Racial disparities in primary ciliary dyskinesia: Defining the problem and potential solutions

To the Editor,

Primary ciliary dyskinesia (PCD) is a genetic disorder of motile cilia associated with recurrent oto-sino-pulmonary infections beginning in early childhood. Nearly all adults with PCD develop bronchiectasis, resulting in progressive impairment in lung function, substantial morbidity, and respiratory failure with need for lung transplantation in 40%–50% of adults.^1,2 The classic pediatric phenotype of PCD usually includes neonatal respiratory distress, daily wet cough and nasal congestion from birth, recurrent lower respiratory tract infections, persistent otitis media with effusion, and organ laterality defects in approximately 50% of people. Diagnosing PCD requires careful recognition of this clinical phenotype combined with diagnostic tests including nasal nitric oxide (nNO) measurement, genetic evaluation, and ciliary electron microscopy.

Recent data suggest that PCD is much more prevalent than previously thought. The general prevalence of PCD has been historically reported between 1 in 11,000 to 1 in 30,000. However, based on genomic analysis of 29 PCD-causing genes, the global prevalence of autosomal recessive PCD is now estimated to be at least 1 in 7554 individuals.³ The actual prevalence of PCD is likely even higher considering there are >50 known disease-causing genes, and this prevalence estimate does not include variants of uncertain significance (VUS), some of which may ultimately be pathogenic. Strikingly, individuals of African descent have the highest prevalence of predicted PCD-causing genetic variants (at least 1 in 9906), followed by nonFinnish European (1 in 10,388), East Asian (1 in 14,606) and Latino (1 in 16,309) populations.³ These data suggest that PCD is not concentrated in the White population and is rather, a racially diverse disease affecting many ethnicities, and more so those of African origin.

Despite the predicted racial heterogeneity of PCD, current North American PCD literature is primarily comprised of data obtained from White populations. We reviewed PubMed for all PCD-focused clinical research papers studying Canadian and American cohorts over the past 10 years. Ultimately, 12 papers of varying subject matter with a sample size of >20 were reviewed (Table 1), of which only 6 (50%) reported race data. In those studies, 64%–86% of the study populations are White (median 81% White), while only 2%–4% were of Black race. Additionally, participant races beyond White and Black were seldom documented. All participants in these studies were recruited from accredited PCD Foundation centers. The PCD Foundation is the leading patient advocacy group in North America, consisting of a Clinical and Research Center Network with more than 40 adult and pediatric sites directly supporting PCD diagnostics and research. Though data suggest that the people currently diagnosed with PCD across North America are predominantly White, there is still a substantial portion of the PCD population who are non-White, and these underrepresented minorities are not being recruited into research studies.

TABLE 1.

Race and ethnicity data in North American PCD literature.

References	Total N	% race/ethnicity
Davis et al.4	118	81% White
		19% Not reported
Davis et al.5	137	82% White
		12% Asian
		2% Black
		2% Multiracial
		2% Not reported
		<1% Native American
Leigh et al.6	392	86% White
		14% Not reported
Kinghorn et al.7	141	74.5% White
		9.2% Asian
		2.8% Black
		2.8% More than 1
		0.7% American Indian/Alaska Native
Behan et al.8	224	64% White
		15% Asian
		8% Other
		7% Missing
		4% Black
Shapiro et al.9	69	81% White
		19% Not reported
Leigh et al.10	373	No data reported
Mullowney et al.11	92	No data reported
Wee et al.12	123	No data reported
Ratjen et al.13	35	No data reported
Bingol et al.14	30	No data reported
Funkhouser et al.15	26	No data reported

Abbreviation: PCD, primary ciliary dyskinesia.

The etiology of the racial disparities in the North American PCD population is undefined, but we hypothesize three potential reasons: (1) diagnostic bias, (2) referral bias, and (3) population difference. Diagnostic bias refers to the lack of diagnostic generalizability associated with studying a racially and ethnically homogenous population.¹⁶ The primary evidence for current PCD diagnostic practices emanates from predominantly White populations. Since non-White populations have not been intensively studied in North America, there may be important diagnostic differences (i.e., genetic mutations, ciliary biopsy findings, intricacies in nNO interpretation, etc.) that are neither defined nor represented in current guidelines, resulting in missed PCD diagnoses in these unstudied, ethnically diverse groups. With high rates of PCD recognized in closed ethnic populations, large numbers of people with atypical and/or novel phenotypes may be missed, as demonstrated in South Asian communities across Great Britain, who have PCD with elevated nNO values from a shared hypomorphic gene variant.¹⁷ Referral bias describes the idea that primary care providers or other general practitioners are less likely to refer non-White individuals to a specialist for PCD evaluation because they are unaware that PCD is a multiracial disease.¹⁶ This is supported by recent reports of possible PCD founder variants in Native North American populations who are known for disproportionately high rates of suppurative respiratory disease yet remain woefully underinvestigated for potential etiologies.^18,19 Additionally, the suppurative respiratory symptoms associated with PCD in childhood are similar to cystic fibrosis (CF).²⁰ Although the CF population has become increasingly more diverse, CF is still much more prevalent in White people. Due to the clinical overlap with CF and the poorly recognized racial variability in PCD, it is possible that front-line providers assume PCD is similarly a disease more-often affecting White individuals and fail to refer non-White people for PCD evaluation. Lastly, population difference refers to the notion that the prevalence of racial groups differs across North America based on geographic location.²¹ The population represented in much of the current North American PCD literature is derived from research centers within the Genetic Disorders of Mucociliary Clearance Consortium (GDMCC), including sites in Colorado, Maryland, North Carolina, Quebec, California, Washington, Missouri, and Ontario. Though these centers strive to recruit from across North America, specific regions with concentrations of certain ethnic minorities (southwestern region for Mexican and Latin American populations, southern region with large Black populations) remained distant from most GDMCC locations. Thus, difficult access for ethnic minorities to GDMCC sites may have inadvertently resulted in racial inequity across North American PCD research populations. It is important to note that these are only hypotheses, and we must continue to make targeted efforts to fully study and comprehend the origins of this problem.

Solely defining the current problem is not sufficient; PCD researchers and clinicians must also search for solutions. When thinking about these, our efforts should target three categories: (1) getting people to consider PCD as a potential diagnosis in non-White populations, (2) combatting barriers to diagnosis in minority populations even after PCD is considered, (3) expanding regional access to PCD Foundation clinical and research centers. One potential solution is raising awareness for PCD in ethnic minorities through expanded education. Providers caring for neonates are typically the first clinicians to evaluate children for a PCD clinical phenotype presenting with neonatal respiratory distress and/or organ laterality defects. Implementing diversity-targeted education to neonatal providers in both community and academic settings may improve disease recognition and reduce referral bias. These educational efforts must specifically target communities with high numbers of racial minorities to increase PCD detection in these underrepresented populations. Expansion of accredited sites to specific regions not currently represented in the PCD Foundation Clinical and Research Center Network and implementing strategies for remote patient access would similarly improve accessibility for minority populations. The newly created PCD Foundation Clinical Patient Registry also has the potential to combat racial inequality, as continued growth and enrollment of minorities with PCD will expand clinical phenotypes and discover novel genotypes affecting diverse ethnic groups. When enrolling minority populations into the PCD Foundation Clinical Patient Registry, we must also be sensitive to the construct of mistrust. Minority populations have historically not participated in research studies due to mistrust related to historical events, health systems issues, and discriminatory events,²² so we must be cognizant of this when recruiting these populations. Financial barriers to PCD testing are a major obstacle to minorities being diagnosed with PCD in the United States. Financial assistance programs covering the cost of PCD genetic and electron microscopy testing would greatly alleviate this burden, and partnerships with commercial genetic testing laboratories to understand the racial makeup of customers will improve our understanding of those actually receiving genetic testing at present. With this knowledge, organized and targeted efforts can be implemented by the PCD Foundation and academic centers across North America to improve access to PCD testing. Finally, the PCD Foundation Clinical and Research Center network has expanded its accredited clinics to previously underserved areas of North America with large minority populations (Texas, Georgia, Alabama, New York, Puerto Rico, and Southern California), and continued expansion with a goal of at least one center in each state will further develop regional access for minority groups. The success of all these potential solutions requires proactive consideration and avoidance strategies for the sources of bias described above.

In summary, PCD is a racially diverse disorder with individuals of African descent estimated to have the highest prevalence of disease-causing variants. This is not reflected in the current North American PCD literature that has primarily studied the White population. The problem of racial inequity in PCD is complex, but with targeted and impactful efforts, including expansion of PCD clinical research centers to previously underserved regions, increasing access to genetic testing for non-White populations, and improved community outreach to local care providers, we can improve the representation of minorities in PCD.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.