Characterizing Enrollment in Observational Studies of Duchenne Muscular Dystrophy by Race and Ethnicity

Abstract

Observational research benefits from inclusion of diverse cohorts. To characterize racial and ethnic diversity in observational and natural history research studies of Duchenne muscular dystrophy (DMD), highly cited and influential observational studies were identified. Fourteen United States-based articles were included. All studies cited >70% White participants with the majority having few racial minority participants. Enrollment of Black/African American individuals was particularly limited (<5% in all but one study), and Hispanic/Latino participants ranged from 3.3– 26.5% of cohorts. These results suggest a need for effective strategies to recruit, enroll, and retain racially and ethnically diverse populations into observational research in DMD.

Keywords

Muscular dystrophies Bibliometrics Healthcare Disparities Minority Health Observational Studies

INTRODUCTION

Duchenne muscular dystrophy (DMD) is a life-limiting muscle wasting disorder that leads to progressive skeletal and cardiac muscle weakness [1]. In the last decade, several natural history studies have been conducted in the United States (US) to better characterize disease progression in DMD. Additional studies have sought to characterize quality of life (QOL) and patient/caregiver preferences for potential therapies. The purposes of these observational research efforts are to inform clinical decision making, improve clinical trial design, develop better trial endpoints, understand what is meaningful to patients/caregivers, and quantify the impact of various factors on QOL [2 –4].

In general, observational research studies such as these are at risk of selection bias because certain groups of people are more likely to volunteer to participate than others [5]. For example, people from racial and ethnic minority groups in the US may be less likely to participate in research than White individuals for a number of reasons, including a distrust of medical research and a lack of access to information and resources [6 –8]. Little is known about the racial and ethnic make-up of the US DMD population, nor about the racial and ethnic makeup of individuals with DMD and caregivers who volunteer to participate in research. This problem is significant as a lack of racial and ethnic representation among study participants could lead to inaccurate evaluations of the true natural history of disease progression and erroneous conclusions regarding QOL and patient preference data. Therefore, the aim of this study was to examine the racial and ethnic composition of highly cited, contemporary, US-centric observational studies in DMD.

METHODS

A bibliometric analysis was conducted to identify the most highly cited observational and natural history studies involving individuals with DMD published within the last decade (Jan 2009 – May 2019) [9]. We chose highly cited studies, defined as the ten articles with the highest total citation count, as they are likely the most influential observational studies informing decision-making. Because older articles tend to have higher total citation counts than newer articles, we also examined articles by citations/year. Any additional articles identified as one of the ten with the highest citations/year were included. Harzing’s Publish or Perish software (Windows 4.17.2019 release) was used to query articles from Google Scholar [10]. Search terms included combinations of the words Duchenne, race, ethnicity, Asian, Hispanic, Caucasian, and Black. Final queries were performed on 5/22/2019.

Results from the queries were reviewed by two independent reviewers (authors AMB, SLR) to identify the top ten articles by citations and citations/year. Included articles were required to meet the following criteria: 1) observational or natural history study design in a US-centric DMD population, 2) inclusion of sample size and race/ethnicity classifications, and 3) optional participation. To focus on individuals with DMD, manuscripts surveying caregivers regarding preferences or treatments for their child were included; however, manuscripts detailing caregiver burdens or other caregiver information were excluded. It was decided a priori to include qualifying Cooperative International Neuromuscular Research Group (CINRG) studies. Although this cohort is partly international, the initial cohort was comprised of nearly 150 individuals from the US [4]. Retrospective studies, clinical trials, and interventional trials were excluded. Discrepancies within the final list were discussed and adjudicated by the two reviewers and coauthors.

In addition to studies identified in the search, self-reported racial/ethnic identity were determined for participants enrolled in ImagingDMD, a HIPAA-compliant and IRB-approved natural history study of muscle magnetic resonance imaging biomarkers (NCT01484678). The US Food and Drug Administration (FDA) categories recommended for clinical trial reporting of race (White, Black/African American, Asian, American Indian/Alaska Native, Native Hawaiian/Pacific Islander, and other/not reported) and ethnicity (Hispanic/Latino, not Hispanic/Latino) were utilized to report results [11]. If studies utilized nonstandard categories, the categories of the original article were used with a note describing the deviation. For example, in several cases, Hispanic/Latino ethnicity was grouped with racial category rather than being reported separately.

RESULTS

In addition to ImagingDMD, 13 observational studies in DMD were identified from the search and identified as highly cited due to being in the top 10 most cited manuscripts or the top 10 manuscripts by citations/year, with seven articles overlapping [12 –24]. The manuscripts include seven natural history, three QOL, three patient preference, and one healthcare utilization studies. Sample sizes in the included studies ranged from 22 to 440 participants. Descriptions of all 14 studies are listed in Table 1.

Table 1

Most Highly Cited Observational Studies in DMD that Include Race/Demographics (2009– 2019)

Article	Study Type	Cohort	Study Description and Outcomes
ImagingDMD NCT01484678	NH	Primarily nationally recruited cohort of boys and adolescents with DMD.^a	Natural history study of muscle magnetic resonance biomarkers.
Arias 2011 [12]	SU	Caregivers recruited via neuromuscular clinics in the MD STARnet network and MDA/PPMD announcements.^a	Survey study of palliative care services utilized by individuals with DMD.
Bello 2015 [13]	NH	Cooperative International Neuromuscular Research Group Duchenne Natural History Study cohort.	LTBP4 and SPP1 polymorphisms examined for differences in age at loss of ambulation.
Chung 2015 [14]	QOL	Subset of individuals with DMD or BMD (born between 1986– 1996) followed at Pittsburgh MDA clinics and their parents.	Survey assessments of quality of life and attitudes regarding newborn screening.
Davis 2010 [15]	QOL	Recruited 8– 18 year olds from the Neuromuscular Disease Clinic at Children’s Medical Center of Dallas.	Administered the PedsQL at baseline and 2– 6 weeks later to determine feasibility, reliability, and validity.
Donders 2009 [16]	NH	6– 16 year olds with DMD recruited from a regional neuromuscular clinic and siblings were included if applicable.^a	Administered tests of neuropsychological function and behavior.
Fee 2011 [17]	NH	Individuals with DMD recruited from four MDA clinics and information distributed by MDA.	Administered the Child Behavior Checklist as a proxy for resilience.
Hollin 2015 [18]	PP	Caregivers were recruited through PPMD and DuchenneConnect.	Compared best-worst scaling assessment of benefit and risk preferences for therapies to conjoint analysis of therapy acceptance
Hollin 2017 [19]	PP	Individuals with DMD, BMD, IMD, and caregivers recruited at the annual PPMD conference and through email to Duchenne Registry participants.	Best-worst scaling survey used to assess benefits, risks, and preferences for therapies for pulmonary health.
Mayer 2015 [20]	NH	Individuals with DMD recruited from the neuromuscular clinic at the Children’s Hospital of Philadelphia.	Cross sectional study of pulmonary function in 5– 24 year olds.
McDonald 2018 A [21]	NH	Cooperative International Neuromuscular Research Group Duchenne Natural History Study cohort.	Compared function, survival, and QOL in steroid treated and untreated individuals.
McDonald 2018 B [22]	NH	Cooperative International Neuromuscular Research Group Duchenne Natural History Study cohort.	Assessed pulmonary function over a period of up to 10 years.
Peay 2014 [23]	PP	Caregivers were recruited using social media, newsletters, PPMD emails, and DuchenneConnect.	Best-worst scaling survey used to assess benefit and risk preferences for therapies.
Uzark 2012 [24]	QOL	Recruited 6– 18yos and their parents from the Comprehensive Neuromuscular Care Center at Cincinnati Children’s Hospital and the annual PPMD conference.	PedsQL assessed in 203 families.

^aCompensation for research participation may be one important factor with regards to who chooses to participate in observational studies. Studies identified with an “a” reported compensating $20– 25 for participation. Other studies did not report compensation or specifically stated they did not compensate participants. (NH = natural history, SU = service utilization, MDA = Muscular Dystrophy Association, PPMD = Parent Project Muscular Dystrophy, QOL = quality of life, BMD = Becker muscular dystrophy, PP = patient preference, IMD = intermediate muscular dystrophy)

The racial and ethnic composition of each study is described in Table 2. All study cohorts were comprised of >70% participants who identified as White/Caucasian (herein “White”), with 9/14 studies reporting ≥85% White participants. Black/African American (herein “Black”) participants were minimally represented with all but one study reporting cohorts of <5% (reported ranges: 1.0– 8.3%). The numbers of American Indian/Alaska Native and Native Hawaiian/Pacific Islander participants were reported in 4/15 studies and were <4% in all cases. Hispanic/Latino (herein “Latino”) ethnicity was reported in 9/14 articles, and representation was highly variable, with reported ranges of 3.3– 26.5% of cohorts.

Table 2

Racial and Ethnic Composition of Highly Cited Observational Studies in DMD

Article	Study size (N)	White	Black/African American	American Indian or Alaska Native	Asian (including South Asian)	Native Hawaiian or Pacific Islander	Other/Unknown	Hispanic/Latino
ImagingDMD	182	164	3	2	10	1	2/0	17
NCT01484678	90.1%	1.6%	1.1%	5.5%	0.5%	1.1/0%	9.3%
Arias	34	25	–	–	–	–	–	9^a
2011 [12]	73.5%	26.5%
Bello	340	248	6	–	55	–	13/0	41^a
2015 [13]	72.9%	1.8%	16.2%	3.8/0%	12.1%
Chung	40^b	37	–	–	3	–	^–	–
2015 [14]	92.5%	7.5%
Davis	44	37	2	–	–	–	2/3	7
2010 [15]	84.1%	4.5%	4.5/6.8%	15.9%
Donders	22^c	21	–	–	–	–	–	–
2009 [16]	95%
Fee	165^d	–	–	–	–	–	–	– ^a
2011 [17]	89%	4%	3%	4%
Hollin	119	109	–	–	–	–	–	–
2015 [18]	91.6%
Hollin	133^e	119	6	5	3	–	2/0	10
2017 [19]	89.5%	4.5%	3.8%	2.2%	1.5/0%	7.5%
Mayer	60	51	5	–	2	–	–	2^a
2015 [20]	85.0%	8.3%	3.3%	3.3%
McDonald	440	315	6	–	77	3	29/10	51
2018 A [21]	71.6%	1.4%	17.5%	0.7%	6.6/2.3%	11.6%
McDonald	397	285	6	–	69	3	28/6	50
2018 B [22]	71.8%	1.5%	17.4%	0.8%	7.1/1.5%	12.6%
Peay	119	109	–	–	–	–	–	–
2014 [23]	91.6%
Uzark	203^f	183	2	–	3	–	8/7	–
2012 [24]	90.1%	1.0%	1.5%	3.9/3.4%

Percents may not sum to 100 due to rounding. ^aEthnicity was reported in combination with race, rather than as a separate category. ^bn = 15 individuals with dystrophinopathy (DMD = 14, BMD = 1) and n = 25 parents (DMD = 22, BMD = 3). ^cIn addition to the 22 individuals with DMD, the study included 18 unaffected siblings (94% White). ^dOnly percentages were reported, precluding reporting of exact sample sizes. ^eParticipants were allowed to choose more than one racial category; thus, numbers do not sum to 133 and percentages do not sum to 100%. N = 51 participants with dystrophinopathy (DMD = 42, BMD = 9). N = 82 caregivers (DMD = 72, BMD = 8, intermediate muscular dystrophy = 2). ^fN = 117 individuals with DMD, and N = 200 parents, representing 203 families. Results describe family units. Asian and Pacific Islander categories grouped by author.

DISCUSSION

The primary purpose of this study was to examine the US racial and ethnic composition of observational DMD studies deemed influential to the field. We found the majority of studies were comprised of participants who identified as White with limited participation of all other racial and ethnic groups. Census data from 2010 revealed that 72% of the US population identifies as White, 13% as Black, 5% as Asian, and 16% as Latino; however, the prevalence of DMD has been estimated to be lower in Black individuals and higher in Latino individuals compared to White individuals [25, 26]. The MD STARnet surveillance studies of Duchenne/Becker muscular dystrophy have found that within the surveillance network, 7.5% of individuals with DMD identified as Black, and 20.5% of individuals identified as Latino [26]. Although these percentages cannot be assumed to be representative of the entire US population with DMD, in our review of highly cited observational literature, only one of the 14 studies had >7.5% Black participants, and only one had >20.5% Latino participants, indicating the potential for underrepresentation in nearly all studies.

The importance of racial diversity in medical research has been well recognized [27]. For natural history studies in DMD specifically, surveillance data demonstrates that racial disparities and differences exist, warranting inclusion of diverse cohorts in observational studies. For example, Black and Latino individuals are first evaluated in the diagnostic process nearly one year after White individuals, and age at DNA testing is nearly two years older [28]. This finding was recently corroborated by a Duchenne Registry study in which White individuals were diagnosed nearly 9 months earlier than individuals of other racial and ethnic backgrounds [29]. Black and Latino individuals are also less likely to be treated with corticosteroids than individuals who are White, and Black individuals with DMD initiate steroid treatment at an older age [30]. In a study in South Carolina, Black individuals with muscular dystrophy had lower overall health care utilization even when controlling for socioeconomic status [31]. Finally, racial and ethnic differences in milestone events such as age at loss of ambulation, development of cardiomyopathy or heart failure, and death are well-described [13, 32].

Genetic differences could also affect the natural history of disease. Polymorphisms in SPP1 and LTBP4, which have been linked to older age at loss of ambulation, occur with different frequencies in individuals of diverse racial or ethnic backgrounds, and within the CINRG cohort, the modifying effects of LTBP4 could only be validated in a Caucasian subgroup analysis [13 , 34]. For QOL and patient preference studies, it is possible that cultural and/or socioeconomic differences lead to differences between racial/ethnic groups. A recent needs assessment of the MD STARnet cohort demonstrated differences in needs and unmet needs between minority and non-minority caregivers of individuals with DMD [35]. Without specific efforts to include racial and ethnic minority populations in observational trials, it appears unlikely the true natural history of the disease is being appropriately captured in these groups.

The limited diversity found in observational studies is likely recapitulated in clinical trials. US trials of edasolonexent and eteplirsen had 100% and 98.6% White cohorts, respectively [36, 37]. Similarly, phase three international trials of ataluren and idebenone, which presented results to the US FDA, had <1% Black and 1.5% Latino participants, respectively [38, 39]. Natural history data from another international ataluren trial has been utilized extensively in clinical trial planning and natural history comparisons in the US and informed the top two most cited articles in our search, but these studies had <2% Black and <3% Latino participants [40, 41]. It can be argued that inclusion of more diverse cohorts into clinical trials may increase outcomes heterogeneity and reduce the ability to detect treatment effects. While this may be true, reducing racial disparities in standards of care and developing novel solutions to address cohort heterogeneity are more sustainable options than exclusion of potential participants. When clinical trials lack racial diversity, the investigational therapeutic is not being evaluated in a cohort that is representative of the entire population. In life-limiting disorders such as DMD, reduced minority participation in clinical trials may unintentionally limit minority access to novel therapeutics.

We do not underestimate the herculean efforts required to recruit large samples in any of the cited studies. We also recognize the challenges of recruiting diverse populations into observational studies in rare diseases such as DMD. Our hope is that this evidence of reduced participation from minority groups will lead to further discussion among academics, healthcare providers, advocacy organizations, the DMD community, and clinical trial sponsors regarding inclusion, participation, and retention of representative cohorts. Cues can be taken from successful efforts in other populations to improve cohort diversity [42 –45]. For example, investigators attempting to increase Black and Latino participation in registries and intervention studies for other pediatric conditions have found that making participation desirable or even possible required more than merely inviting families or translating materials into Spanish. Some strategies that may need to be examined in DMD research include partnering with community organizations, utilizing participant navigators, understanding the impact of cultural differences and information access, examining how inclusion criteria or data collection tools may disqualify particular cultures or family structures, and considering what forms of compensation are necessary to enable participation in research (e.g., transportation, childcare). In investigational studies, obtaining better representation from diverse individuals leads to the best chances of maximizing impact on the entire DMD community.

CONFLICTS OF INTEREST

Dr. Alison M Barnard has no conflicts of interest to report.

Mr. Samuel L Riehl has no conflicts of interest to report.

Dr. Rebecca J Willcocks has no conflicts of interest to report.

Dr. Glenn A Walter receives grant support from the NIH for R01 AR056973. Dr Walter has also received funding from Sarepta Therapeutics, Italfarmaco SPA, and Catabasis Pharmaceuticals through grant awards to the University of Florida unrelated to this study.

Dr. Amber M Angell has no conflicts of interest to report.

Dr. Krista Vandenborne receives grant support from the NIH for R01 AR056973. Dr. Vandenborne has also received funding from Sarepta Therapeutics, ltalfarmaco SPA, Summit Therapeutics, Catabasis Pharmaceuticals, Pfizer Inc., ldera Pharmaceuticals, BMS, and Eli Lilly through grant awards to the University of Florida unrelated to this study.

Footnotes

ACKNOWLEDGMENTS

NCT01484678 (ImagingDMD) is supported by NIH grant R01 AR056973 (NIAMS). Dr. Barnard is supported in part by NIH grant U54 AR052646 (NIAMS), and Dr. Angell is supported by K12 HD055929 (NICHD). We appreciate the thoughtful feedback from John A. Barnard, MD.

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