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J Cyst Fibros. Author manuscript; available in PMC 2024 Jun 30.
Published in final edited form as:
J Cyst Fibros. 2023 May; 22(3): 443–449.
Published online 2022 Nov 10. doi:10.1016/j.jcf.2022.10.008
PMCID: PMC11214606
NIHMSID: NIHMS1999186
PMID: 36371312
Anne L. Stephenson, MD, PhD,1,2 Sana Swaleh, MD,1 Jenna Sykes, MMath,1 Sanja Stanojevic, PhD,3 Xiayi Ma, MSci,1 Bradley S. Quon, MD, MSc,4,5 Albert Faro, MD,6 Bruce Marshall, MD,6 Kathleen J. Ramos, MD, MSc,7 Josh Ostrenga, MSc,6 Alex Elbert, PhD,6 Sameer Desai, MSc,5 Elizabeth Cromwell, PhD,6 and Christopher H. Goss, MD, MSc7,8
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The publisher's final edited version of this article is available at J Cyst Fibros
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Abstract
Background:
The availability of new diagnostic algorithms for cystic fibrosis (CF), changing population demographics and programs that impact family planning decisions can influence incidence rates. Thus, previously reported incidence rates in Canada and the United States (US) may be outdated. The objectives of this study were to estimate contemporary CF incidence rates in Canada and the US and to determine if the incidence rate has changed over time.
Method:
This population-based cohort study utilized data between 1995–2019 from the Canadian CF Registry (CCFR), Statistics Canada, US CF Foundation Patient Registry (CFFPR) data, and US Center for Disease Control (CDC) National Vital Statistics System. Incidence was estimated using the number of live CF births by year, sex, and geographic region using Poisson regression, with the number of live births used as the denominator. To account for delayed diagnoses, we imputed the proportion of diagnoses expected given historical trends, and varying rates of newborn screening (NBS) implementation by region.
Results:
After accounting for implementation of NBS and delayed diagnoses, the estimated incidence rate for CF in 2019 was 1:3848 (95% CI: 1:3574, 1:4143) live births in Canada compared to 1:5130 (95% CI:1:4996, 1:5267) in the US. There was substantial regional variation in incidence rates within both Canada and the US. Since 1995, incidence rates have decreased at a rate of 1.6% per year in both countries (p<0.001).
Conclusion:
Contemporary CF incidence rates suggest CF incidence is lower than previously reported and varies widely within North America. This information is important for resource planning and for tracking how programs (e.g., genetic counselling, modulator availability etc.) may impact the incidence of CF moving forward.
Keywords: incidence, cystic fibrosis, regional differences, international comparison
BACKGROUND
The incidence of cystic fibrosis (CF) has historically been reported to be 1:3600 live births in Canada and 1:4000 live births in the United States 1–4. However, the landscape of CF has dramatically evolved over the past three decades, which could influence incidence rates in a contemporary period for several reasons. Firstly, carrier screening, genetic counselling and pre-implantation genetic testing have been available for several decades and may reduce CF births as an individual may choose to terminate a pregnancy based on in utero diagnosis 5,6. Secondly, increased immigration rates to North America could influence birth rates of CF because individuals from regions such as Asia, India, Middle East, and Africa reportedly have lower carrier rates of the cystic fibrosis transmembrane regulator protein (CFTR) mutation than those of European descent 7. On the other hand, it is increasingly being recognized that CF occurs in non-European populations. This increasing awareness to consider CF in populations who might have been overlooked in prior years may impact incidence rates in the opposite direction 8,9. Thirdly, recent widespread implementation of newborn screening (NBS) programs has shifted the timing of diagnosis. This program has a potential downstream effect on the incidence of CF because women who deliver a child during the era of NBS would become aware of their risk of having a child with CF earlier and this knowledge may influence their decisions to consider subsequent pregnancies. Fourthly, it is often unclear whether previously reported incidence rates take into consideration the impact of individuals diagnosed later in life 3,10. Prior to NBS programs in Canada, 46% of individuals were diagnosed after 1-year of age once symptoms developed. Without considering future diagnoses, incidence rates would be underestimated 2. Lastly, updated diagnostic guidelines describe clear criteria and guidance on complex or atypical diagnostic scenarios which may influence incidence rates 11. For these reasons, it is important to re-examine incidence rates to provide contemporary estimates. Such estimates also contribute to our understanding of the epidemiologic trends and the burden of CF moving forward which will allow for appropriate resource allocation and planning.
The objectives of this study were (1) to estimate the overall incidence rate of CF in North America, by country, by region, and by sex; and (2) to evaluate the longitudinal trends in incidence rates between 1995 and 2019. We hypothesized that (1) overall incidence rates will be similar in the two countries but vary across geographical regions within countries and (2) incidence rates will decrease over time.
METHODS
This population-based cohort study utilized CF registry data from 1995 to 2019.
Data Sources:
Individuals’ data are entered into the Canadian CF Registry (CCFR) and the US CF Foundation Patient Registry (CFFPR) once patient consent has been obtained and a diagnosis has been confirmed based on diagnostic guidelines 11. Registry data in both countries undergo routine validation checks to minimize errors and discrepancies. Individuals with a diagnosis of CFTR-related disorder or CF-screen positive indeterminate diagnosis are also collected within the CF registries, however, these individuals were excluded from this analysis.
Canadian CF Registry (CCFR)
The CCFR has been in existence since the early 1970s and all 42 accredited CF centers across Canada collect both demographic and clinical data on individuals living with CF. At site accreditation visits, clinics report the number of patients who decline participation in the registry, which is <1% of the patients followed at CF centers in Canada. There are several incentives for individuals to receive care at CF centers within Canada and for centers to submit data to the Registry. Firstly, the Canadian health care system provides universal, publicly funded health services to its population. Coverage includes visits to specialized care such as that provided by CF centers. As such, there are no direct barriers for patients to receive care at a CF center. Secondly, in most provinces, coverage for CF medications requires a prescription from a CF center and in some provinces, coverage requires the medication is dispensed from the CF center. Lastly, CF Canada provides financial incentives to the clinic which are dependent upon registry data submission. For these reasons, the majority of people with a diagnosis of CF are followed within the CCFR.
CF Foundation Patient Registry (CFFPR)
The CFFPR has recorded data dating back to 1982 and contains detailed demographic and annual clinical information on individuals receiving clinical care at the 110 accredited CF centers across US. Knapp et al. reported a high rate of patient participation in the US Registry, 93.7% of patients seen at accredited sites consented to participate in the registry 12. In addition, national birth and mortality data were compared and it was estimated that the US CFFPR captured 81–84% of persons with CF in 2012.
Data elements
In order to calculate incidence rates, the following variables were utilized from the respective CF Registries: date of birth, date of diagnosis, race/ethnicity, sex, genotype, NBS diagnosis indicator, province or state of birth. How and/or when the diagnosis of CF was made was classified as follows: (1) Newborn screened: diagnosed at birth through a NBS program (as indicated in the registry) (2) Not newborn screened: Diagnosed without NBS but within 2 months of age (3) Late diagnosis: diagnosed after 2 months of age and captured in the registry during the observation period (4) Anticipated diagnosis: these represent imputed individuals based on historical data within the registry that are anticipated to be born in the study period but have not yet been formally diagnosed with CF, hence not captured in the registry.
Patients born in Canadian Territories (n=4) were excluded due to the small sample size while people born in Puerto Rico or the Virgin Islands (n=32) (US Territories) and those born outside the US (n=350) or Canada (n=55) were excluded because national statistics for live births would not capture these individuals. If the province was missing in Canada, the province where the CF diagnosis was made was utilized (n=541, 14.7%), and if the state of birth was missing in the US, the earliest available state of residence was used (n=2803, 13.1%). To evaluate regional differences, Canada was categorized into Western region (British Columbia, Alberta, Saskatchewan, Manitoba), Ontario, Quebec, and Eastern region (Nova Scotia, Prince Edward Island, New Brunswick, Newfoundland) to account for small sample sizes in some provinces. In the US, states were categorized into Divisions (n=9) according to the US Census Bureau (Figure S1).
National Vital Statistics
Publicly available national vital statistics data between 1995 and 2019 were obtained for both countries. Canadian Vital Statistics Birth database (CVSB) between 1995–2019 was utilized, specifically data from 3 CVSB tables: live births by month, live births by place of residence of mother, estimates of births by sex annually. Center for Disease Control (CDC) WONDER database (https://wonder.cdc.gov/) was used to determine number of live births in the US by sex, race and state of mother’s residence. The earliest data publicly available for CDC WONDER was 1995 which is why this starting time period was chosen. Although birth data by race were available in US, similar Canadian data were not available, thus incidence by race was not examined.
Statistical Analysis
Descriptive statistics were reported as frequency and proportion for categorical variables and median and range for continuous variables.
Incidence rates calculated using observed data are known to be underestimated because a proportion of individuals with CF born in any given year may not yet be diagnosed by the end of the study period and hence not captured by the registry (this is referred to as ‘anticipated diagnosis’). The majority of these individuals will eventually be captured by the registry upon diagnosis. Figure S2 illustrates the concept of delayed diagnosis. For each birth year, we can only identify patients diagnosed up to a certain age. The red triangle illustrates a ten-year old patient, born in June 2000 just entering into the registry at time of diagnosis in the year 2010. However, a ten-year old individual born in June 2010 who is diagnosed in 2020 would not be captured yet by the registry as this is outside of the study window.
In order to model the impact of these anticipated diagnoses, we used the entire CCFR up to 2019 (i.e. including births prior to 1995) to determine the proportion of CF diagnoses that were made for each age and that would be missing in a given calendar year. For example, as the study period ends December 31, 2019, for CF patients born in the year 1995 we are missing all CF diagnoses occurring at age 26 years of age or older (Figure S2). We calculated the proportion of patients diagnosed older than age 25 years out of the total number of patients diagnosed with CF in the registry up until the year 1995. The calculated proportion of missing cases for each birth year is shown in Table S1. However, these historical estimates do not take into account NBS, as many of these anticipated diagnoses will be captured by NBS once this is available in a region. To account for anticipated diagnoses in the era of NBS, for Canadian and US individuals who had variants listed in Table S2, we assumed these patients would have been captured via NBS. We re-calculated a different proportion for each province/state using a revised age of diagnosis for these patients who would have been captured by NBS. This recalculated proportion is used to impute the number of births for the years following NBS implementation in that geographical area (i.e., 1983 for Colorado, 2008 for Alberta etc.). The years that NBS was implemented for each province and state are in Table S3.
Overall incidence (accounting for NBS and anticipated diagnoses) during the study period (1995–2019) and by year was estimated. The incidence of CF out of the total number of live births was modeled using a Poisson regression. The number of CF births in a given year (as determined by the individual’s birth year) was used as the primary outcome variable of interest and the total number of live births that year was used as the denominator. Country, gender, and province/state/region were used as explanatory variables. Birth year was added as a covariate to estimate the longitudinal trend in the incidence rate over the study period. Linear, quadratic, and piecewise regression segmented at 2009 to represent the implementation of NBS were all investigated as possible functional forms for birth year, with the best model identified as the model with the smallest residual error. All p-values are two-sided and analyses were conducted in software R version 4.0.3.
RESULTS
There were 2,478 and 21,356 individuals with CF born in Canada and the US respectively between 1995 to 2019 (Table 1). Figure 1 shows the number of CF births by year within each country by categories: ‘NBS’, ‘No NBS’, ‘Late Diagnosis’, and ‘Anticipated Diagnosis’. As illustrated in Figure 1, as NBS programs were implemented, the number of diagnoses captured through NBS increased while the other categories decreased. The overall number of live births based on national data sources appeared stable in Canada whereas birth rates were trending downward in the US (solid black line in Figure 1).
Figure 1:
Number of births by year in (A) US (B) Canada
*solid black line represents the number of live births based on Statistics Canada and CDC WONDER
**Legend: NBS, infants diagnosed through newborn screening program; No NBS, infants diagnosed within 2 months of age but not through a newborn screening program; Late diagnoses, individuals diagnosed after 2 months of age; Anticipated diagnoses, imputed individuals anticipated to be diagnosed based on historical data but who are not yet captured within the registry.
Table 1:
Demographic Characteristics of CF cohort in Canada and US (1995–2019)
| Canada (N=2,478) | USA (N=21,356) | |||||
|---|---|---|---|---|---|---|
| Variable | Categories | Frequency | % | Categories | Frequency | % |
| Sex | Female | 1192 | 48.1% | Female | 10390 | 48.7% |
| Male | 1286 | 51.9% | Male | 10966 | 51.3% | |
| Race/Ethnicity | Non-White | 184 | 7.5% | Non-White | 2263 | 10.6% |
| White | 2241 | 90.4% | White | 19081 | 89.3% | |
| Missing | 50 | 2.0% | Missing | 12 | 0.1% | |
| Birth Region | AB | 355 | 14.3% | East North Central | 3665 | 17.2% |
| ATL | 192 | 7.7% | East South Central | 1570 | 7.4% | |
| BC | 231 | 9.3% | Middle Atlantic | 2604 | 12.2% | |
| MB | 81 | 3.3% | Mountain | 1606 | 7.5% | |
| ON | 867 | 35.0% | New England | 1186 | 5.6% | |
| QC | 677 | 27.3% | Pacific | 2647 | 12.4% | |
| SK | 75 | 3.0% | South Atlantic | 3927 | 18.4% | |
| West North Central | 1823 | 8.5% | ||||
| West South Central | 2328 | 10.9% | ||||
| Newborn Screened* | 671 | 27.1% | 8929 | 41.8% | ||
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Abbreviations: BC, British Columbia; AB, Alberta; SK, Saskatchewan; MB, Manitoba; ON, Ontario; QC, Quebec; ATL, Atlantic provinces including New Brunswick, Nova Scotia, Prince Edward Island, Newfoundland & Labrador; US states were categorized by divisions and regions according to US Census Bureau.
*Newborn screened refers to those individuals who were recorded as having a diagnosis through newborn screening program with the respective registry.
Table 2 shows the observed and imputed incidence rates for 1995 and 2019 by country. In both countries, observed birth rates underestimate 2019 incidence rates by 11.7% and 10.1% in Canada and the US respectively compared to imputed rates which account for anticipated diagnoses and the staggered implementation of NBS. Furthermore, the contemporary incidence rates for 2019 are higher (i.e. less common) for both countries than what has historically been reported. There were no differences in incidence rates by sex (data not shown). Using US data only, we calculated the percentage of births for CF-specifically by racial groups which is shown in Table S5. The relative overall birth rate is increasing in people not identified as white and decreasing in the white population. However, the incidence of CF is decreasing across all racial groups. Births by racial group was not available in Statistics Canada data.
Table 2:
Trends and incidence rates by country*
| Country | Simulation | Relative Risk | Estimated incidence 1995 (95% CI) | Estimated incidence 2019 (95% CI) |
|---|---|---|---|---|
| Canada | Observed Imputed | 0.986 0.984 | 1:3071 (1:2853; 1:3307) 1:2607 (1:2435; 1:2792) | 1:4357 (1:4028; 1:4713) 1:3848 (1:3574; 1:4143) |
| US | Observed Imputed | 0.985 0.984 | 1:3938 (1:3841; 1:4038) 1:3435 (1:3355; 1:3516) | 1:5650 (1:5496; 1:5808) 1:5078 (1:4947; 1:5213) |
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*The relative risk represents the incidence rate ratio from one year to the next. Observed results are using raw data without taking into consideration the impact of delayed diagnoses or newborn screening programs. Imputed results account for the impact of delayed diagnoses and varying time of implementation of newborn screening programs within each province/state.
Both Canadian and US incidence rates were found to significantly decrease over the time period 1995 to 2019; for each birth year, the incidence rate ratio decreased by a factor of 0.984 in Canada (p<0.0001) and 0.984 per year in the US (p<0.001) corresponding to a 1.6% decrease per year. The incidence rates for both countries declined at a similar rate over time (p=0.98) (Figure 2). The predicted incidence rates for 2019 were 1:3848 (95% CI 1:3574, 1:4143) in Canada and 1:5078 (95% CI 1:4947, 1:5213) for the US. Using the imputed birth total for 2019, if we assume the incidence decrease at the same rate, we anticipate 79 births in 2025 and 73 births in 2030 in Canada and 515 births in 2025 and 474 in 2030 for the US.
Figure 2.
Incidence rates for CF in Canada and the US from 1995 to 2019*
*Solid line – Calculated incidence using the observed data. Dashed line represents the calculated incidence rates after accounting for anticipated diagnoses and the varying implementation of newborn screening programs in provinces and states. The curves are not parallel in Canada because newborn screening was implemented in the latter half of the study period due to fewer imputed values.
Regional incidence rates are shown in Figure 3 and Table S4. CF is most common in the Atlantic region and Quebec in Canada, and New England and West North Central in the US. It is least common in the Pacific region, and West South Central US regions. Estimated 2019 incidence rates vary from 1:3000 (95% confidence interval CI 1:2592 to 1:3472) in Atlantic provinces to 1:6925 (95% CI 1:6634 to 1:7227) in the Pacific US. The proportion of individuals with CF of European ancestry reported in each region can be found in Figure 3. Although the majority of individuals reported on within CF registries are of European ancestry, the proportion is lower in regions where CF is less common. Provincial and state level 2019 estimated incidence rates are in Table S4.
Figure 3:
Regional incidence rates in North America*
* Represents the calculated incidence rates after accounting for anticipated diagnoses and the varying implementation of newborn screening programs in provinces and states. Heat map reflects the 2019 estimates.
Acknowledging that the CFFPR captures nearly 85% of patients with CF in the US, we also artificially increased the number of births in each year by 15% for the US as a sensitivity analysis. This would amount to a predicted overall incidence rate of 1 in 3602 or a 2019 predicted incidence rate of 1 in 4413, assuming that the proportion of individuals not captured remained constant over time.
DISCUSSION
Contemporary CF incidence rates for 2019, taking into consideration anticipated diagnoses and the timing of regional implementation of NBS programs, are 1:3848 for Canada and 1:5078 for the US suggesting CF incidence is lower than previously reported. Furthermore, our analyses showed that CF incidence rates vary dramatically across Canada and the US, 1 in ~7000 to 1 in 3000 live births, making it challenging to apply one rate to an entire country. Interestingly, the incidence of CF was higher in Canada compared to the US which may reflect of a variety of factors including differences in carrier rates amongst different ethnic populations13. Furthermore, our data highlight the fact that the relative birth rate is increasing in the US population not identified as white and is decreasing in the white population. Meaning that overall, the population is becoming more diverse. However, the incidence of CF is decreasing across all racial groups suggesting that this diversity does not fully explain the decreasing incidence of CF in the US.
If anticipated diagnoses and timing of NBS implementation are not considered in the calculation of incidence rates, we showed that CF incidence would be underestimated by approximately 10%. NBS programs have allowed for a timelier determination of the number of babies born with CF rather than waiting for symptoms to develop to make the diagnosis. With time, the bias that occurs with missed diagnoses will be minimized as NBS program will pick up the majority of cases. However, there will continue to be a small percentage of individuals diagnosed later in life as NBS panels may miss less common mutations. In addition, the diagnostic accuracy of NBS algorithms vary which may result in some missed diagnoses although the false-negative rates are relatively low14–17. As well, migration of individuals with undiagnosed CF to North America who come from countries without NBS programs or where CF is underdiagnosed will continue to contribute to diagnoses later in life.
Comparing the overall incidence rate of CF in North America to Central Europe, rates fall somewhere between those reported in our paper for Canada and the US. Central European countries, specifically France, Germany, Italy, and Spain, have a reported incidence rate of ~1:4500.7 A recent publication from the Tuscany region of Italy reported the CF incidence to be slightly higher at 1:3939 between the 2011 to 2018 time period which is closer to the rate found in our study for Canada.18 Our results confirm that the incidence of CF is decreasing, and at a similar rate in both countries. As the population dynamics (trends in the number of live births) differed between Canada and the US, it is likely that the factors which influence incidence differ between the countries. The decreasing incidence could be explained by differential impact of factors that may influence family planning decisions such as genetic counselling, carrier testing or pre-implantation genetic testing in the two countries although this needs targeted research to confirm this hypothesis. Consistent with our findings, decreasing CF incidence has also been observed in other countries 5,6,19,20. In Western France, the incidence of CF has declined over a 35-year period from 1:1983 in the 1970s to 1:3268 between 2005 and 2009 which was noted after the availability of prenatal diagnosis the end of the 1980s 21. As genetic admixture and migration into North America may explain some of the decreasing incidence, it is important to note that diagnostic capabilities vary widely around the world. Under-diagnosis is more likely in people of non-European ancestry and thus the true incidence of CF may have higher than reported.
The geographic variation in incidence rates may relate to the genetic ancestry of a region. For example, due to a founder effect as well as genetic drift, some smaller isolated communities like the Hutterite population have a high rate of CF with genotypes limited to a small number of CFTR variants compared to individuals living in other communities 22. Interestingly, the proportion of individuals with CF who come from European ancestry was lower in the regions that had the lowest incidence rates. This may reflect the underlying population ancestral mix but it also may be non-white individuals in those regions have undiagnosed CF as NBS panels are biased towards mutations found in the European population.
CFTR modulators have created a new sense of optimism for the future of CF. The number of pregnancies amongst women with CF reported in the US CFFPR more than doubled from 2018 to 2020 after the availability of elexacaftor/tezacaftor/ivacaftor 23. Access to this medication has the potential to impact future incidence rates in that women with CF who have children will pass on a CFTR variant thus those children would be carriers and at risk of conceiving a child with CF. Furthermore, decisions around termination of CF pregnancies may be altered with the availability of an effective therapy that ameliorates the detrimental effects of CF. Another potential impact of modulators that may affect future incidence rates is the fact that CF babies born to women with CF on modulator therapy may be missed on NBS because of ongoing impact of modulator therapy during early life however this is expected to be a small number 24.
Our study has strengths and limitations that must be acknowledged. We utilized two established, long-standing registries that capture well-defined populations over many decades. Using these data over a 25-year period produces robust estimates increasing confidence in the results particularly around time trends. We included adjustments to account for anticipated diagnoses leading to more reliable estimates. We applied a unified approach to both countries and utilized detailed knowledge of the timing of implementation of NBS in the geographical regions thus providing greater precision in terms of which diagnoses were missed within each region allowing for regional estimates. However, it is possible that individuals with mild clinical phenotypes, those who die prior to a CF diagnosis or prior to inclusion in the registries, or individuals in certain ethnic groups may be under-diagnosed and are thus missing from the registries leading to underestimated incidence rates. However, both the Canadian and US registries report a high rate of capture due to incentives for individuals with CF to be followed at CF care centers and low rate of decline to participation in the registry. Furthermore, even if incidence rates are underestimated because of a small number of individuals missing from the registry, they reflect the incidence estimates of individuals with CF seeking medical care which is important from a healthcare planning perspective. A small proportion of patients were missing their location of birth and may have been misclassified. Also, there may be some diagnostic misclassification in the NBS era with individuals with CF-SPID/CRMS recorded as CF resulting in an overestimation of CF incidence.25 Our analysis adjusted for varied implementation of NBS across states and provinces. However, we recognize that our approach may not fully reflect the true complexity of CF NBS as there is considerable variability in the specific NBS algorithms used across regions. Furthermore, some DNA-based algorithms may be more likely to miss the diagnosis in non-white racial groups.26 This may result in underestimating the incidence rates. Capturing such granular data into a single national data resource should be considered in the future. Our study used registry data up to 2019 which is before the wide availability of elexacaftor/tezacaftor/ivacaftor. Access to this therapy may alter decisions around family planning thus, it will be important to re-evaluate incidence in the coming years.
CONCLUSION
Contemporary incidence rates show the incidence of CF is higher in Canada than in the US. National estimates are changing over time with significant variability between regions within countries. Accurate estimation of CF incidence is important for resource planning and for understanding how various programs such as genetic counselling or CFTR modulator availability may impact the incidence of this disease in the future. Reporting incidence rates as well as the rate of change over time can provide important information for future planning to ensure adequate resources to care for the CF community.
Supplementary Material
Supplementary Material
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Acknowledgements
We would like to acknowledge the financial support of the US CFF which made this study possible (STEPHE14A0). Also, we are grateful to Cystic Fibrosis Canada and the US CFF for providing registry data for this project. In addition, we would like to acknowledge and thank all of the CF patients and families in the US and Canada who consent to be part of their respective national CF patient registries as well as the CF clinic staff who spend many hours inputting the data.
Funding:
This work was funded through a grant from the US Cystic Fibrosis Foundation (STEPHE14A0).
Funding
The Cystic Fibrosis Foundation provided funding for this study. KJR receives funding from the Cystic Fibrosis Foundation and the NIH (K23HL138154). CHG receives funding from the Cystic Fibrosis Foundation, the NIH (R01HL103965, R01HL113382, R01AI101307, U M1HL119073, P30DK089507) and the FDA (R01FD003704).
ABBREVIATION LIST
| CCFR | Canadian CF Registry |
| CDC | Center for Disease Control |
| CF | cystic fibrosis |
| CFFPR | CF Foundation Patient Registry |
| CFTR | cystic fibrosis transmembrane regulatory protein |
| CI | confidence interval |
| CVSB | Canadian Vital Statistics Birth database |
| NBS | newborn screening |
| US | United States |
Footnotes
Conflict of Interest Statement: There are no conflicts to disclose.
Conflict of Interest Statement: No conflicts to declare for any authors
References
1. Scotet V, L’Hostis C, Férec C. The Changing Epidemiology of Cystic Fibrosis: Incidence, Survival and Impact of the CFTR Gene Discovery. Genes (Basel). 2020;11(6). [PMC free article] [PubMed] [Google Scholar]
2. Dupuis A, Hamilton D, Cole DE, Corey M. Cystic fibrosis birth rates in Canada: a decreasing trend since the onset of genetic testing. The Journal of pediatrics. 2005;147(3):312–315. [PubMed] [Google Scholar]
3. Lilley M, Christian S, Hume S, et al. Newborn screening for cystic fibrosis in Alberta: Two years of experience. Paediatrics & child health. 2010;15(9):590–594. [PMC free article] [PubMed] [Google Scholar]
4. Kosorok MR, Wei WH, Farrell PM. The incidence of cystic fibrosis. Statistics in medicine. 1996;15(5):449–462. [PubMed] [Google Scholar]
5. Castellani C, Picci L, Tamanini A, Girardi P, Rizzotti P, Assael BM. Association between carrier screening and incidence of cystic fibrosis. Jama. 2009;302(23):2573–2579. [PubMed] [Google Scholar]
6. Stafler P, Mei-Zahav M, Wilschanski M, et al. The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2016;15(4):460–466. [PubMed] [Google Scholar]
7. Scotet V, Gutierrez H, Farrell PM. Newborn Screening for CF across the Globe-Where Is It Worthwhile?Int J Neonatal Screen. 2020;6(1):18. [PMC free article] [PubMed] [Google Scholar]
8. Bosch B, Bilton D, Sosnay P, et al. Ethnicity impacts the cystic fibrosis diagnosis: A note of caution. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2017;16(4):488–491. [PubMed] [Google Scholar]
9. Chin M, Strug L, Stephenson AL. Don’t judge a book by its cover: the emerging challenge of diagnosing CF in non-Caucasians. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2017;16(4):439–440. [PubMed] [Google Scholar]
10. Chong MY, Hamilton DC, Cole DE. Retrospective estimation of the birth prevalence for delayed onset disorders: application to cystic fibrosis in Nova Scotia. Statistics in medicine. 2000;19(5):743–751. [PubMed] [Google Scholar]
11. Farrell PM, White TB, Ren CL, et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. The Journal of pediatrics. 2017;181s:S4–S15.e11. [PubMed] [Google Scholar]
12. Knapp EA, Fink AK, Goss CH, et al. The Cystic Fibrosis Foundation Patient Registry. Design and Methods of a National Observational Disease Registry. Annals of the American Thoracic Society. 2016;13(7):1173–1179. [PubMed] [Google Scholar]
13. Zvereff VV, Faruki H, Edwards M, Friedman KJ. Cystic fibrosis carrier screening in a North American population. Genetics in medicine : official journal of the American College of Medical Genetics. 2014;16(7):539–546. [PubMed] [Google Scholar]
14. Health CAfDaTi. Newborn Screening for Cystic Fibrosis: A Review of the Clinical and CostEffectiveness. 2012. [Google Scholar]
15. Kay DM, Langfelder-Schwind E, DeCelie-Germana J, et al. Utility of a very high IRT/No mutation referral category in cystic fibrosis newborn screening. Pediatric pulmonology. 2015;50(8):771–780. [PubMed] [Google Scholar]
16. Kharrazi M, Yang J, Bishop T, et al. Newborn Screening for Cystic Fibrosis in California. Pediatrics. 2015;136(6):1062–1072. [PubMed] [Google Scholar]
17. Sinclair G, McMahon V, Schellenberg A, Nelson TN, Chilvers M, Vallance H. Performance of a Three-Tier (IRT-DNA-IRT) Cystic Fibrosis Screening Algorithm in British Columbia. Int J Neonatal Screen. 2020;6(2):46. [PMC free article] [PubMed] [Google Scholar]
18. Taccetti G, Botti M, Terlizzi V, et al. Clinical and Genotypical Features of False-Negative Patients in 26 Years of Cystic Fibrosis Neonatal Screening in Tuscany, Italy. Diagnostics (Basel). 2020;10(7). [PMC free article] [PubMed] [Google Scholar]
19. Hale JE, Parad RB, Comeau AM. Newborn screening showing decreasing incidence of cystic fibrosis. The New England journal of medicine. 2008;358(9):973–974. [PubMed] [Google Scholar]
20. Parker-McGill K, Nugent M, Bersie R, et al. Changing incidence of cystic fibrosis in Wisconsin, USA. Pediatric pulmonology. 2015;50(11):1065–1072. [PMC free article] [PubMed] [Google Scholar]
21. Scotet V, Duguépéroux I, Saliou P, et al. Evidence for decline in the incidence of cystic fibrosis: a 35-year observational study in Brittany, France. Orphanet J Rare Dis. 2012;7:14. [PMC free article] [PubMed] [Google Scholar]
22. Pasterkamp H, Menzies KJ, Bayomi DJ. Cystic fibrosis in Canadian Hutterites. Pediatric pulmonology. 2020;55(2):526–532. [PubMed] [Google Scholar]
23. Foundation CF. Cystic Fibrosis Patient Data Registry Report. Bethesda, Maryland, USA2020. [Google Scholar]
24. Fortner CN, Seguin JM, Kay DM. Normal pancreatic function and false-negative CF newborn screen in a child born to a mother taking CFTR modulator therapy during pregnancy. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2021;20(5):835–836. [PubMed] [Google Scholar]
25. Ren CL, Fink AK, Petren K, et al. Outcomes of infants with indeterminate diagnosis detected by cystic fibrosis newborn screening. Pediatrics. 2015;135(6):e1386–1392. [PubMed] [Google Scholar]
26. McColley SA, Martiniano SL, Ren CL, et al. Disparities in first evaluation of infants with cystic fibrosis since implementation of newborn screening. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2022. [PubMed] [Google Scholar]
