Health-Related Quality of Life in Children with Duchenne Muscular Dystrophy: A Review.

In pediatric chronic illness, improving health-related quality of life (HRQOL) has become one of the most important goals of disease management. Duchenne muscular dystrophy (DMD) is a debilitating, progressive and chronic neuromuscular disorder affecting boys. The purpose of this review is to provide an overview of published research on HRQOL in the pediatric DMD population, describe the instruments used and summarize the study findings. The databases searched were Medline, Embase and PsycInfo. The literature search yielded 167 articles, of which 19 were included in this review. The studies were published between 2005 and 2013 across nine countries. Thirteen different generic and disease-specific measures were used, the most common being the Pediatric Quality of Life 4.0 Generic Core module.HRQOL in boys with DMD is worse than that of healthy peers and children with other chronic illnesses, especially in the physical domains. Boys who are at a more severe stage of the disease reported worse physical HRQOL but not necessarily psychosocial HRQOL than boys at a less severe stage. Traditional clinical outcome measures correlated well only with physical HRQOL. Parents' proxy-reports of their sons' HRQOL and the boys' self-reports had poor concordance. More research is needed to assess trends in HRQOL over time and to elucidate factors that affect HRQOL.

ABBREVIATIONS

child health questionnaire

Duchenne muscular dystrophy

Food and Drug Administration

health-related quality of life

intraclass correlation coefficient

Life Satisfaction Index-Adolescent

Neuromuscular

Pediatric Outcomes Data Collection Instrument

strips of life with emoticons

INTRODUCTION

Duchenne muscular dystrophy (DMD) is the most common and severe form of neuromuscular illness in children, affecting between 1 in 3, 500 and 1 in 6, 000 newborn boys [1, 2]. It is characterized by progressive muscle loss that begins in proximal, lower extremity muscles. Muscle degeneration eventually leads to loss of ambulation, occurring between 10 to 14 years of age [3]. The respiratory, cardiac and bone health of boys with DMD are compromised. There is also a higher prevalence of cognitive disability in this population [4]. Respiratory or cardiac failure eventually leads to premature death, typically in the second to third decade of life [5, 6].

Medical interventions have extended the quantity of life of DMD patients, however, their quality of life (QOL) remains greatly jeopardized by the condition [7]. The World Health Organization Quality of Life group has defined quality of life as ‘individuals’perception of their position in life, in the context of culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns [8]. Health-related quality of life (HRQOL) narrows the scope of QOL and focuses specifically on the impact of illness and treatments on a person’s life [9-11]. Although the concept of HRQOL has been operationalized rather inconsistently across the various measures developed, there are two elements of the concept that are widely agreed to be core: that it includes both subjective and objective dimensions of the impact a health condition and/or its management has on an individual and that it is multidimensional, encompassing multiple aspects of a person’s life. Thus, most instruments are made up of multiple domains, including emotional, social and physical health [12].

The Food and Drug Administration (FDA) has mandated that all clinical trials include patient reported outcomes such as HRQOL [13]. A number of promising molecular therapies for DMD are currently undergoing various stages of clinical trials [14]. A greater understanding of HRQOL would enable researchers and clinicians to meaningfully interpret forthcoming trial results and better incorporate HRQOL measures into future studies. Furthermore, understanding the state of HRQOL in the DMD population is important in and of itself due to its chronic nature and the prolonged life expectancy that has become possible.

While research on HRQOL in DMD is still scarce, it has gained momentum in the past few years. The aim of this article is to provide a thorough review of existing literature on HRQOL in the pediatric DMD population. Key themes, such as comparison of HRQOL with healthy children and other disease groups will be addressed and the limitations of existing literature will be discussed.

METHODS

A literature search was conducted in between October 2014 and April 2015 in the electronic databases Medline, Embase and PsycINFO using the following key words: 1) Duchenne Muscular Dystrophy; 2) quality of life OR health related quality of life OR health-related quality of life OR health status; 3) pediatri * OR paediatri OR teenage * OR adolescent OR child OR child * 4) 1 AND 2 AND 3. Medical Subject Heading (MeSH) terms were used whenever possible. Through the initial search criteria, 167 articles were identified that were published from 1986 to 2015. The abstracts were examined and, if suitable, full-length articles were retrieved (Figure 1). Articles were included in this review if they met the inclusion criteria. The reference lists of relevant studies were used to identify potential studies not discovered upon initial search.

Fig.1

Process of selecting studies included in this reviewProcess of selecting studies included in this review.

Inclusion criteria:

1) Child or parent-reported QOL or HRQOL was the main outcome of the study; 2) study population was specific to or included children with Duchenne Muscular Dystrophy (≤18); and 3) was published in the English language.

RESULTS

Nineteen studies were identified that fit the inclusion criteria. The studies were published between 2005 and 2013 and were conducted in the following countries: United States, the Netherlands, Germany, China, Brazil, France, Australia, Italy, and Canada. There are regional differences in the selection of HRQOL measures: almost all studies carried out in North America used either the PedsQL4.0 Generic Core or the CHQ-50 while almost none of the European countries used these two measures even though they are available in the languages of these countries. Each of the studies done in Europe used a different HRQOL measure.

Thirteen measures of HRQOL were used. Ten were generic measures and most consisted minimally of physical, psychological and social domains. Four studies used disease specific questionnaires: the English [15] and Chinese [16] versions of the PedsQL 3.0 Neuromuscular module, the PedsQL 3.0 DMD module [17] and the Strips of Life with Emoticons [18]. The development of the PedsQL 3.0 Neuromuscular module was described in detail by Iannacone [19]. It underwent extensive review with input from clinicians and families of children with spinal muscular atrophy and DMD. The Neuromuscular module and DMD module were developed simultaneously. A summary of all measures used can be found in Table 1.

Table 1

Summary of health-related quality of life instruments used by studies reviewed

Instrument	Dimensions or domains	Scoring	Psychometric properties *
Pediatric Quality of Life	Physical, emotional, social and schoolfunctions	23 items	English version valid
4.0 Generic Core			and reliable in DMD
(PedsQL 4.0 Generic)		Scores on four domains	population [15]
English and Chinese		Physical and Psychosocial	α= 0.45–0.89
		summary scores
Parent and child reports
available		Has total score
Life Satisfaction Index for	General wellbeing, interpersonalrelationship,	45 items	Validated on
Adolescents (LSI-A)	personal development, personal satisfaction,		adolescents with DMD
	recreation	Scores on five domains
English and Dutch			α= 0.52–0.88 [37]
		No total score
Child report available
Personal Adjustment and	Peer relations, dependency, hostility,	28 items	Valid and reliable in US
roles Skills Scale (PARS-	productivity, anxiety/depression, and		and Dutch DMD
III)	withdrawal	Scores on six domains	populations
Dutch		Has total score	α= 0.75–0.91[20]
Parent report only
PedsQL Neuromuscular	About My Neuromuscular Disease,	25 items	Both English [15] and
Module	communication, About our family resources		Chinese[16] versions
		3 domain scores	valid and reliable in
English and Chinese			children with DMD.
		Has total score
Parent and child reports			α= 0.71-0.89
available
PedsQL DMD module	Daily Activities, Treatment, Worry,	4 domainscores	Valid and reliable in
	communication		children with DMD
English version		No total score	[17].
Parent and child reports			α= 0.66-0.86
available
Child Health	Physical Functioning, Role/Social Limitations–	50 items; Scores on 15	Valid and reliable in
Questionnaire Parent	Physical,	domains	UK, US, German and
Form 50	General Health Perceptions, Bodily		Canadian English and
(CHQ-50)	Pain/Discomfort, Family Activities, Role/Social	2summary scores: physical	French populations [38]
	Limitations - Emotional, Role/Social	and psychosocial
English	Limitations - Behavioral, Parent Impact Time,
	Parent Impact Emotion, Self-Esteem, Mental	No total score
Parent report only	Health, Behavior, Family Cohesion, Change in
	health
KIDSCREEN-52	Physical, psychological, moods/emotions, self-	52items	Valid and reliable in
	perception, autonomy, parent relations/home		healthypopulation [39].
Dutch version	life, financial resources, social support/peers,	Scores on ten domains
	school environment, social acceptance
Child report only		No total score
DISABKIDS	Independence, emotion, social inclusion, social	37items; Scores on six	Valid and reliable in
	exclusion, physical limitation, treatment	domains and totalscore	children and adolescents
German version			with various chronic
			illnesses [40].
Child report only
TACQoL	Motor functioning, physical symptoms, social	56 items;Scores on seven	Valid and reliable in
	functioning, cognitive functioning, positive	domains	children with various
Dutch	emotions, negative emotions, autonomy		chronic illnesses [41]
		No total score
Child report only
Vecu Sante percu par	Vitality, leisure, relationship withparents,	36 items	Valid and reliable in
l’adolescent	relationship with friends, relationship with		group of healthy and ill
(VSPA)	teachers, body image, school performance,	Scores 9domains	adolescents [42].
	physical and psychological wellbeing
French		No total score
Child report only
Paediatric Outcome Data	Upper extremity, transfer/basicmobility,	Scores on five domains	Valid and reliable in a
Collection Instrument	sports/physical function, pain, happiness, and		range of children with
(PODCI)	global functioning	Global functioning score is	functional limitations
		mean of all domains	[43]
English		excluding happiness
Child and parent reports
available
Strips of Life with	33 individual items that assess how a childat	Total score of all 33 items	Not validated
Emoticons (SOLE)	different times in a typical day
		No domain scores
Italian
Child report only
Short Form 36	Vitality, physical functioning, bodily pain,	36items; Scores on eight	Not validated in the
	general health perceptions, physical role	domains	pediatricpopulation
English	functioning, emotional role functioning, social
	role functioning, mental health	No total score

 *Internal consistency reliability (Cronbach’salpha) of instruments that have been tested in the pediatric DMDpopulation are reported; validity and reliability instruments thathave not been tested in other populations are referenced.

The PedsQL 4.0 Generic Core, PedsQL 3.0 Neuromuscular, PedsQL 3.0 DMD modules as well as the PARS-III have been validated in pediatric DMD populations; none of the other measures has been validated in this population. The PedsQL 4.0 Generic core module and the PedsQL 3.0 Neuromuscular module were tested in a group of 44 boys with DMD and their parents [15]. Both modules were found to be feasible and have adequate construct validity for child and parent reports. The internal consistency reliability on the PedsQL Neuromuscular module exceeded the conventional minimum alpha coefficient of 0.7 for all scales in child and parent reports. The internal consistency reliability on the PedsQL Generic Core module exceeded the minimum alpha coefficient for all scales on the parent report. The test-retest reliability of the PedsQL Neuromuscular module is supported for child and parent reports [15]. The PedsQL 3.0 DMD module was tested in a group of 203 families of boys with DMD. All scales on child and parent reported questionnaires exceeded the minimum alpha coefficient needed for group comparisons [17]. Construct validity was also found to be adequate. The PARS-III was tested in a group of 282 males with DMD [20]. Internal consistency reliability was found to be good for the total score and most scale scores. Construct and convergent validities were also found to be adequate.

Six of the studies used parent reports only, seven used child report only, and six used both child reports and parent reports. Two studies had the same cohort of patients [21, 22], one used parent reports only, one used both child and parent reports. Seventeen of the studies were cross-sectional and two were longitudinal, conducted over the span of nine months and one year [23, 24]. The sample sizes of the studies ranged from 25 to 287. It should be noted, however, that some of studies’ patient populations included adults with DMD or children with other types of neuromuscular disorders [18, 25–27].

Although almost all of the studies of HRQOL in children with DMD are descriptive, some comparative analyses were completed. Four recurring themes were identified: 1) comparison of HRQOL between boys with DMD to either healthy peers or those with another chronic illness; 2) comparison among sub-groups within the pediatric DMD sample; 3) investigation of relationship between clinical measures of function and HRQOL; and 4) comparison of children’s and parents’ perception of children’s HRQOL. Each of the four themes will be discussed in detail below. A summary of major findings of all nineteen studies reviewed can be found in Table 2.

Table 2

Summary of studies reviewed

Citation	Study design; DMD sample characteristics [N; mean age, (age range)]; Recruitment method	HRQOL measure used	Major findings
[15]	Cross-sectional;	PedsQL 4.0 Generic Core	All HRQOL scores significantly
		and PedsQL 3.0	poorer than normative sample.
	[44; 12.9 years; (8–18)]	Neuromuscular modules
			Poorer physical HRQOL in both modules
	Neuromuscular clinics in	Child and parent report	among non-ambulatory boys.
	the United States
[16]	Cross-sectional;	Chinese version of PedsQL	The Chinese translation of the
		4.0 Generic Core and	Neuromuscular module was feasible,
	[56; 7.5 years; (2–13)]	Neuromuscular 3.0 module	reliable and valid
	Tertiary hospitals in urban China	Child and parent report	Moderate agreement between
			parent and child
[17]	Cross-sectional;	PedsQL 4.0 Generic Core	All HRQOL scores significantly
		and DMD module	lower than healthy children.
	[203; 10.4 years; (5–17)]
		Child and parent report	Self-reported psychosocial scores
	Neuromuscular clinics in the		significantly higher for older than
	United States (Michigan)		younger boys.
			Psychosocial score not related to
			use of mobility aids.
[18]	Cross-sectional;	Strips Of Life with	Poorer HRQOL than
		Emoticons (SOLE)	healthy controls.
	[43; 8.6 years; (range 5–13)]	questionnaire	HRQOL not related to degree
			of functional disability.
	Six tertiary centres in Italy	Child report
[20]	Cross-sectional	Personal Adjustment and	Adjustment score did not differ significantly
		Role Skills Scale (PARS-III)	from boys with other chronic conditions.
	[287; 10.9 years; (5–18)]		Adjustment score increased with age.
	Dutch and American Parent
	Project Muscular Dystrophy	Parent report
	organizations
[23]	Longitudinal	Life Satisfaction Index	HRQOL in most domains
		for Adolescents	improved over time.
	[95; unknown; (5–17)]
		Child report	No significant difference
	Single neuromuscular centre		between age groups.
	in Brazil
[24]	Longitudinal	PedsQL 4.0 Generic	Decline in PODCI score but not
		Core PODCI	PedsQL were significantly correlated
	[24; 7.9 years; (4–12)		with decline in 6 minute walk test.
		Parent-report
	Neuromuscular clinics in the
	United States (California)
25]	Cross-sectional	TACQoL children for	Only the ‘motor functioning’ domain
		under 16 year olds	was poorer than healthy peers
	[36; 12.6 years; (8–17)]	TACQoL adult for 16 and older
	Dutch Neuromuscular centres
		Child report
[26]	Cross-sectional	PedsQL 4.0 General Core	Children who required ventilation had
			significantly lower overall HRQOL than
	[24 (out of 109 NM patients;	Parent-report	children not on ventilation
	10.5 years; (2–18)]
	Single Neuromuscular centre
	in Canada
[27]	Cross-sectional	Vecu Sante Percu par	HRQOL scores not significantly
		L’adolescent (self-perceived	different than nondisabled group.
	[19 (out of 43 NM patients);	perceived health states in
	13.8 years; (10–17)]	adolescents)	HRQOL scores did not correlate
		Self-report	with physical impairment
	Single neuromuscular centre
	in France
[21] *	Cross-sectional	PedsQL 4.0 Generic Core	Self-reported scores significantly correlated
			with physical domain and Vignos scale
	[35; 12.5 years; (9–17)]	Child and parent reports
			Parent-child concordance range from poor
	Neurogenetics clinics and		to modest for different domains.
	community newsletters
	in Australia
[22] *	Cross-sectional	Child Health	Parents reported significantly lower
		Questionnaire 50-Parent	HRQOL score than normative sample and
	[34; 9.9 years; (5–18)]	Form	Charcot-Marie-Tooth disease sample.
	Three urban paediatric hospitals	Parent-report	Parents experienced greatest stress during
	in Australia		disease transition points.
[28]	Cross-sectional	PedsQL 4.0 Generic Core	All HRQOL scores poorer than healthy
			sample except for emotional domain.
	[50; 8.0 years; (5–17)]	Child and parent report
			Participation level is not
	Neuromuscular clinic in the		correlated to HRQOL
	United States (Florida)
			Older boys had significantly lower
			participation level, but not lower
			HRQOL scores than younger boys
[29]	Cross-sectional	PedsQL 4.0 Generic Core	HRQOL in both measures are
		Module	poorer than controls
	[52; 8.4 years; (4–17)]
		PODCI	The physical function domain of PedsQL
	Neuromuscular clinics in the		and of PODCI correlated with age and
	United States	Parent report	clinical measures of strength
[30]	Cross-sectional	Child Health	HRQOL scores significantly poorer
		Questionnaire 50- Parent	than healthy sample
	[27, 11.4 years; (unknown)]	Form
			Use of wheelchairs and ventilation were
	Neuromuscular clinics in Italy	Parent report	significantly associated with lower physical
			HRQOL.
[31]	Cross-sectional	DISABKIDS chronic	In children, all HRQOL scores poorer than
		generic module for	children with other chronic illnesses. In
	[50; 15.4 years; (8–23)]	children and adolescents;	adolescents, only social inclusion domain
		Short Form-36 for young	was poorer.
		adults
	Single paediatric neurology		No correlation between total HRQOL score
	clinic in Germany	Child report	and Vignos function score.
	[32]	Cross-sectional	KIDSCREEN-52	Apart from physical domain, HRQOL
			in not significantly different from that
	[40; 11.5 years; (8–20)];	Child report	of healthy boys.
	Dutch Duchenne Parent		Significant correlations between physical
	Database		domain and some functional scales
			Parent scores were significantly lower
			than child score in three domains.
[33]	Cross-sectional	Short Form-36	Physical and mental HRQOL not found to
			be correlated with physical impairment or
	[N = 35; 17 years; (8–33)]	Child report	FVC.
	Swiss facility for NM patients
[34]	Cross-sectional	PedsQL 4.0 Generic Core	Parents reported significantly lower
	DMD sample N = 63		physical and psychosocial HRQOL than
	parent-child pairs	Child and parentreport	boys themselves.
	Mean age 10.3 (range 5-16)
			The agreement between children and
	Florida, United States		parents in physical domain was better
			than psychosocial domains.

 *Participants of two studies by Bray andcolleagues were from the same cohort of families.

Comparison to healthy peers or those with another chronic illness

Ten studies compared HRQOL in boys with DMD to a healthy cohort or children with other chronic illnesses, such as diabetes, cerebral palsy and epilepsy. Four of these studies recruited healthy controls along with their DMD sample [18, 24, 28, 29], and six studies used established normative data from the literature as basis of their comparison to healthy children [15, 17, 22, 30–32].

Elsenbruch et al. [31] divided their sample into child and adolescent groups. In the children’s group, all domain scores as well as the total HRQOL score were significantly lower than the scores of age-matched children with other chronic illnesses. In the adolescent group, only the social inclusion domain score was significantly lower in boys with DMD than the normative data. Orcesi et al. [18] developed a new HRQOL instrument targeting young children with neuromuscular illnesses, the Strips of Life with Emoticons (SOLE), which only has an overall score and no domains scores. Compared to healthy boys, boys with DMD had significantly lower scores on the SOLE.

Eight studies found that boys with DMD had significantly worse physical HRQOL than healthy boys or children with other types of chronic illnesses [15, 17, 22, 24, 28–30, 32]. Five studies reported that boys with DMD had significantly lower psychosocial score than healthy controls [15, 22, 28–30]. The difference in physical HRQOL score were consistently larger than difference in psychosocial score, and these deficiencies were observed in both children’s and parent’s reports.

Comparison among sub-groups within the pediatric DMD sample

In DMD studies, age is often used as a proxy for disease progression given that generally, older children are at a more severe stage of the illness. Patients with DMD may also be classified by ambulation status (ambulant or non-ambulant) or ventilation status (requires ventilation or not).

Three studies used the PedsQL 4.0 Generic Core scale and reported that younger boys had significantly higher physical HRQOL scores than older boys [17, 21, 29]. In contrast, another study reported that boys younger than 10 years of age did not report significantly higher physical score than those who were older [28]. Two studies reported boys using wheelchairs had significantly lower physical domains scores than boys who were still ambulant [15, 30]. Kohler et al. [33], found that boys with DMD who required ventilation did not report significantly lower physical or mental HRQOL scores than those not requiring ventilation. However, this study used the Short Form-36, which was designed to assess HRQOL in adults rather than in children.

There is less consistency across studies assess psychosocial HRQOL. Four studies reported that there were no significant differences between older and younger boys in psychosocial HRQOL scores, [22, 28–30]. Similarly, Davis et al. reported no significant differences in psychosocial HRQOL scores between children using wheelchairs and those who were not [15]. In contrast, Hendriksen et al. found the psychosocial adjustment score to be positively associated with age in a survey of parents of boys with DMD [20]. As well, Uzark et al. found that boys in the oldest age group reported significantly higher psychosocial scores than boys in younger age groups; this difference was not observed in parent report [17]. Mah et al. found that, based on parent reports, children who require ventilation support had significantly lower physical and psychosocial HRQOL scores than children not requiring ventilation [26].

In a longitudinal study, Simon et al. followed a group of boys with DMD over nine months and found that life satisfaction score improved over time for all age groups [23]. One major limitation of the study was that the questionnaire used, the LSI-A, was designed for adolescents, but the majority of the study sample was under 12 years of age. There was no psychometric evaluation to justify this deviation.

On the PedsQL 3.0 Neuromuscular module, boys who were using wheelchairs full-time and their parents reported lower about My Neuromuscular Disease domain score than part-time wheelchair users and those not using wheelchairs [15]. There were no significant differences in the other domains or the total score. On the PedsQL 3.0 DMD module, boys receiving steroids had significantly higher scores on the Daily Activities domain than boys not receiving steroids by parent-reports; and higher Worry score (less worry) by self-reports. Parents of children in the youngest age group reported them to have significantly higher scores in Daily Activities, Treatment Barriers and Worry domains than the two olderage groups.

Overall, physical HRQOL in children who are at a more severe stage of the disease is worse than children who are at a less severe stage. Less consistent is the relationship between disease severity andpsychosocial HRQOL. Some studies found older children reported better psychosocial HRQOL despite having more severe disease progressions [17, 20], while others reported no significant differences between older and younger children [22, 28–30]. It is worth noting that no conclusions can be drawn regarding a possible causal relationship between disease severity and HRQOL from cross-sectionalstudies.

Correlation with clinical measures

Traditional outcomes used in clinical trials of DMD involve quantitative measures of strength and mobility. With the increasing recognition of the importance of patient-reported outcomes such as HRQOL, some studies have examined the relationship between clinical measures and HRQOL.

The self-reported domains of the KIDSCREEN-52 [17, 20] and the DISABKIDS [31] did not correlate well with clinical measures. The only significant correlations were between the physical domain of the KIDSCREEN-52 and the Vignos scale, a measure of upper body strength; and between emotional domain of the DISABKIDS and the Vignos scale. McDonald et al. [29] found that only the physical domains of the parent-reported PedsQL 4.0 Generic Core and the Pediatric Outcomes Data Collection Instrument (PODCI) significantly correlated with functional measures. Similarly, in two separate studies, Bray and colleagues [21, 22] found that only the physical domains of the CHQ-50 parent report and the physical domain of the self-reported PedsQL 4.0 Generic Core module correlated with the Vignos scale. The 6-minute walk test is a recently adopted outcome measure in clinical trials of DMD (NCT01462292). Henricson et al. [24] found that decline in 6-minute walk test over one year correlated significantly with decline in parent-reported PODCIscore.

Vuillerot et al. [27] examined self-reported well-being of a group of 43 adolescents with various neuromuscular disorders, 19 of whom were DMD patients. They concluded that HRQOL did not correlate with motor function.

Overall, it appears that while the physical domains of some HRQOL measures correlated significantly with commonly used clinical measures, neither the psychosocial domains nor the overall HRQOL scores correlated with clinical end points.

Comparison and agreement between child report and parent report

Parents generally rated their child’s HRQOL lower than children themselves did [15–17, 21, 34], although no statistical comparisons were conducted in these studies. This difference tended to be greater in the psychosocial domains than the physical domain.

Six studies included both child self-reports and parent proxy-reports, and of these, five studies examined concordance between child and parent reports. Parent and child concordance is determined by intraclass correlation coefficient (ICC). For the purposes of this review, an ICC of ≤0.40 is considered poor, of 0.41 to 0.75 is considered moderate, of >0.75 is considered excellent [17].

In studies that used the PedsQL 4.0 Generic Core module [15, 17, 21], only the school domain had moderate concordance, while other domains had poor concordance. Davis et al. [15] found that all subdomains of the English PedsQL 3.0 Neuromuscular have poor parent-child concordance. Hu et al. [16] tested the Chinese version of the same questionnaire and found that for 50 child-parent pairs, the ICC of the overall score and subdomains were moderate. Lim et al. [34] found that by both classical test analysis, which examines scale-level agreement, and Rasch analysis, which examines item-level agreement, there was better concordance between children and parents on the physical scale than psychosocial scale.

Overall, parents tend to rate their child’s HRQOL as worse than children themselves do, and the concordance between parent and child is in the poor to moderate range with the majority of domains and total scores in the poor range. The more observable aspects of a child’s life, such as school function tended to yield higher concordance.

DISCUSSION AND LIMITATIONS OF CURRENT STUDIES

There is heterogeneity across studies in the definition and constructs HRQOL. Some measures focus only on individuals’ feelings about their well-being (PARS-III, LSI-A), while other instruments are closer to measures of health status in that the questions evaluate the extent of a problem has occurred (CHQ and PedsQL questionnaires). Furthermore, it is difficult to compare results across measures that have different domains, particularly if they do not have summary score(s). Fortunately, the most commonly used questionnaires are CHQ and PedsQL, both of which have physical and psychosocial summary scores, making it easier to compare the findings.

Many of the studies used convenience sampling and drew participants from a single clinic. Given the severity of the disease, it is reasonable to assume that almost all boys with DMD are managed at a tertiary-care clinic, thus patients recruited through such clinics are likely to be representative of the DMD population. However, most studies did not report a response rate and it is unclear whether the respondents differ from those who chose not to participate.

Most of the studies had relatively small sample sizes, with 10 of the 18 studies having a sample size of 50 participants or less. When subgroup comparisons were made, the sample sizes became even smaller. Thus the lack of any significant differences across groups could be due to insufficient statistical power. Additionally, of all HRQOL measures, only the PedsQL modules and the PARS-III have been validated specifically in a pediatric DMD population [15, 20]. The reliability and validity of other measures in this population are unknown. Some studies have employed measures designed for adults [33] or adolescents [23] to children, without any psychometric evaluation of their appropriateness in pediatric populations.

In four of the studies [18, 25–27], boys with DMD were part of a sample that included children with other types of neuromuscular disorders, making it hard to elucidate specifically the HRQOL of boys with DMD. Some studies excluded boys younger than 8 years old [15, 31], or boys who have lost ambulation [24, 29]. Finally, not all of the studies assessed HRQOL from both parent and child perspectives, and few studies used disease-specific measures [15-18].

CONCLUSIONS

Based on existing literature, the HRQOL of boys with DMD appears to be significantly poorer than that of their healthy peers, particularly in the physical domain. Within the DMD sample, boys who are at a more severe stage of the disease consistently reported poorer physical HRQOL than boys who are at a less severe stage of the disease; such a difference was not as consistent for psychosocial HRQOL. Similarly, while the physical domains of HRQOL instruments correlated well with clinical measures of functioning, psychosocial domains did not. Finally, the parent and child concordance for most measures of HRQOL was poor.

The PedsQL Inventory has both generic and disease-specific measures, available in multiple languages, with the English versions having been validated in the pediatric DMD populations [15, 17]. Their brevity is advantageous in the clinical and research settings. Many past and current clinical trials in DMD have used PedsQL instruments as outcomes [35]. However, the internal consistency reliability of PedsQL instruments is low to moderate in some domains, and none has reached the level of 0.9 ideal for use at the individual patient level [36]. Furthermore, their responsiveness to important clinical changes has not been established, but this is the case for all other HRQOL measures in the DMD population. Although further psychometric testing, as well as establishing values such as minimally clinically important differences should be carried out, the PedsQL inventory at present, appear to be the most comprehensive and validated measures for clinical and research use in this population. Other multidimensional instruments such as DISABKIDS are available in multiple languages, including English, and are also candidates for clinical use. However, psychometric testing in the DMD population should be performed.

Most of the existing studies have significant limitations that restrict generalizability of the data and comparison of results. Further, the methodological variability in this emerging literature makes it difficult to establish conclusive ideas about sensitivity to change and minimally clinically important differences that will be important for interpreting patient reported outcomes in clinical trials. Longitudinal studies, in large and diverse DMD patient populations, with examination of multiple aspects of HRQOL and disease characteristics, are needed to evaluate HRQOL over time, and to potential determinants of HRQOL.

COMPETING INTEREST

The authors declare that they have no competing interests.

AUTHOR’S CONTRIBUTIONS

This review was adapted from the Master’s thesis of YW, who contributed to the design of the study, extracted the relevant articles and drafted the manuscript. CC and KS were involved in the design of the study, reviewed relevant articles and contributed to the manuscript at all stages.