ABSTRACT
Background
Early diagnosis of cystic fibrosis (CF) through newborn screening (NBS) programs has improved health outcomes in people with CF (pwCF). NBS programs can vary in specific protocols and genetic variants tested, which may not perform equitably for all infants. The objective of this study was to summarize the Canadian CF NBS programs to understand if there are any gaps that may drive inequities.
Methods
Details about each of the Canadian CF NBS programs were gathered by collating publicly available information and consulting directly with each program. The Canadian CF Registry (CCFR) was used to identify Canadians with CF in 2022, to estimate the proportion of individuals that would have been identified by each NBS program in Canada.
Results
All jurisdictions in Canada include CF in their NBS programs, which follow a similar multistep process: (1) evaluation of immunoreactive trypsinogen (IRT), (2) genetic testing of a predefined set of variants. Most jurisdictions analyzed IRT locally, whereas genetic testing was centralized to five programs. Applying the current NBS CFTR variant panels from each program to the 4445 individuals in the CCFR identified over 96% of the Canadian CF population. All variant screening panels were more likely to identify pwCF who were: (1) born before 2018, (2) diagnosed as children, and (3) described as White.
Interpretation
Canadian NBS panels would have captured over 96% of all people in the CCFR; however, they would fail to identify 12%–20% of non‐White individuals. As Canada's population becomes more diverse, updates to NBS programs may be needed to ensure inequities in screening and diagnosis do not further widen.
Keywords: cystic fibrosis, genetic diseases, neonatal screening
1. Introduction
Early diagnosis of cystic fibrosis (CF) through newborn screening (NBS) programs has improved health outcomes for people with CF (pwCF). Notably, pwCF who are identified through NBS programs have better nutritional status and lung function in childhood [1, 2, 3], and longer survival [4], compared with those diagnosed after clinical symptoms appear. NBS programs across the world are similar in that they (1) identify infants with elevated immunoreactive trypsinogen (IRT) levels and (2) test for CF‐causing genetic variants. However, they can vary with respect to the specific protocols and genetic variants tested. For example, an elevated IRT can be identified using a fixed cut‐off (e.g., 60 ng/mL) or a floating cut‐off (e.g., top 5% of samples that are run that week). Consequently, these differences can affect the sensitivity and specificity of the NBS program and may not perform equitably for all infants. Another key difference between NBS programs is the panel of CF transmembrane conductance regulator (CFTR) variants for which there is testing.
There are thousands of identified variants in the CFTR gene, over 1000 of which have been identified as CF‐causing or variants of varying clinical consequences by the Clinical and Functional Translation of CFTR (CFTR2) database. However, most NBS panels consist of the most commonly observed variants, and these are often more prevalent in White populations of European ancestry. Previous analyses of NBS programs across the United States have found minoritized individuals are more likely to have rare variants not captured in the panels, which can lead to diagnostic delays in these specific populations [5, 6, 7, 8]. Recently published consensus guidelines from the US CF Foundation have provided recommendations to address this [9]. In this study, we aimed to analyze the current landscape of NBS in Canada by conducting a thorough, cross‐sectional review of Canadian CF NBS programs to understand if there are gaps that may drive inequities.
2. Materials and Methods
2.1. Review of CF NBS Programs in Canada
Details were gathered about each of the Canadian CF NBS programs by collating publicly available information and consulting directly with each program. The information collected included: geographical catchment area, testing algorithm, name/brand of the genetic testing panel, number and name of the CFTR variants included in the screening panel, and when CF was included within the NBS program. A summary of information gathered, along with any additional questions, was sent to a representative from each NBS program to verify and update the information. If necessary, a follow‐up by phone interview was conducted with the NBS program. The information gathered was current as of December 2023.
2.2. Comparison of CF NBS Programs in Canada
The Canadian CF Registry (CCFR) was used to identify individuals with a confirmed diagnosis of CF in Canada, who were followed by a Canadian CF clinic between 2007 and 2022. The annual prevalence of each CFTR variant was determined based on patient data reported in the CCFR in that year. The top 20 most frequent CF‐causing variants were identified. CFTR variants are described throughout using the “legacy name.”
To identify the proportion of all Canadians with CF who would have been identified by each NBS program, each of the CFTR screening panels identified through the review of NBS programs were applied to pwCF reported in 2022. An individual was considered “identified by the NBS program” if that program would have identified at least one of that individual's CFTR variants. The proportion identified was stratified by jurisdiction of residence, race (as recorded by the clinical team in the CCFR), age at diagnosis, and year of birth. The last jurisdiction in Canada to incorporate CF within their NBS program did so in 2018. So, year of birth was stratified by those born < 2018 and ≥ 2018. Jurisdiction of residence was determined from the CCFR using the forward sortation area (FSA; first three digits of the postal code), and if unknown, it was imputed as the province in which they receive CF care.
Each pwCF in the CCFR provides informed consent for their data to be captured in the CCFR. The CCFR Registry Review panel reviewed the request for this analysis, and the study was approved by the Dalhousie Research Ethics Board (#2024‐7124).
3. Results
In 2023, all jurisdictions (10 provinces and 3 territories) in Canada included CF in their NBS programs (Table 1). The province of Alberta was the first jurisdiction to introduce NBS for CF in 2007, whereas Quebec was the last to include CF in 2018. The largest program was Newborn Screening Ontario, covering four jurisdictions (province and/or territory) with a catchment area of 43.4% of the Canadian births in 2022.
Table 1.
Comparison of CF NBS programs across Canada (as of December 31, 2023).
| Newborn screening program and jurisdictions covered | Start of CF NBS | Catchment area: Canadian births in 2023 # (%) | IRT cut‐off | CFTR variants analyzed # | Coverage of top 20 prevalent CFTR variants in Canada #/20 (%) |
|---|---|---|---|---|---|
|
Newborn Screening BC [IRT → CFTR variant panel → IRT] | |||||
| British Columbia | November 2009 | 41268 (11.7%) | Fixed + Floating cutoff | 130 | 19/20 (95%) |
| Yukon | Unknown | 395 (0.1%) |
|
||
|
Alberta Newborn Screening Program [IRT → CFTR variant panel] | |||||
| Alberta | April 2007 | 48293 (13.7%) | Fixed + Floating cutoff | 39 | 16/20 (80%) |
| Northwest Territories | Unknown | 477 (0.1%) |
|
||
| Saskatchewana | January 2009 | 12923 (3.7%) |
|
||
|
Newborn Screening Ontario [IRT → CFTR variant panel → CFTR full sequencing] | |||||
| Manitobaa | July 2011 | 15229 (4.3%) |
|
50 | 18/20 (90%) |
| Ontario | April 2008 | 136858 (38.9%) |
Fixed + Floating cutoff
|
||
| Newfoundland and Labrador | June 2015 | 3183 (1.0%) | |||
| Nunavuta | Unknown | 793 (0.2%) | |||
|
Québec Neonatal Blood and Urine Screening Program [IRT → CFTR variant panel → IRT] | |||||
| Quebec | September 2018 | 77746 (22.1%) | Fixed cutoff: > 46 ng/dL | 77 | 18/20 (90%) |
|
Maritime Newborn Screening [IRT → IRT → CFTR variant panel] | |||||
| New Brunswick | April 2014 | 6054 (1.7%) | Fixed cutoff | 53 | 19/20 (95%) |
| Nova Scotia | April 2014 | 7323 (2.1%) |
|
||
| Prince Edward Island | 2015 | 1336 (0.4%) |
Fail safe cutoffs:
|
||
Note: Statistics Canada. Table 13‐10‐0414‐01 Live births, by place of residence of mother.
Blood spot screening for IRT conducted in‐province.
Genetic screening for Nunavut births also conducted in Alberta.
In all jurisdictions, NBS generally involves a multistep process: (1) IRT levels are measured from bloodspot samples collected shortly after birth, and (2) individuals with IRT levels above the cut‐off value are sent for genetic testing, which typically includes a predefined set of variants to be tested that differ by jurisdiction. IRT cutoff levels differed by jurisdiction: five jurisdictions (45.5%) use fixed cut‐offs, one (9.1%) uses floating cut‐off values, and five (45.5%) use a combination of fixed and floating. In some jurisdictions, a repeat IRT is performed depending on the results of the first IRT and/or the genetic screening panel. In some jurisdictions (British Columbia, Yukon, Quebec), when genetic testing identifies only one CF‐causing variant, a repeat IRT is conducted to differentiate between CF carriers and infants requiring sweat testing. In other jurisdictions (Saskatchewan, Manitoba, and the Maritime provinces), a repeat IRT is ordered before genetic testing when initial IRT values are borderline elevated.
Ontario is currently the only jurisdiction that performs CFTR full gene sequencing (Figure 1). Most Canadian jurisdictions conducted IRT analysis locally (7/11), whereas genetic testing was centralized to five programs: Newborn Screening BC (NSBC), Alberta Newborn Screening Program (ANSP), Quebec Neonatal Blood and Urine Screening Program (QNBUSP), Newborn Screening Ontario (NSO), and Maritime Newborn Screening (MNBS). Newborn Screening BC had the most comprehensive CFTR variant screening panel with 130 variants capturing 19 of the 20 most prevalent CFTR variants in Canada. The Maritime Newborn Screening included a more limited panel (53 variants) and also captured 19 of the 20 most prevalent CFTR variants in Canada. The 20 most prevalent variants have not changed over the past 20 years, and there has been little change in prevalence, with only two variants changing by over 1% (F508del −2.3%, L206W + 1.4%) (Figure 2).
Figure 1.
CF NBS algorithms across Canada (as of December 31, 2023). Note: *Map (lefthand side of figure) illustrates the screening algorithm employed in each jurisdiction, while the table (righthand side of figure details) the jurisdictions that are part of each of the five genetic screening programs. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2.
Change in the 20 most prevalent CFTR variants in Canada, 2007–2022. [Color figure can be viewed at wileyonlinelibrary.com]
In 2022, there were 4445 individuals with CF in Canada with data recorded in the CCFR. Applying the current NBS CFTR variant panels from each screening program identified over 96% of the Canadian CF population in each of the jurisdictions (Table 2). There are subtle differences observed by jurisdiction of residence (e.g., 95% of those living in Saskatchewan compared with nearly 100% of those living in Quebec, Newfoundland and Labrador, and the Yukon). Further, each screening panel would have identified different individuals. For example, the Newborn Screening Ontario panel would have only identified 95.1% of the CF population residing in the province of Ontario, whereas nearly 97% of those residing in Ontario would have been identified if the Newborn Screening BC panel was used.
Table 2.
Proportion of individuals in each jurisdiction who would hypothetically be identified by each newborn screening program variant panels.
| Proportion of individuals who would hypothetically be identified by each newborn screening program, N (%) | |||||
|---|---|---|---|---|---|
| Newborn Screening BC (NSBC) | Alberta Newborn Screening Program (ANSP) | Newborn Screening Ontario (NSO) | Quebec Neonatal Blood and Urine Screening Program (QNBUSP) | Maritime Newborn Screening (MNBS) | |
| Canada | 4329 (97.4) | 4271 (96.1) | 4283 (96.4) | 4301 (96.8) | 4288 (96.5) |
| British Columbia | 430 (96.2) | 429 (96.0) | 429 (96.0) | 429 (96.0) | 429 (96.0) |
| Alberta | 590 (98.7) | 580 (97.0) | 583 (97.5) | 584 (97.7) | 584 (97.7) |
| Saskatchewan | 125 (95.4) | 125 (95.4) | 125 (95.4) | 125 (95.4) | 125 (95.4) |
| Manitoba | 128 (97.7) | 126 (96.2) | 126 (96.2) | 126 (96.2) | 126 (96.2) |
| Ontario | 1393 (96.9) | 1364 (94.9) | 1367 (95.1) | 1376 (95.7) | 1366 (95.0) |
| Quebec | 1287 (98.2) | 1272 (97.1) | 1278 (97.6) | 1286 (98.2) | 1283 (97.9) |
| Nova Scotia | 119 (96.7) | 119 (96.7) | 119 (96.7) | 119 (96.7) | 119 (96.7) |
| New Brunswick | 159 (95.2) | 159 (95.2) | 159 (95.2) | 159 (95.2) | 159 (95.2) |
| Prince Edward Island | 21 (95.5) | 21 (95.5) | 21 (95.5) | 21 (95.5) | 21 (95.5) |
| Newfoundland and Labrador | 72 (98.6) | 71 (97.3) | 71 (97.3) | 71 (97.3) | 71 (97.3) |
| Yukon | 5 (100.0) | 5 (100.0) | 5 (100.0) | 5 (100.0) | 5 (100.0) |
Table 3 shows the proportion of individuals that would have hypothetically been identified by each panel across several key characteristics. Except for the Newborn Screening BC program, which would have identified > 97% of individuals no matter the birth year, all other programs would have identified approximately 97% of those born before 2018 (the year all jurisdictions had NBS programs for CF) and only 94% of those born after. Across all NBS panels, a greater proportion of those who were diagnosed as children would have been identified compared with those who were diagnosed as adults. The largest difference observed was using the Alberta Newborn Screening Program, where 97.1% of individuals diagnosed as children would have been identified compared with less than 90% of those diagnosed as adults. Importantly, pwCF described as non‐White would have been less likely to be identified by all the panels compared with those that were described as White. For example, the Maritime Newborn Screening panel would have missed 20% of non‐White individuals. Even the Newborn Screening BC panel, the one that included the most CFTR variants, would have missed more than 12% of non‐White individuals. By comparison, the proportion of White individuals who would have been identified was > 97% by all the screening panels.
Table 3.
Proportion of individuals who would hypothetically be identified by newborn screening program variant panels, by birth year, age at diagnosis, and race.
| Proportion of individuals who would hypothetically be identified by each newborn screening program, N (%) | |||||
|---|---|---|---|---|---|
| Newborn Screening BC (NSBC) | Alberta Newborn Screening Program (ANSP) | Newborn Screening Ontario (NSO) | Quebec Neonatal Blood and Urine Screening Program (QNBUSP) | Maritime Newborn Screening (MNBS) | |
| Birth year | |||||
| < 2018 | 3965 (97.4) | 3918 (96.3) | 3930 (96.6) | 3946 (97.0) | 3934 (96.7) |
| ≥ 2018 | 364 (97.1) | 353 (94.1) | 353 (94.1) | 355 (94.7) | 354 (94.4) |
| Age at diagnosis | |||||
| Child | 3930 (98.3) | 3883 (97.1) | 3890 (97.3) | 3900 (97.5) | 3892 (97.3) |
| Adult | 329 (92.7) | 319 (89.9) | 324 (91.3) | 331 (93.2) | 327 (92.1) |
| Unknown | 70 (76.9) | 69 (75.8) | 69 (75.8) | 70 (76.9) | 69 (75.8) |
| Race | |||||
| Non‐White | 311 (87.6) | 290 (81.7) | 290 (81.7) | 295 (83.1) | 284 (80.0) |
| White | 4018 (98.2) | 3981 (97.3) | 3993 (97.6) | 4006 (97.9) | 4004 (97.9) |
4. Discussion
Overall, the Canadian NBS programs are very effective at identifying the majority of pwCF in Canada (more than 96% of people captured in the CCFR in 2022 would have been captured by existing NBS panels). Conversely, the panels on average would have missed approximately 5% of individuals with CF and are less likely to identify people with rare variants, particularly minoritized Canadians. There were notable differences between NBS programs across Canada, from IRT cut‐off levels to the CFTR variants included on the screening panel. The differences observed between NBS programs across the country also highlight opportunities for a standardized protocol to facilitate an equitable chance of early diagnosis for all infants in Canada.
The higher likelihood of a missed diagnosis among minoritized individuals was consistent with evidence from the United States [6, 7, 8] and the United Kingdom [5]. The Canadian panels on average were more comprehensive than the commonly used panels in the United States in 2015 [6]; however, recently published consensus guidelines from the US Cystic Fibrosis Foundation recommend that CF NBS panels should not be limited to the F508del variant or variants included in the American College of Medical Genetics‐23 panel and recommend that programs should screen for all CF‐causing variants in CFTR2 [9]. At most, 20% of non‐White individuals would have been missed with the most limited Canadian panel, compared with up to 40% using the most limited US panels (e.g., four states only test for a single CFTR variant, F508del) [6, 7]. The potential for diagnostic delays [8], combined with misconceptions about the low incidence of CF in non‐White populations, may contribute to existing inequities in outcomes for non‐White Canadians with CF [10]. None of the Canadian panels fully reflect the heterogeneity of the CF variants observed in Canadians with CF, for whom nearly 400 unique variants have been documented. One estimate suggests the inclusion of 139 variants in a screening panel would identify 97% of the known CF‐causing variants described in the CFTR2 database [11]. At least four states in the United States now include CFTR gene sequencing as part of the NBS program [7]. Notwithstanding the economic and practical implications of implementing next generation sequencing, this approach would identify a high proportion of variants of unknown consequence, which may outweigh the benefits of fewer false negatives [12]. The uncertainty and stress on families, along with the medicalization of those with CF Screen Positive Inconclusive Diagnosis (CFSPID), and how results are reported (e.g., reporting only disease‐causing variants and/or variants of varying clinical consequences) must be considered in weighing the risks and benefits of next generation sequencing.
The lower percentage of individuals born on or after 2018 that would have been identified with current CFTR variant panels also suggests that the Canadian population may be becoming more diverse, and that, despite capturing the majority of the CF population, these panels will become increasingly unsuitable for the changing demographics of the population. Further, these findings suggest that current CF NBS panels do not identify up to 10% of individuals diagnosed in adulthood, suggesting that there will continue to be individuals diagnosed with CF as adults, even with universal NBS for CF in Canada. Recognition of the potential false negative NBS results, that individuals will continue to present with clinical symptoms, and that CF may occur in people of any genetic ancestry, highlights the need for education across the healthcare continuum, especially in primary care, to ensure CF symptoms are not overlooked. It will be important to track the missed cases to inform future changes to NBS programs.
In Canada, jurisdictional programs were designed to ensure the variants most prevalent in each region were captured in the specific panels. Although there are some differences in the genetic and ethnic backgrounds between residents living across the Canadian jurisdictions, the population is becoming more diverse, and people are more likely to move between jurisdictions. It is challenging to continue to justify the need for regional panels. Rather, these findings emphasize the need for a standardized approach to the regional NBS programs, where each program is screening using the same panel of variants. If a standardized panel is implemented, equity must be considered to ensure that the panel is inclusive and that minoritized individuals are not systematically excluded. Furthermore, NBS programs should continue to adapt their screening panels as more CF‐causing variants are identified. CFTR variant‐specific eligibility for CF treatment (like modulator therapy) should also be considered when re‐evaluating and updating the screening panels, since these therapies have the potential to significantly change the disease trajectory. NBS programs can also consider the novel approaches implemented in some parts of the country. In British Columbia, all newborns receive the targeted panel analysis, but if clinically indicated, and via request from the CF physician, an expanded panel of CF variants can be used. In Ontario, if an IRT is greater or equal to the 99.9th percentile or if only one CFTR variant is found, CFTR full sequencing is conducted. Infants at risk of CF, for instance, those with a family history of CF or those born to mothers on highly effective modulator therapy, should also be considered for CFTR full sequencing, irrespective of NBS results. Whether or not an infant has the opportunity to be diagnosed with CF soon after birth and to start early intervention should not depend on their postal code, especially now in the era of highly effective modulator therapies that may alter disease progression and prevent the long‐term sequelae of disease [13, 14].
This study has several notable limitations. The review of NBS programs in Canada was a cross‐sectional snapshot of the programs and relied on program personnel to inform the survey. As such, there could not be consideration given to the evolution of NBS programs over time, and the study here provides only a snapshot of the current state. This study should, therefore, be repeated in the future to determine the effectiveness of changes, if any, in NBS programs on identifying newborns with CF, and how the changing demographics in Canada may be impacting early CF identification. Transparent reporting of NBS protocols is important to be able to monitor effectiveness and equity. Our data were limited to the CCFR, which only included people with a diagnosis of CF. We cannot comment on the sensitivity and specificity of the NBS programs overall and how many individuals are missed at the first stage (elevated IRT), nor whether the IRT stage disproportionately misclassifies minoritized individuals [15]. With the availability of CFTR modulator therapies and a growing number of individuals on treatment during pregnancy [16, 17], infants may be born with IRT levels below the screening threshold that have two CF‐causing variants [18], highlighting the need for alternative pathways to diagnosis. Finally, we cannot rule out that the CCFR may be incomplete and that there are Canadians, particularly minoritized Canadians, that are not included in the CF Registry. Therefore, this analysis may underestimate the proportion of individuals missed.
In conclusion, Canadian NBS panels would have captured more than 96% of all people in the CCFR; however, there are gaps in detection that particularly impact minoritized individuals. This includes pwCF in Canada with rare CF variants, which include an overrepresentation of minoritized Canadians, who are more likely to be missed by current NBS programs (12%–20%). Consideration must be given to adopting more extensive genetic screening protocols, including next generation sequency, especially as these become more economically and logistically feasible. As Canada's population becomes more diverse and greater numbers are treated with modulator therapy (whose newborns are more likely to be missed by current NBS programs), updates to the NBS programs are needed to ensure the inequities in screening and diagnosis do not further widen.
Author Contributions
Stephanie Y. Cheng: conceptualization, formal analysis, writing – original draft, validation, methodology, writing – review and editing, data curation. Berke Sahin: formal analysis, writing – original draft, validation, writing – review and editing, data curation. Noma Abdulrahem: formal analysis, writing – original draft, validation, writing – review and editing. Paul D. W. Eckford: writing – review and editing. Zofia Zysman‐Colman: writing – review and editing. Mark Chilvers: writing – review and editing. Anne L. Stephenson: writing – review and editing. Jocelyn Arpin: writing – review and editing. Christine Donnelly: writing – review and editing. Karen Doyle: writing – review and editing. Sara Fernandez: writing – review and editing. Corey Filiaggi: writing – review and editing. Zaiping Liu: writing – review and editing. Angela Nowak: writing – review and editing. Mary Jane Smith: writing – review and editing. Sanja Stanojevic: formal analysis, writing – original draft, methodology, supervision, writing – review and editing, data curation.
Ethics Statement
This study was approved by the Dalhousie Research Ethics Board (#2024‐7124).
Conflicts of Interest
The authors declare no conflicts of interest. Outside of this study, the following authors declare payments or honoraria to them or their institution for a combination of lectures, presentations, educational events, advisory boards, steering groups, grants, or consultancy fees: M.C.‐Vertex; Z.Z.C.‐Vertex; A.L.S.‐Vertex, GSK, Viatris; S.S.‐BiomX, Vyvaire Medicine, GOLD, Ndd Technologies. Stephanie Y. Cheng, Noma Abdulrahem, and Paul D. W. Eckford have no personal disclosures to make. However, their employer, Cystic Fibrosis Canada, receives sponsorship funds from Vertex, Horizon Therapeutics, Amgen, Viatris, BioGeneric Pharma, and Mylan, and honoraria from Takeda Canada.
Acknowledgments
We would like to acknowledge the involvement and continued participation of those living with cystic fibrosis who consent to have their data submitted to the Canadian Cystic Fibrosis Registry, and the exceptional effort from CF clinic team members who collect and enter the data.
Cheng S. Y., Sahin B., Abdulrahem N., et al., “A Review of Newborn Screening Programs for Cystic Fibrosis: Are Current Protocols Appropriate for Canada's Diverse Population?,” Pediatric Pulmonology 60 (2025): 1‐9, 10.1002/ppul.71386.
Portions of this data were presented as a poster abstract presentation at the North American CF Conference in 2024.
Data Availability Statement
Data are available from CF Canada upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available from CF Canada upon reasonable request.