Newborn screening for Duchenne muscular dystrophy: the perspectives of stakeholders

Summary

Background

The rapidly evolving clinical landscape of Duchenne muscular dystrophy (DMD) is driving innovative approaches for early diagnosis through genomic newborn bloodspot screening (NBS). However, the potential impact of these programs on families and healthcare systems remains unexplored. This study assessed the perceived benefits, harms, barriers, and enablers for DMD NBS amongst primary caregivers of children with DMD and healthcare professionals (HCPs).

Methods

This Australian multi-centre cross-sectional study used a mixed-methods convergent methodology. Participants completed a codeveloped questionnaire and their perceptions on the utility, model of care, and processes of DMD NBS were thematically analysed.

Findings

Participants included 50 caregivers and 26 HCPs (68.5% and 53.1% response rate respectively). Most caregivers (40/50, 80%) perceived net benefits of DMD NBS and highlighted an early diagnosis as actionable knowledge, even with the current paucity of disease modifying therapies. This knowledge was valued to enable access to multidisciplinary supportive care (29/50, 58%), clinical trials (27/50, 54%), psychological support (28/50, 56%), inform reproductive planning (27/50, 54%), and facilitate financial planning based on the future needs of their child (27/50, 54%). Whilst HCPs acknowledged these opportunities, only 16/26 (61.5%) believed there were definite net benefits, with notable concerns over the psychological harms of diagnostic knowledge without a recourse to disease modifying therapeutic intervention early in life.

Interpretation

Caregivers and HCPs perceived a range of potential benefits of DMD NBS. Health system readiness will be founded on developing an integrated model of care that not only supports the psychosocial and information needs of families receiving a newborn diagnosis of DMD, but also provides care and clinical surveillance for individuals for whom a diagnosis may remain uncertain.

Funding

Medical Research Futures fund (GNT2017165, MRF2015965).

Research in context.

Evidence before this study

A literature search was performed to identify original research exploring the perspectives of parents and/or healthcare professionals (HCPs) on newborn bloodspot screening (NBS) for Duchenne muscular dystrophy (DMD) in the genomic era, which is driving changes in medical practice. A search in PubMed from January 1, 2010, to February 14, 2023, using search terms “newborn screening” AND “Duchenne” AND/OR “perspectives” AND/OR “experiences” AND/OR “attitudes” AND/OR “stakeholders” identified only three such studies engaging a total of 157 stakeholders, all conducted within the United States of America (exploring parent perspectives [n = 2], exploring HCP perspectives [n = 1]). While these few studies show stakeholders generally support DMD NBS, none have evaluated perceptions on how NBS services for DMD should be sustainably delivered to a whole population at high quality and requirements for health system readiness.

Added value of this study

Our Australian multi-centre mixed-methods study uniquely found that despite the current lack of approved disease-modifying therapies for children with DMD, caregivers still valued receiving a newborn diagnosis facilitated by NBS. Perceived benefits to the newborn included enabling access to earlier monitoring and multidisciplinary supportive care, and early intervention for children at risk for learning and behavioural problems, planning of future resource needs and the ability to engage in clinical research. Caregivers also recognised secondary benefits for the family unit including enabling reproductive planning, financial planning and access to psychological support. Australian HCPs perceived substantial risks of providing a newborn diagnosis through NBS, mitigated by actioning an integrated model of care to directly address the psychosocial and information needs of families. Adequate health infrastructure and equitable access to clinical expertise and genetic counselling were emphasised in the development and implementation of population screening programmes.

Implications of all the available evidence

The suitability of implementing NBS for DMD has been a subject of ongoing debate, with complex considerations surrounding perceptions of “net benefit.” Traditional screening principles adhere to benefits to the newborn and place emphasis on the need for treatment for conditions to be considered on routine NBS panels. This study informs the need for a potentially broader and modernised framework on which to evaluate net benefits to the child, including the positive consequences of an early diagnosis in allowing monitoring and tailored early interventions, access to support, education and research for children and families and reducing the burden of extraneous diagnostic investigations and interventions. Whilst the hypothetical harms of receiving an early diagnosis need consideration, evidence based mitigating strategies may be deployed to optimise the benefit–risk profile of NBS for DMD.

Introduction

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy with a global incidence of 19.8 per 100,000 live male births.¹ DMD is caused by pathogenic variants in the X-linked dystrophin gene, where absent or dysfunctional dystrophin protein results in deterioration of skeletal muscle tissue and function. This typically leads to wheelchair dependency by 12 years of age and death at a median age of 30 years.^2,3 Currently in Australia, initiation of glucocorticoids (from around four to six years of age, where motor function generally plateaus)⁴ remains the only disease modifying therapy widely available to individuals with DMD. Although not a curative treatment, glucocorticoids slow disease progression with established long-term benefits including delayed loss of ambulation, preserved upper limb and pulmonary function, and reduced risk of scoliosis.⁵

The term “diagnostic odyssey” is often used to describe the lengthy and complex diagnostic journey that individuals with rare disease often face, typically involving multiple interactions with the health system, inconclusive results, misdiagnosis, and diagnostic delay.⁶ For boys with DMD, diagnostic delays have remained unchanged over the past three decades,⁷ with late diagnosis persistently noted in ethnic minority groups.⁸ For many children, this results in missed opportunities for implementation of standards of care, participation in clinical trials, and access to newly approved dystrophin restoration therapies. Likewise, families lose opportunities for timely genetic counselling and testing. Such limitations of current diagnostic models are driving evaluations of new initiatives such as newborn bloodspot screening (NBS) for DMD to enable equitable and timely diagnoses.⁷

NBS is a public health program which aims to detect infants with serious health conditions shortly after birth to enable timely intervention, and improvement of health outcomes.⁹ Recognising the importance of a timely diagnosis, 15 centres around the world have implemented pilot DMD NBS programs, most utilising biochemical screening methods. Since 1975, more than two million neonates have been screened across these programs with 363 individuals confirmed to have DMD (Supplementary Information: Appendix A). Despite this, there has been limited progress in incorporating DMD into routine NBS panels due to concerns about high false positive rates, the lack of therapeutic interventions initiated early in life, and psychological implications for families of establishing the diagnosis in a pre-symptomatic infant.¹⁰

However, the genomic era has given rise to a new and evolving landscape for therapeutics and diagnostics relevant to DMD, in which prior concerns surrounding its inclusion in NBS should be re-evaluated. Outside of Australia, five agents aimed at dystrophin restoration (ataluren, eteplirsen, golodirsen, viltolarsen and casimersen) have received regulatory approval for use in individuals with specific DMD variants, with ongoing studies investigating their patient-centred value.¹¹ Additionally, in June 2023, the Food and Drug Administration (FDA) granted accelerated approval of delandistrogene moxeparvovec-rokl gene therapy (enhancing production of micro-dystrophin) for the treatment of ambulatory patients with DMD aged four to five years, with hope that benefits observed may facilitate expansion of treatment eligibility to younger age groups.¹² With the prospect of disease modifying agents being initiated in the first months to years of life for children with DMD, there is an urgent need to develop new diagnostic paradigms involving NBS so that children have equitable access to diagnosis and potentially life-altering medical interventions once available. Furthermore, new screening methods have been proposed, utilising next-generation sequencing of the dystrophin gene following an elevated result on a first-tier biochemical test for the muscle isoform of creatine kinase (CK-MM).¹⁰ The use of second-tier genomic testing is anticipated to reduce high false positive rates associated with traditional biochemical screening methods which caused unwarranted psychological distress and necessitated extensive follow up.¹³

Despite these advances in therapeutic and screening technologies, the question remains whether the benefits of screening for DMD in the newborn period outweighs the potentials for harm and how this will impact existing high public confidence in NBS programs. However, there are limited studies which explore the perspectives of families directly affected by a DMD diagnosis in the era of genomic technologies,¹⁴ coupled with a paucity of information on how NBS services for DMD should be delivered, and requirements for health system readiness. Thus, there is need for a contemporary evaluation of the perspectives on DMD NBS among key stakeholders including parents, as participants in the program, and healthcare professionals (HCPs) who play an integral role in shaping and delivering effective healthcare services.

Accordingly, the objectives of our study were to explore perceived benefits, risks, barriers, and enablers for implementing NBS for DMD among key stakeholders (HCPs and primary caregivers of children with DMD) and elicit perspectives on relevant workflow issues such as consent, timing and method of delivering screening results, and expectations about supports that should be offered.

As the first study to comprehensively assess both perspectives and workflow preferences of these key stakeholders in the genomic era, we anticipate that our findings will be important to: (i) gain insight into the needs of affected families, (ii) inform a model of care which benefits individuals and families in a manner that is consistent with their expectations and values, and (iii) optimise clinical translation of genomic technologies and NBS services for DMD and other medically actionable conditions.

Methods

A convergent parallel mixed-methods design, where quantitative and qualitative data was collected concurrently, was used for this multi-centre cross-sectional study. This approach was utilised to provide further depth and understanding of perspectives as well as develop novel lines of enquiry to inform future health policy and practice.¹⁵ This methodology has been similarly and successfully used to explore parent and HCP perspectives on NBS for spinal muscular atrophy (SMA).¹⁶

Participants and recruitment

Primary caregivers of children aged <18 years with genetically confirmed DMD were invited to partake in the study. Participants were identified through Sydney Children's Hospitals Network (SCHN) neuromuscular and neurogenetics outpatient clinics at Sydney Children's Hospital, Randwick and The Children's Hospital at Westmead. The SCHN is the largest paediatric health entity in Australia and provides care for over 120,000 families each year.¹⁷ Exclusion criteria for the study included caregivers deemed likely by the treating HCP to experience significant emotional distress whilst participating in the study and caregivers of children who had been living with a diagnosis of DMD for less than two months. This two-month timeframe was chosen to accommodate for the potential for acute stress reactions following a diagnosis, typically observed within four weeks of a traumatic event.¹⁸ This timeframe also aimed to facilitate psychological adjustment to the diagnosis, mitigating potential cognitive bias and ensuring that caregivers were in a psychological state conducive to providing informed consent to participate in the study. Non-English speakers received assistance from face-to-face or phone interpreters.

All known HCPs, comprising clinicians and allied health professionals involved in NBS or in the diagnosis and/or management of individuals with DMD within SCHN specialist neuromuscular teams were also invited to participate in the study. HCPs were recruited via SCHN investigator networks. Clinicians invited to participate included neurologists, geneticists, nurses, and scientists in NBS and diagnostic laboratories. Allied health professionals included physiotherapists, occupational therapists, social workers, and genetic counsellors.

Participant recruitment methodology is detailed in Fig. 1. The study was approved by the SCHN Human Research Ethics Committee (2022/ETH02196).

Fig. 1.

Participant recruitment and data collection methodology.^a Eligible caregivers were identified at neuromuscular clinics. Exclusion criteria included caregivers of children who had been living with a diagnosis of Duchenne muscular dystrophy (DMD) for less than two months and caregivers likely to experience emotional distress whilst participating in the study. ^b Eligible healthcare professionals (HCPs) were identified through Sydney Children's Hospitals Network (SCHN) investigator networks. ^c Contact details were obtained from the caregiver in attendance. Abbreviations: DMD; Duchenne muscular dystrophy, HCPs; healthcare professionals, NBS; newborn bloodspot screening, SCHN; Sydney Children's Hospital Network.

Data collection

Separate questionnaires were completed by caregivers (Supplementary Information: Appendix B) and HCPs (Supplementary Information: Appendix C), both codeveloped by experts knowledgeable in DMD and NBS practices. These questionnaires included a series of validated and study specific measures informed by previous studies¹⁶ which were pilot tested with four clinicans within this current study.

Caregivers

Data collection from caregivers occurred between February 17, 2023, and October 20, 2023. Depending on participant preferences, questionnaires were completed either face-to-face or over the phone. All survey responses were then manually added to the electronic study database, hosted by Qualtrics XM.

The first section of the questionnaire assessed caregiver demographics (age, gender, ethnicity, education, employment, and income). Health-related quality of life was assessed using the EQ-5D-5L, which includes a descriptive system questionnaire and a visual analogue scale (EQ VAS). The descriptive system comprises five dimensions; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.¹⁹ Using the Australian EQ-5D-5L value set,²⁰ utility weights were applied to each of the five levels in each dimension to convert EQ-5D-5L health states for each individual to a single index score. These index scores were reported on a scale from zero (death) to one (perfect health). The EQ VAS provides a quantitative measure of overall health perception on a scale from zero (worst health imaginable) to 100 (best health imaginable).¹⁹

Another section explored the method and timing of their child's diagnosis, other comorbidities, current level of mobility, and management options accessed. Caregiver perspectives on potential enablers of improved outcomes (early diagnosis, earlier and wider access to clinical trials/treatments, improved education, and greater financial support) were assessed using a five-point Likert scale ranging from one (strongly disagree) to five (strongly agree).

The last section explored caregiver perspectives on a proposed model of NBS for DMD involving measurement of CK-MM, and for those with elevated levels (CK-MM ≥ 1000 ng/mL), comprehensive sequencing of the dystrophin gene. Customised multiple-choice questions were used to assess acceptability and explore expectations for the screening pathway including (i) the consenting process, (ii) timing of screening, (iii) timing and method of delivering screening results (including HCPs involved), and (iv) locations for clinical evaluation and diagnostic testing. Caregivers provided their opinions on perceived risks and benefits through free response questions. Caregiver expectations regarding false negative and false positives results, as well as supports that should be offered were also examined. Furthermore, a five-point Likert scale ranging from one (strongly disagree) to five (strongly agree) was utilised to gather perspectives on the specific populations that should be identified by muscular dystrophy NBS.

Healthcare professionals

Data collection from HCPs occurred between April 27, 2023, and June 5, 2023. Consenting HCPs were provided with an anonymous link to the Qualtrics XM data collection portal, where the questionnaire was self-administered. The HCP questionnaire comprised of two sections.

The first section of the questionnaire assessed HCP demographics including profession and experience in NBS and/or in the diagnosis or management of children with DMD. To triangulate caregiver and HCP responses, the second section, exploring HCP perspectives and expectations for NBS for DMD, utilised the same questions as in the last section of the caregiver questionnaire. However, the HCP questionnaire delved deeper into the challenge posed by the lack of early-life therapies for DMD and its impact on the acceptability of NBS for DMD. This was explored using a range of customised multiple choice, visual analogue scales (scoring from zero to 100) and free response questions.

Data analysis

Quantitative and demographic data were analysed using descriptive statistics and graphs in IBM SPSS version 27 and Microsoft Excel. For analysis, five-point Likert scales were regrouped into three categories as in other studies¹⁶: ‘disagree’ (strongly disagree and disagree), ‘neutral’ and ‘agree’ (strongly agree and agree). Frequencies and percentages were reported for categorical variables while continuous variables were summarised using medians, interquartile ranges (IQRs) and ranges. Pearson's chi squared test for categorical variables, reported as χ², was used to explore differences in perspectives between caregivers and HCPs. In instances where expected cell count was less than five in more than 20% of cells, Fisher's exact test (for 2 × 2) or the Fisher-Freeman-Halton exact test (for 2 × 3) were used. An exploratory probability-value (P) less than 0.05 was taken as significant.

Qualitative and quantitative results were merged such that quantitative data were linked with qualitative themes. Qualitative data from field notes and open field responses to survey questions were thematically analysed using the conceptual framework by Miles et al.²¹ Researchers CJ, MAF and DSK independently familiarised themselves with qualitative responses, noting salient themes. Researchers then collaboratively established a set of major themes and developed a coding tree. Open-ended responses were transcribed and coded within NVivo 14 for qualitative analysis, during which the coding tree was iteratively refined until consensus was reached among all researchers.

Results

Demographics

Primary caregivers and children

Of 73 eligible primary caregivers who were invited to participate in the study, 50 caregivers from 38 families of 40 boys with DMD consented to and completed the survey (68.5% response rate, 38/73 [52.1%] of all families living with DMD attending SCHN clinics). Of this cohort, 38/50 (76.0%) caregivers completed a face-to-face survey and 12/50 (24.0%) completed a telephone survey. Children of the study population had a median age of nine (IQR 6.0–13.0) years and had been living with a diagnosis of DMD for a median duration of 5.3 years (IQR 2.0–9.0) (Table 1). Of the 38 families, 12 had two primary caregivers complete the survey. Most primary caregivers surveyed were mothers (28/50, 56.0%), with 21 (42.0%) fathers and one (2.0%) grandmother participating. Caregivers were from diverse sociocultural backgrounds (Table 2).

Table 1.

Characteristics of children as reported by their primary caregiver(s).

Characteristics of children	n = 40
Age (years), median (IQR) range	9 (6–13) 3–17
Gender, n(%)
Male	40 (100)
Female	0 (0)
Age of diagnosis (years), median (IQR) range	4 (2–5) 0.1–8.0
aAge at development of first signs/symptoms (years), median (IQR) range	2.5 (1.5–4.0) 0–6
Time living with a diagnosis of DMD (years), median (IQR) range	5.3 (2.0–9.0) 0.17–13.5
aTime from perceived symptom onset to diagnosis (years), median (IQR) range	0.5 (0.0–1.8) 0–5
Method of diagnosis, n(%)
Clinical signs and symptoms	25 (62.5)
Incidental diagnosis	12 (30.0)
Family history of DMD leading to cascade screening and identification of affected child	2 (5.0)
Prenatal carrier screening (based on a sibling diagnosis)	1 (2.5)
Types of management accessed, n(%)
Multidisciplinary supportive care	40 (100.0)
Steroid initiation	31 (77.5)
Clinical trials	10 (25.0)
Other medical conditions, n(%)
bYes	13 (32.5)
No	27 (67.5)
Current mobility, n(%)
Can walk independently in all settings	5 (12.5)
Can walk independently in most settings	20 (50.0)
Non-ambulant	15 (37.5)

Abbreviations: n; number, IQR; interquartile range, DMD; Duchenne muscular dystrophy.

^aMissing for three children where caregiver(s) were uncertain of when signs/symptoms began.

^bOther medical conditions included neurobehavioral disorders (n = 9: anxiety, attention deficit hyperactivity disorder, autism spectrum disorder, oppositional defiant disorder), respiratory (n = 2) and gastrointestinal conditions (n = 1).

Table 2.

Characteristics of primary caregivers.

Characteristics of primary caregivers	n = 50
Age (years), median (IQR) range	40.5 (35.0–43.3) 25–58
Gender, n (%)
Male	21 (42.0)
Female	29 (58.0)
Number of children, median (IQR) range	2 (2–3) 1–7
Number of children with DMD, n (%)
One	48 (96.0)
Two	2 (4.0)
Highest level of education completed, n (%)
Year 10 or below	7 (14.0)
Year 12	10 (20.0)
Apprenticeship	3 (6.0)
Certificate/diploma	14 (28.0)
Bachelor's degree	9 (18.0)
Postgraduate degree	7 (14.0)
Employment, n (%)
Employed	35 (70.0)
Unemployed	15 (30.0)
Cultural background, n (%)
Australian or New Zealander	26 (52.0)
Southern and Central Asian	11 (22.0)
South-East Asian	1 (2.0)
North African and Middle Eastern	2 (4.0)
Sub-Saharan African	1 (2.0)
North-West European	6 (12.0)
Southern and Eastern European	3 (6.0)
First language, n (%)
English	38 (76.0)
Non-English language	12 (24.0)
Household income, n (%)
Nil income	3 (6.0)
Less than $29,999	2 (4.0)
$30,000–$59,000	7 (14.0)
$60,000–$89,000	11 (22.0)
$90,000–$119,000	7 (14.0)
Greater than $120,000	16 (32.0)
Prefer not to answer	4 (8.0)
Insurance, n (%)
None (Medicare only)	27 (54.0)
Private health fund	22 (44.0)
Life insurance	7 (14.0)

Abbreviations: n; number, IQR; interquartile range.

Healthcare professionals

A total of 49 eligible HCPs were invited to participate in the study and 26 responses were received (53.1% response rate). Among respondents, 15/26 (57.7%) were clinicians and 11/26 (42.3%) were allied health professionals, with a median career duration of 8.5 (IQR 2.9–15.5) years (Table 3). All HCPs reported having experience in diagnosing and/or managing children with DMD. The majority (18/26, 69.2%) had experience in NBS practices, particularly for SMA, with some (7/26, 14.3%) reporting experience in NBS practices for cystic fibrosis and other metabolic disorders.

Table 3.

Characteristics of healthcare professionals.

Characteristics of healthcare professionals	n = 26
Profession, n (%)
Clinician	15 (57.7)
Paediatric neurologist	6 (23.1)
Paediatric neurology fellow	1 (3.8)
Geneticist	3 (11.5)
Nurse	5 (19.2)
Allied health professional	11 (42.3)
Physiotherapist	3 (11.5)
Occupational therapist	3 (11.5)
Genetic counsellor	4 (15.4)
Social worker	1 (3.8)
Experience in designated profession (years), median (IQR) range	8.5 (2.9–15.5) 1 to 30
Experience in the following areas, n (%)
Diagnosis/management of children with DMD and NBS	18 (69.2)
Diagnosis/management of children with DMD only	8 (30.8)

Abbreviations: n; number, IQR; interquartile range, DMD; Duchenne muscular dystrophy, NBS; newborn bloodspot screening.

Caregiver reported health-related quality of life

The median caregiver EQ-5D-5L index score was 0.945 (IQR 0.920–1.000) and few caregivers reported any problems with mobility (4/50, 8.0%), personal care (1/50, 2.0%) or usual activities (4/50, 8.0%). However, almost half (24/50, 48.0%) reported chronic pain and a majority indicated some level of anxiety or depression (31/50, 62.0%) (Supplementary Information: Appendix D). Median caregiver EQ VAS was 75 (IQR 63.8–85.0).

Newborn screening for Duchenne muscular dystrophy: acceptability, perceived benefits and risks, barriers and enablers

Caregiver perspectives

Most (40/50, 80.0%) caregivers believed that receiving their child's diagnosis of DMD in the newborn period would be beneficial and indicated their preference for DMD NBS if it were available. Caregivers who expressed a preference for early diagnosis through NBS for DMD described the potential clinical utility (value in informing patient management and care) and personal utility (other nonclinical benefits) of a newborn diagnosis (Fig. 2). Qualitative results affirmed quantitative survey responses, with the major theme of personal utility including subthemes of eliminating the diagnostic odyssey and particularly enabling forward planning emerging strongly (Table 4). One caregiver admitted:

“If I had known … I wouldn’t have had a second child” (C25)

Fig. 2.

Main perceived benefits and risks influencing caregiver preference regarding newborn screening for Duchenne muscular dystrophy. Data was collected from 50 primary caregivers. The x-axis represents the percentage of caregivers indicating each item as main reason(s) for their preference. Abbreviations: NBS; newborn bloodspot screening, DMD; Duchenne muscular dystrophy.

Table 4.

Caregiver and healthcare professional perspectives on the utility of newborn screening for Duchenne muscular dystrophy, with illustrative quotes.

Theme	Subtheme	Illustrative quotes
Clinical utility	Early intervention when needed and facilitating timely initiation of therapies	An earlier diagnosis may make it easier to engage in therapies … and present to doctor/clinic earlier for more timely multidisciplinary care (HCP19, occupational therapist) Early intervention such as stretching and baby yoga may be beneficial for the muscles (C37, mother of a six-year-old boy with DMD)
	Access to research opportunities	Early diagnosis would enable promotion of clinical trial readiness and attracting high impact trials in patient groups (HCP24, paediatric neurologist) [Child's name] was diagnosed at five years old which meant we missed out on the exon skipping trial for four to five-year-old boys (C38, father of a six-year-old boy with DMD)
	Earlier access to support services	Early diagnosis means you are able to … access supports and gain information to help care for the child better at an earlier point in time (C34, father of an eight-year-old boy with DMD)
	Uncertainty	Administration of gene therapy in the two to four window …. is likely to be better but honestly we don't know this nor do we know the durability of the treatment (HCP25, paediatric neurologist)
Personal utility	Enabling forward planning	Having to learn how to care for a child with DMD all of a sudden was really difficult ….By the time we accessed NDIS funding we had already spent so much money on speech pathology and other allied health (C11, father of an eight-year-old boy with DMD) An early diagnosis will allow couples to make informed reproductive choices and access health care in line with their personal wishes and values (HCP17, paediatric neurologist)
	Eliminating the diagnostic odyssey	We went to over 10 different doctors to figure out what was wrong before he was finally diagnosed. It was a very emotional and frustrating time. An earlier diagnosis would give us peace of mind (C9, mother of a seven-year-old boy with DMD)
	Harm in knowing	My youngest boy was diagnosed with DMD at six months. I felt like it robbed me of the joy of having a newborn child (C25, mother of one six-year-old and one eight-year-old boy with DMD) Trauma and grief of a devastating diagnosis at a time when they should be bonding with their baby … for parents with pre-existing mental health issues, this may escalate their problems (HCP4, occupational therapist)
	No value of knowing	Personally, an earlier diagnosis in the newborn period would only be stressful and provide no benefits as there is nothing available to change the outcome of the disease (C20, father of 13-year-old boy with DMD) For the child themselves, there would seem to be little benefit in the newborn period … the lack of treatment is an issue (HCP12, genetic counsellor)

Data was collected from 50 primary caregivers and 26 healthcare professionals.

Abbreviations: DMD; Duchenne muscular dystrophy, HCP; healthcare professional, C; caregiver.

While many caregivers also commented on the clinical utility of a newborn diagnosis including early intervention when needed and facilitating timely initiation of therapies, access to research opportunities and support services (Table 4), two caregivers perceived no clinical utility in the context of Australia's current therapeutic landscape:

“there is nothing available to change the outcome of the disease” (C20)

In caregivers who indicated that they would not have wanted to receive a diagnosis in the newborn period (10/50, 20.0%), some disagreed with screening for DMD at any stage of life (4/50, 8.0%) while others supported screening after the newborn period (6/50, 12.0%). Caregivers who did not prefer NBS for DMD perceived psychological distress and impact on parent-child bonding as prominent risks (Fig. 2), with several caregivers (9/50, 18.0%) describing these potential harms of knowing (Table 4):

“… living in constant stress and fear about when symptoms will begin and worrying about the future” (C20)

Healthcare professional perspectives

Considering the proposed two-tiered screening approach for screen positive newborns within the context of the current therapeutic landscape, the proportion of HCPs perceiving net benefits of NBS for DMD (16/26, 61.5%) was significantly lower than for caregivers (40/50, 80.0%) (Fisher's Freeman-Halton exact test P < 0.001). Some (9/26, 34.6%) HCPs were uncertain and 1/26 (3.8%) believed that benefits would not outweigh risks.

Aligning with caregiver responses, benefits including enabling forward planning, particularly the opportunity to optimise reproductive choice, in addition to early intervention when needed and facilitating timely administration of therapies emerged consistently as predominant subthemes in HCP responses. However, compared to caregivers (9/50, 18.0%), a greater proportion of HCPs (20/26, 76.9%) expressed concerns about the potential harm in knowing (Table 4). While the use of second-tier genomics was anticipated to reduce false positive results, 3/26 (11.5%) HCPs acknowledged the potential harms of false positive or false negative screening results and emphasised the need for an accurate test and appropriate consent processes to ameliorate this psychological burden (Table 5). The median acceptable false positive rate perceived by HCPs was 1.5% (IQR 0.3%–4.8%) and 1.0% (IQR 0.1%–5.0%) for false negatives.

Table 5.

Caregiver and healthcare professional perceived barriers and enablers of newborn screening for Duchenne muscular dystrophy, with illustrative quotes.

Theme	Illustrative quotes
Infrastructure for diagnosis and management	NBS for DMD is a considerable undertaking. All screen positive children will require diagnostic confirmation and families will require cascade genetic testing and counselling. This may overwhelm finite resources within the healthcare system and requires workforce planning to ensure that this model is integrated into clinical service feasibly and sustainably (HCP15, paediatric neurologist)
Test performance	A false positive would cause unwarranted distress and be mentally and emotionally exhausting (C32, mother of a 12-year-old boy with DMD) Risk of misdiagnosis, although this would low with second-tier genomics as the boy would need elevated CK and a falsely called DMD variant. There is also the issue of missing girls who will manifest due to X-inactivation (HCP8, geneticist)
Gaining informed consent	To reduce risks of emotional distress to the family, healthcare professionals need to ensure families are aware of what screening entails, its implications and its uncertainties (C4, mother of an eight-year-old boy with DMD) There needs to be a separate discussion with parents outlining the differences between DMD and other conditions routinely tested for in the NBS program (HCP10, genetic counsellor)
Ongoing multidisciplinary care and support for families	Such a significant and stressful diagnosis requires expert care, support and education in a multidisciplinary setting (HCP26, nurse) Parents need psychological support from a trained professional who is good at handling grief (C11, father of an eight-year-old boy with DMD)

Data was collected from 50 primary caregivers and 26 healthcare professionals.

Abbreviations: NBS; newborn bloodspot screening, DMD; Duchenne muscular dystrophy, HCP; healthcare professional, C; caregiver, CK; creatine kinase.

For the ten HCPs who were uncertain or against NBS for DMD, 8/10 (80.0%) indicated that they would be more inclined to support its implementation if a clear, comprehensive and well-resourced care plan was established for the child and family. HCPs elaborated that a clear post diagnosis pathway may provide “hope for the future” and mitigate caregiver distress when confronted by a diagnosis which currently lacks immediate treatment options for the newborn. The subtheme of ongoing multidisciplinary care and support for families, specifically psychological support, was a priority identified by many HCPs (14/26, 53.8%) and caregivers (28/50, 56.0%) (Table 5). Many (44/50, 88.0%) caregivers also agreed that ensuring better education for families was important.

In the HCP cohort, the current lack of disease modifying therapies initiated early in life was perceived as a moderate to high barrier for the inclusion of DMD in NBS (median: 71.5, IQR: 40.0–92.0 on visual analogue scale). While HCP perspectives were divided (9/26 [34.6%] agreed and 9/26 [34.6%] disagreed), most (34/50, 68.0%) caregivers disagreed with the notion that screening should only be implemented if there was a disease modifying treatment or clinical trial available at time of screening (Fig. 3), though this difference was not found to be significant (χ2 = 5.26, P = 0.07).

Fig. 3.

Caregiver and healthcare professional perspectives on the statement “A screening program for Duchenne muscular dystrophy should only identify individuals who have a disease modifying therapy or clinical trial available at the time of screening”. Data was collected from 50 primary caregivers and 22 healthcare professionals (missing for four healthcare professional non-respondents)Percentages displayed are of the total cohort of caregivers (50) and healthcare professionals (26).

The importance of understanding caregiver values and perceptions of the risk-benefit balance when considering the utility of NBS for DMD was emphasised by three HCPs:

“This is very much influenced by … health literacy, resources, coping mechanisms, social supports, cultural/religious background, etc. For some, these factors may not result in the proposed model of care being beneficial.” (HCP19)

In line with the need to understand caregiver perspectives, 8/26 (30.8%) HCPs emphasised the importance of informed consent for DMD NBS so that parents can decide whether they would like to participate in NBS for DMD based on their own values and preferences (Table 5).

In the ten HCPs who were uncertain or against NBS for DMD, 7/10 (70.0%) indicated that the approval of gene therapy in Australia would influence their position in favour of NBS. Nevertheless, HCPs highlighted the existence of gaps in evidence, specifically regarding the impact on clinical outcomes and the ideal age for initiation, within the subtheme of uncertainty of clinical utility in the wake of a rapidly evolving therapeutic landscape (Table 4). As one HCP stated:

“I think as the evidence builds for disease modifying therapies for DMD, the role of newborn screening will become clearer.” (HCP22)

A majority (21/26, 80.8%) of HCPs also perceived the need to establish robust and sustainable infrastructure for the diagnosis and management of screen positive newborns with predominant concerns about personnel and specialist availability (Table 5). Most (19/26, 73.1%) HCPs envisioned that once implemented, NBS could decrease burdens on the healthcare system due to (i) reduced prevalence of DMD as parents engage in reproductive planning, (ii) improved health outcomes for children with DMD and (iii) reduced investigations required for diagnosis. However, several (5/26, 19.2%) HCPs disagreed. As one HCP emphasised:

“There are significant implications for the healthcare system due to additional follow up and care required for patients from birth to the age they would otherwise have been referred for diagnostic investigations … need to ensure this improves outcomes, as it is time and resource intensive.” (HCP7)

Despite varying opinions about the acceptability of NBS for DMD, no caregivers or HCPs thought that NBS participation rates would decrease with the inclusion of DMD in the routine screening panel.

Newborn screening for Duchenne muscular dystrophy: preferences for workflow

Screening males and females for an X-linked disorder

A greater proportion of caregivers (42/50, 84.0%) compared to HCPs (11/26, 42.3%) believed that all neonates should be screened and that positive screening results should be given to parents regardless of the baby's sex (χ2 = 14.09, P < 0.001).

Consenting process

In line with current opt out processes, 13/26 (50%) HCPs and 37/50 (74.0%) caregivers believed that DMD should be included as part of the routine NBS panel (χ2 = 4.38, P = 0.036). A prominent reason raised in both participant groups was to reduce complexity of decision making. Meanwhile, 11/26 HCPs (42.3%) and 13/50 (26.0%) caregivers perceived that with a lack of an overwhelming benefit (due to no treatment during the newborn period), an opt-in process where parents are consented separately for DMD would be the most suitable.

Delivery of screen positive results

With an assumption that NBS for DMD would occur in the immediate postnatal period, HCPs (22/26, 84.6%) and caregivers (41/50, 82.0%) similarly believed that a screen positive result should be disclosed and diagnostic testing commenced as soon as the result was available (Fisher's exact test P = 1.0). One HCP reasoned:

“It presumably makes sense to tell families before a second child. I am also uncomfortable with the screening result being known but held onto us.” (HCP11)

In both caregiver and HCP responses, provision of screening results by a neuromuscular specialist within a multidisciplinary setting was the preferred pathway (Fig. 4). Clinical evaluation and diagnostic testing at a neuromuscular specialist unit was also highly preferred by both caregivers and HCPs.

Fig. 4.

Preferences for involvement of healthcare professionals in the delivery of screen positive results. Data was collected from 50 primary caregivers and 26 healthcare professionals. The x-axis represents the percentage of each participant group indicating their preference for the involvement of each healthcare professional. Abbrevations: DBS; dried bloodspot.

Referral of newborns with other conditions causing elevated muscle isoform of creatine kinase

Most (21/26, 80.8%) HCPs believed that an additional pathway for newborns identified with elevated CK-MM but no DMD-causing genetic variant on second-tier testing should be developed. Specifically, 10/26 (38.5%) believed that these infants should be referred to a neuromuscular clinic for multidisciplinary review while 11/26 (42.3%) perceived that further diagnostic evaluation with collection of a second dried bloodspot and repeat CK-MM should be conducted to investigate for non-DMD muscular dystrophies.

Discussion

To our knowledge, this study is the first to comprehensively evaluate perspectives on DMD NBS in the genomic era among caregivers of children with DMD and HCPs involved in their management. Importantly, our study found that caregivers valued the potential utility of a newborn diagnosis of DMD despite the lack of disease-modifying therapies administered early in life. HCPs expressed greater uncertainty about the presence of net benefits with notable concerns about the potential harms associated with receiving a screen positive result, emphasising the need for a model of care that supports the psychosocial and information needs of families receiving a newborn diagnosis. With the rapidly evolving therapeutic landscape and expansion of screening capabilities driving the need for new diagnostic paradigms, our findings are critical to inform a model of care and plan service delivery to maximise benefits valued by families while minimising potential harms.

Notably, our study adds a unique consumer perspective to a growing international rare disease stakeholder perspective that screening principles as outlined by Wilson and Jungner,²² whilst still relevant in the modern genomic age, require review and revision to accommodate the wider benefits of NBS within a modern paradigm.²³ Caregivers perceived personal utility or secondary benefits to the family which were as thematically dominant as primary benefits to the newborn. These secondary benefits included eliminating the diagnostic odyssey, enabling reproductive planning and allowing for financial preparations based on the future needs of their child. Our study thus advances knowledge in this field and gives weight to recommendations for incorporation into health technology assessments.²⁴ Understanding these benefits perceived by caregivers in our study is important to drive a changing paradigm in healthcare service delivery that emphasises value-based healthcare promoting health outcomes esteemed by affected individuals and their families. Our study adds to this body of evidence and provides the rationale for greater emphasis to be placed on the risk-benefit ratio of screening, instead of the presence of a treatment, to meet the needs of affected children and their families.²³

HCPs similarly acknowledged potential benefits of NBS for DMD and perceived the need to anticipate a changing therapeutic landscape and horizon scan for the emergence of disease modifying interventions initiated in the newborn period. Delays and challenges associated with establishing an evidence base for SMA NBS and developing infrastructure on a state-by-state basis to incorporate the screening test into existing NBS services have led to inequities in access to diagnosis and therapeutic intervention in newborns across Australia.²⁵ These disparities have dire consequences for conditions like SMA and DMD which are irreversibly progressive, highlighting the need to build health system readiness for NBS in parallel with the rapid development of therapeutic pipelines.²⁶

HCPs in our Australian study were more cautious in their support for DMD NBS than caregivers, with the lack of early disease-modifying interventions available perceived as a significant barrier. This contrasts with perspectives of HCPs from the United States (US), where substantial advocacy for NBS for DMD has been perceived.^27,28 This is perhaps a testament to the stringent pharmaceutical regulatory landscape and health technology assessment processes within Australia, precluding the availability of reimbursed and approved therapeutic interventions for DMD outside of access to oral glucocorticoids.²⁹ In contrast to caregivers who generally felt empowered by an early diagnosis which they perceived had multiple primary and secondary benefits to the newborn and family, HCPs in our study expressed greater uncertainty about the net benefits of a newborn diagnosis, with notable concerns over the psychosocial harms of diagnostic knowledge through NBS without a recourse to therapeutic intervention early in life. This is consistent with literature revealing cautious HCP views of other expanded models of NBS where potential harms to families, including psychological distress, increased anxiety and hypervigilance regarding symptom onset for later onset conditions and disruption of family dynamics have been raised.^30,31

The potential psychosocial harms and strategies to reduce these risks as perceived by stakeholders in our study are vital to inform the delivery of NBS services, particularly with a DMD NBS pilot program recently proposed for New South Wales (NSW) and Australian Capital Territory (ACT), Australia.¹⁰ Indeed, stakeholder engagement, strong consumer support and satisfaction with (newborn) screening programs are essential for their success and continuity.¹⁶

Our findings emphasise that a clear post diagnosis pathway and model of care supporting the psychosocial and information needs of families may ameliorate psychological ramifications of a newborn diagnosis of a condition without a recourse to therapeutic intervention early in life. Empowering parents and caregivers of screen-positive newborns by providing instructive material to enhance and support face-to-face health provider communication should potentially focus on the meaning and implications of a positive result alongside available interventions.³² Stakeholders in our study also identified ongoing psychological support as a priority in this model of care, which is unsurprising given higher levels of stress, anxiety and depression reported in prior studies for caregivers of children with chronic conditions.^33,34

In order to provide a clear post diagnosis pathway for screen positive infants and realize the benefits of NBS for DMD, facilities for diagnosis and follow up must be available. Given the strong preference of caregivers and HCPs in our study for specialist neuromuscular involvement in the further investigation and follow up of screen positive newborns, the importance of establishing robust infrastructure is evident and will require significant workforce planning to accommodate these specialist needs. This issue is particularly pertinent considering that equity of access to care remains a significant challenge in Australia as we consider how to expand existing NBS programs, with required specialised services often concentrated in a limited number of major metropolitan centres.³⁵

While a majority of caregivers and HCPs in our study supported the inclusion of DMD into routine NBS panels, existing opt-out approaches used in NBS programs across Australia, Canada and the US have been found to be associated with poor recall and limited understanding of pre-screening information provided to parents.^16,36,37 A separate opt-in consent process for DMD NBS (in addition to current routine panels) has been suggested to circumnavigate ethical dilemmas associated with screening for a condition that currently cannot be cured.³⁸ However, such changes would require a dramatic increase in trained staff to conduct pre- and post-test counselling, potentially jeopardising the currently high uptake and introducing financial and scalability issues to NBS programs.³⁹ Instead, digital consent modalities which provide simple, accurate, engaging, and relevant online information and consent may mitigate additional workforce requirements.⁴⁰

Strengths and limitations

A strength of our study was the heterogeneity of participants, with our sample including caregivers of various genders and backgrounds and HCPs from diverse professions, increasing the generalisability of our findings. Member checking, that is actively seeking participant clarification during data collection and analysis to verify the accuracy of data interpretation, further enhanced our study's credibility. Moreover, the high intercoder reliability rate (96%) conformed to qualitative research standards.⁴¹

There are, however, limitations to consider when interpreting the study results. While their responses may have offered additional insights, this study did not include caregivers deemed likely to experience significant emotional distress. A further carefully designed study assessing the perspectives of these caregivers would inform tailored psychosocial care and support for these sub-populations.

Furthermore, this study posed hypothetical questions, such as asking caregivers to consider potential benefits and harms of receiving a diagnosis of DMD for their child in the newborn period. Results from these questions are subject to hypothetical bias and may not accurately reflect the experiences of families had they learned about their child's diagnosis at the newborn stage. Hence, further research into the perspectives of caregivers directly affected by a newborn diagnosis of DMD through NBS is also warranted.

Whilst false positive results can be reduced through the introduction of a high CK threshold and the addition of second-tier genomic screening for DMD variants, there is still potential that NBS for DMD programs will identify children with other dystrophinopathies, including that of Becker's muscular dystrophy (BMD) as sometimes it can be difficult to predict the phenotype. Caregivers of diagnosed children with BMD were not included in this study. However, further research assessing the perspectives of all caregivers graduating through an NBS for DMD pilot (including the experiences of families with a false positive result), individuals with DMD and families without an experience of DMD would be essential to inform supportive clinical referral processes and follow-up for these families.

While we achieved code saturation (no new themes) at 23 survey responses (15 caregiver and eight HCP) and meaning saturation (no new perspectives) at 60 survey responses (35 caregiver and 25 HCP), a larger sample size may have provided a broader spectrum of perspectives and allowed us to optimally compare caregiver and HCP perspectives. Nevertheless, given the inherent challenges of rare disease research, our comprehensive sampling technique and diversity of participants involved, we maintain confidence that our findings adequately represent the perspectives of caregivers and HCPs. Further research on caregiver and HCP perspectives across Australia and in other countries may be needed to determine the generalisability of our findings to other jurisdictions, especially those where there is variability in access to specialist neuromuscular services such as in low- or middle-income nations. These investigations may shed light on unique challenges related to healthcare access, engagement, and reimbursement in diverse national and global contexts.

Conclusion

Our research carries significant implications for future policy and practice. Importantly, caregivers of children with DMD recognise the clinical and personal utility of a newborn diagnosis even without an available disease modifying therapy. We also emphasise the need for a model of care that integrates education, testing, clinical services and provides support for the ongoing psychosocial needs of families receiving a newborn diagnosis. As the therapeutic landscape continues to evolve and international best practice recommendations advance, findings from this study will ensure that the impacts of NBS for DMD on children, families and healthcare systems are anticipated and planned for in collaboration with stakeholders. Furthermore, we shed light on the changing value of actionable knowledge for conditions where immediate intervention is not indicated, potentially informing future advocacy efforts for the inclusion of similar conditions in NBS programs.

Contributors

MAF and DSK formulated the concept of the manuscript and developed the study questionnaires. CJ performed all patient recruitment, data collection and quantitative analyses. CJ, MAF and DSK contributed to qualitative analyses. CJ wrote the first and subsequent drafts of the manuscript, including constructing all tables and figures. DSK, MAF, KJJ, HS and ML contributed to manuscript revision. All authors read and approved the final manuscript. CJ, MAF and DSK accessed and verified the data.

Data sharing statement

Data underlying the results reported in this manuscript can be made available to suitably qualified researchers through reasonable request and after de-identification. Applicants should apply between one and 12 months after the manuscript has been published in print and should demonstrate that the proposed use of the data has been approved by an independent review committee identified for this purpose. The data request should then be sent to the corresponding author, and de-identified data will be shared with a signed data access agreement.

Declaration of interests

MAF is the recipient of a National Health and Medical Research Council of Australia Investigator (grant APP1194940). Other authors declare no competing interests.