenty or sftwenty or "shortform

twenty” or “ short form twenty" "20-item short*")

20. TI (euroqol or "euro qol" or eq5d or "eq 5d" or "eq-5d") OR AB (euroqol or

"euro qol" or eq5d or "eq 5d" or "eq-5d")

21. TI (hql or hqol or "h qol" or hrqol or "hr qol") OR AB (hql or hqol or "h qol" or

hrqol or "hr qol")

22. TI (hye or hyes) OR AB (hye or hyes)

23. TI "health* year* equivalent*" OR AB "health* year* equivalent*"

24. TI (health utilit*) OR AB (health utilit*)

25. TI (hui or hui1 or hui2 or hui3) OR AB (hui or hui1 or hui2 or hui3)

26. TI (disutil*) OR AB (disutil*)

27. TI rosser OR AB rosser

28. TI qwb OR AB qwb

29. TI "willingness to pay" OR AB "willingness to pay"

30. TI "standard gamble*" OR AB "standard gamble*"

31. TI "time trade off" OR AB "time trade off"

32. TI "time tradeoff" OR AB "time tradeoff"

33. TI tto OR AB tto

34. TI (Index N2 "well being") OR AB (Index N2 "well being") OR DE (Index N2

"well being")

35. TI (quality N2 well being)OR AB (quality N2 well being) OR DE (quality N2

well being)

36. TI (index N2 wellbeing) OR AB (index N2 wellbeing) OR DE (index N2

wellbeing)

37. TI (quality N2 wellbeing) OR AB (quality N2 wellbeing) OR DE (quality N2

wellbeing)

38. TI (multiattribute* or multi-attribute*) N5 (“health ind*” or theor* or “health

stat*” or utilit* or analys*) or AB (multiattribute* or multi-attribute*) N5 (“health

ind*” or theor* or “health stat*” or utilit* or analys*)

39. TI (health N3 utilit* ind*) OR AB (health N3 utilit* ind*)

40. TI "stated preference*" OR AB "stated preference*"

41. TI "discrete choice" OR AB "discrete choice"

42. TI HDQol OR AB HDQol

43. ZE "value of life; forgone income")

of 43

CINAHL

1. TI Huntington* OR AB Huntington*

2. TI (Chorea N4 hereditary) OR AB (Chorea N4 hereditary)

3. TI (Chorea N4 Chronic) OR AB (Chorea N4 chronic)

4. TI (Chorea N4 progressive) OR AB (Chorea N4 progressive)

5. TI (Westphal AND variant) OR AB (Westphal AND variant)

6. TI (Westphal AND dis*) OR AB (Westphal AND dis*)

7. (MH "Huntington's Disease")

8. TI "quality adjusted life" OR AB "quality adjusted life"

9. TI (qaly* or qald* or qale* or qtime*) OR AB (qaly* or qald* or qale* or qtime*)

10. TI "disability adjusted life" OR AB "disability adjusted life"

11. TI daly* OR AB daly*

12. TI "health state valu*" OR AB "health state valu*"

13. TI "health status" OR AB "health status"

14. TI "health related quality of life" OR AB "health related quality of life"

15. TI (sf36 or "sf 36" or "short form 36" or "shortform 36" or "sf thirtysix" or "sf

thirty six" or "shortform thirtysix" or "shortform thirty six" or "short form thirty

six" or "short form thirtysix" or "short form thirty six" or "36-item short*") OR AB

(sf36 or "sf 36" or "short form 36" or "shortform 36" or "sf thirtysix" or "sf thirty

six" or "shortform thirtysix" or "shortform thirty six" or "short form thirty six" or

"short form thirtysix" or "short form thirty six" or "36-item short*")

16. TI ("sf6" or "sf 6" or "short form 6" or "shortform 6" or "sf six" or "sfsix" or

"shortform six" or "short form six" or "6 item short*") OR AB ("sf6" or "sf 6" or

"short form 6" or "shortform 6" or "sf six or sfsix" or "shortform six" or "short

form six" or "6 item short*")

17. TI (sf12 or "sf 12" or "short form 12" or "shortform 12" or "sf twelve or

sftwelve" or "shortform twelve" or "short form twelve" or "12-item short*") OR

AB (sf12 or "sf 12" or "short form 12" or "shortform 12" or "sf twelve or

sftwelve" or "shortform twelve" or "short form twelve" or "12-item short*")

18. TI (sf16 or "sf 16" or "short form 16" or "shortform 16" or "sf sixteen" or

sfsixteen or "shortform sixteen" or "short form sixteen" or "16-item short*") OR

AB (sf16 or "sf 16" or "short form 16" or "shortform 16" or "sf sixteen" or

sfsixteen or "shortform sixteen" or "short form sixteen" or "16-item short*") -

19. TI (sf20 or "sf 20" or "short form 20" or "shortform 20" or "sf twenty or sftwenty

or "shortform twenty of short form twenty" "20-item short*") OR AB(sf20 or "sf

20" or "short form 20" or "shortform 20" or "sf twenty or sftwenty or "shortform

twenty” or “ short form twenty" "20-item short*")

20. TI (euroqol or "euro qol" or eq5d or "eq 5d" or "eq-5d") OR AB (euroqol or

"euro qol" or eq5d or "eq 5d" or "eq-5d")

21. TI (hql or hqol or "h qol" or hrqol or "hr qol") OR AB (hql or hqol or "h qol" or

hrqol or "hr qol")

22. TI (hye or hyes) OR AB (hye or hyes)

23. TI "health* year* equivalent*" OR AB "health* year* equivalent*"

of 43

24. TI (health utilit*) OR AB (health utilit*)

25. TI (hui or hui1 or hui2 or hui3) OR AB (hui or hui1 or hui2 or hui3)

26. TI (disutil*) OR AB (disutil*)

27. TI rosser OR AB rosser

28. TI qwb OR AB qwb

29. TI "willingness to pay" OR AB "willingness to pay"

30. TI "standard gamble*" OR AB "standard gamble*"

31. TI "time trade off" OR AB "time trade off"

32. TI "time tradeoff" OR AB "time tradeoff"

33. TI tto OR AB tto

34. TI (Index N2 "well being") OR AB (Index N2 "well being") OR DE (Index N2

"well being")

35. TI (quality N2 well being)OR AB (quality N2 well being) OR DE (quality N2

well being)

36. TI (index N2 wellbeing) OR AB (index N2 wellbeing) OR DE (index N2

wellbeing)

37. TI (quality N2 wellbeing) OR AB (quality N2 wellbeing) OR DE (quality N2

wellbeing)

38. TI (multiattribute* or multi-attribute*) N5 (“health ind*” or theor* or “health

stat*” or utilit* or analys*) or AB (multiattribute* or multi-attribute*) N5 (“health

ind*” or theor* or “health stat*” or utilit* or analys*)

39. TI (health N3 utilit* ind*) OR AB (health N3 utilit* ind*)

40. TI "stated preference*" OR AB "stated preference*"

41. TI "discrete choice" OR AB "discrete choice"

42. TI HDQol OR AB HDQol

43. (MH "Economic Value of Life")

44. (MH "Quality-Adjusted Life Years")

45. (MH "Health Status Indicators")

Search strategy for Cochrane

1. Huntington*:ti,ab

2. (chorea near/4 Chronic):ti,ab

3. (Chorea near/4 Progressive):ti,ab

4. (hereditary near/4 Chorea):ti,ab

5. Westphal and dis*:ti,ab

6. Westphal and variant:ti,ab

7. MeSH descriptor: [Huntington Disease] explode all trees

8. #1 or #2 or #3 or #4 or #5 or #6 or #7

9. "quality adjusted life":ti,ab

10. (qaly* or qald* or qale* or qtime*):ti,ab

of 43

11. "disability adjusted life":ti,ab

12. daly*:ti,ab

13. "health state valu*":ti,ab

14. "health status":ti,ab

15. "health related quality of life":ti,ab

16. (sf36 or sf 36 or shortform 36 or sf thirtysix or sf thirty six or shortfom thirtysix

or shortform thirty six or short form thirty six or short form thirtysix or short

form thirty six):ti,ab

17. (sf6 or sf 6 or short form 6 or shortform or sf six or sfsix or shortform six or

short form six):ti,ab


shortfom sixteen or short form sixteen):ti,ab

19. (sf 12 or sf 12 or short form 12 or shortform 12 or sf twelve or sftwelve or

shortform twelve or short form twelve):ti,ab

20. (sf20 or sf 20 or short form 20 or shortform 20 of sf twenty of shorfform

twenrty or short form twenty):ti,ab

21. (euroqol or euro qol or eq5d or eq 5d or eq-5d):ti,ab

22. (hql or hqol or h qol or hrqol or hr qol):ti,ab

23. (hye or hyes):ti,ab

24. "health* year* equivalent*":ti,ab

25. "health utilit*":ti,ab

26. (hui or hui1 9or hui2 or hui 3):ti,ab

27. dusutil*":ti,ab

28. "rosser":ti,ab

29. "quality of wellbeing":ti,ab

30. "qualtiy of well being":ti,ab

31. qwb:ti,ab

32. "willingness to pay":ti,ab

33. "standard gamble*":ti,ab

34. "time trade off":ti,ab

35. "time tradeoff":ti,ab

36. "tto":ti,ab

37. "index Near/2 well being":ti,ab,kw

38. "quality NEAR/2 well being":ti,ab,kw

39. "quality NEAR/2 wellbeing":ti,ab,kw

40. ((multiattribute* or multiattribute*) near/3 (health ind* or theor* or health state*

or utilit* or analys*)):ti,ab

41. "stated preference":ti,ab

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42. "discrete choice":ti,ab

43. HDQOL:ti,ab

44. MeSH descriptor: [Value of Life] explode all trees

45. MeSH descriptor: [Health Status Indicators] explode all trees

46. MeSH descriptor: [Quality-Adjusted Life Years] explode all trees

47. 9 or10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 23

or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or


48. 49 8 and 48

Appendix 2

Data Extraction form

Data Comments

Study details

Authors

Year

Country

Study design

Sample size

Demographic and clinical

information

Age

Gender

Disease type

Disease duration

HD stage

Health state values

Measure used

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Health state values (mean,

standard deviation, range, median,

inter-quartile range)

Health state values by HD stage

Appendix 3

Details

The descriptive system

1. Was a generic or condition-specific descriptive system used?

2. Was a standardised questionnaire used? y / n

3. If yes, which questionnaire was used?

4. If no, what descriptive system was used?

5. Was the questionnaire or descriptive system that was used

appropriate for use in HD in terms of:

y / n

a. Face validity: Were the items relevant and appropriate to MS? y / n

b. Content validity: Were all dimensions of health of interest

included?

y / n

6. Could the sampling method for those who completed the

descriptive system have introduced selection bias (i.e. the sample

was unlikely to have been representative)?

y / n

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7. Was the response rate achieved likely to have introduced

significant bias (e.g. a response rate of less than 50%)?

y / n

The health state valuation process

8. Were health state values from the general population used? y / n

9. If yes, which dataset/algorithm was used?

10. Were health state values from people with HD used? y / n

11. If yes:

a. What method of valuation was used?

e.g. standard gamble, time trade-off, VAS?

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Appendix 4

HDQOL

Cognitive Hopes

and

Worries

Services Physical and

Functional

Mood

States

Self and

vitality

Everyday

memory

HD Family

Worry

Management

of HD

Hobby Sleep HD family

worry

Organise day HD worry Services on

HD

Weight Irritated Support

Remember

Date

Hope Information

on HD

Eating Temper Socialise

Concentration Financial

Concerns

Dressing Low mood Role in

family

Multitask Other’s

attitude to

HD

Walking Socialised Motivation

Slow Operate

television

Get on

with life

Tired

Follow

Conversation

Swallowing Motivation

Use Words Carrying

things

Decision

Making

Balance

Personal

wishes

Independence

Jobs around

the house

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Appendix 5 EQ-5D Mobility I have no problems in walking about I have some problems in walking about I am confined to bed Self-Care I have no problems with self-care I have some problems with washing or dressing myself I am unable to wash or dress myself Usual Activities (e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities I have some problems with performing my usual activities I am unable to perform my usual activities Pain / Discomfort I have no pain or discomfort I have moderate pain or discomfort I have extreme pain or discomfort Anxiety / Depression I am not anxious or depressed I am moderately anxious or depressed I am extremely anxious or depressed

systematic reveiw huntingtons disease

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