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RATIONALE: Studies estimating rate of lung function decline in cystic fibrosis (CF) have been inconsistent regarding methods used. How the methodology used impacts validity of the results and comparability between studies is unknown.OBJECTIVES: The Cystic Fibrosis Foundation established a workgroup whose tasks were to examine the impact of differing approaches to estimating rate of decline in lung function and to provide analysis guidelines.METHODS: We utilized a natural history cohort of 35,252 individuals with CF aged > 6 years of the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified rate of forced expiratory volume in 1 second (FEV1) decline (% predicted/year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (RESULTS: Rate-of-FEV1-decline estimates (% predicted/year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios except for short-term follow-up (both were ~1.4). Rate-of-decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best except for short-term follow-up (< 2 years). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted/year in FEV1 associated with a 1.52-fold (52%) increase in the hazard of death/lung transplantation, but results exhibited immortal cohort bias.CONCLUSIONS: Differences were as high as 0.5% predicted/year between rate-of-decline estimates, but we found estimates were robust to lung function data availability scenarios except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

INTRODUCTION Chronic rhinosinusitis is common among individuals with cystic fibrosis (CF) and has an impact on quality of life. Sinus surgery is a treatment option, but minimal literature exists regarding prevalence and indications. METHODS Using the linked CF Foundation Patient Registry (CFFPR) - Pediatric Health Information Systems (PHIS) database, we investigated variability in receipt of surgery, predictors of surgery, and time to first surgery. We included individuals less than 18 receiving care between 2006 and 2015 at a CF Foundation care program that is also a PHIS-participating-hospital. We used logistic regression to examine predictors of receipt of surgery and a Kaplan-Meier curve to examine time to first surgery among those born 2005-2007. RESULTS There were 11,545 children and adolescents and 2156 (18.7%) received at least one surgery. Variation in number of surgeries was observed across hospitals (median: 63 [IQR, 33-110]). There was an inconsistent pattern between receipt of surgery and markers of disease severity; those receiving surgery having increased odds of treatment use and pulmonary exacerbations and decreased odds of lower lung function and body mass index. Among the cohort of young children, 159 (14%) had at least one surgery with a median age at first surgery of 5.6 (IQR, 3.9-7.0). CONCLUSIONS The use of sinus surgery is frequent, but variable, among children and adolescents. Clinical factors are associated with receipt of surgery, but further understanding is needed on other factors that impact variability in use. Our study indicates the need for additional evaluation of the management of CF-related CRS and indications for surgery.

Background Understanding how health outcomes differ for patients with advanced cystic fibrosis (CF) lung disease living in the United States compared with Canada has health policy implications. Research Question What are rates of lung transplant (LTx) and rates of death without LTx in the United States and Canada among individuals with FEV1 Study Design and Methods This was a retrospective population-based cohort study, 2005 to 2016, using the US CF Foundation, United Network for Organ Sharing, and Canadian CF registries. Individuals with CF and at least two FEV1 measurements Results There were 5,899 patients (53% male) and 905 patients (54% male) with CF with FEV1 Interpretation There are lower rates of LTx and an increased risk of death without LTx for US patients with CF with FEV1

Previous literature in cystic fibrosis (CF) has shown a 10-year survival gap between Canada and the United States (US). We hypothesized that differential access to and survival after lung transplantation may contribute to the observed gap. The objectives of this study were to compare CF transplant outcomes between Canada and the US and estimate the potential contribution of transplantation to the survival gap.Data from the Canadian CF Registry and the US Cystic Fibrosis Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. The probability of surviving after transplantation between 2005 and 2016 was calculated using the Kaplan‒Meier method. Survival by insurance status at the time of transplantation and transplant center volume in the US were compared with those in Canada using Cox proportional hazard models. Simulations were used to estimate the contribution of transplantation to the survival gap.Between 2005 and 2016, there were 2,653 patients in the US and 470 in Canada who underwent lung transplantation for CF. The 1-, 3-, and 5-year survival rates were 88.3%, 71.8%, and 60.3%, respectively, in the US compared with 90.5%, 79.9%, and 69.7%, respectively, in Canada. Patients in the US were also more likely to die on the waitlist (p0.01) than patients in Canada. If the proportion of who underwent transplantation and post-transplant survival in the US were to increase to those observed in Canada, we estimate that the survival gap would decrease from 10.8 years to 7.5 years.Differences in waitlist mortality and post-transplant survival can explain up to a third of the survival gap observed between the US and Canada.

Rationale The prevalence of adults living with cystic fibrosis (CF) who have early-stage lung disease is increasing. Objectives Describe the prevalence and evaluate spirometric risk factors associated with the subgroup of patients with early-stage lung disease and FEV1 decline of ≥5% predicted/year. Methods Retrospective cohort study of patients ≥18 years with FEV1% predicted ≥80% included in the US CF Foundation Patient Registry from 2010–2013. Regression models were developed to estimate FEV1 rate of decline. Multivariable logistic analysis was used to assess if spirometric risk factors were associated with FEV1 decline. Measurements and main results 3,029 subjects were in the study cohort. Approximately 15% of the cohort had a substantial decline in lung function ≥5% predicted/year. In multivariable models adjusted for confounders, FEV1/FVC ratio Conclusions Even among adults with early-stage lung disease, approximately 15% are shown to progress and experience a large decline in lung function. This reinforces the concept that lung function in early-stage CF is not normal or mild. Rather, lung function decline may be delayed, but not avoided, in these individuals. Variability in FEV1% predicted and airway obstruction as measured by FEV1/FVC ratio may identify individuals at increased risk of decline. Adults with early-stage lung disease should be followed in clinic to monitor for onset of decline.

Current guidelines recommend screening for Cystic Fibrosis (CF) related bone disease (CFBD) using dual-energy x-ray absorptiometry (DXA) for all people ≥ 18 years of age and select people ≥ 8 years of age. However, adherence to these guidelines is variable. This study aims to evaluate screening practices among adult programs in the US and identify patient and program-based characteristics which may influence screening.The CF Foundation Patient Registry (CFFPR) was used to identify all people over the age of 18 who were seen at adult CF programs and received screening for CFBD using DXA at least once between 2014 and 2018. Associations with patient and program level characteristics were assessed using the Chi Square test. Patient level variables were also examined using standardized difference to assess for meaningful clinical differences in rates of screening.From 2014 to 2018, a total of 15,134 people over the age of 18 were identified in the CFFPR. Of these people, 9,023 (60%) received a DXA during the time period. The median rate of screening by program was 66% and programs in the highest quartile of screening obtained DXAs on76% of their population. At the program level, larger size and increased adherence to other guideline practices such as OGTT screening and 4 visits, 4 cultures in a year correlated with higher rates of screening for CFBD. At the patient-level, people with lower lung function (FEV190%) and those with CF related diabetes were more likely to be screened. People without health insurance were less likely to receive recommended screening.Screening practices for CFBD vary widely across adult programs in the US despite recommendations to screen all people over the age of 18. Factors identified in this analysis may be used to identify those people at highest risk of missing appropriate screening. CFBD has significant implications for our patients and therefore routine screening should be emphasized as part of standard care moving forward.

Strong emphasis has been placed historically on increasing weight and improving nutritional status in cystic fibrosis patients. Due to correlation between nutritional indices (e.g. BMI) and lung function, CF Nutrition Guidelines have recommended BMI percentile goals at the 50th percentile or higher. Trends in increasing BMI across CF programs suggest significantly increasing proportions of overweight and obese status in recent years. We identify that between 2000 and 2019 there has been a relative decrease in underweight status by ∼40%, simultaneously with a 300% increase in overweight status, and400% increase in obesity. Patient specific factors associated with higher prevalence of obesity included age ≥46, living in a zip code where the median income was$20,000, having at least one allele with a class IV or V mutation, a ppFEV

RationaleA previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results.ObjectivesTo compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences.MethodsWe used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics).ResultsWe included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK.ConclusionsChildren with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.

Rationale: Clinical variables associated with shortened survival in patients with advanced-stage cystic fibrosis (CF) are not included in the lung allocation score (LAS).Objectives: To identify variables associated with wait-list and post-transplant mortality for CF lung transplant candidates using a novel database and to analyze the impact of including new CF-specific variables in the LAS system.Methods: A deterministic matching algorithm identified patients from the Scientific Registry of Transplant Recipients and the Cystic Fibrosis Foundation Patient Registry. LAS wait-list and post-transplant survival models were recalculated using CF-specific variables. This multicenter, retrospective, population-based study of all lung transplant wait-list candidates aged 12 years or older from January 1, 2011, to December 31, 2014, included 9,043 patients on the lung transplant waiting list and 6,110 lung transplant recipients between 2011 and 2014, comprising 1,020 and 677 with CF, respectively.Measurements and Main Results: Measured outcomes were changes in LAS and lung allocation rank. For CF candidates, any Burkholderia sp. (hazard ratio [HR], 2.8; 95% confidence interval [CI], 1.2-6.6), 29-42 days hospitalized (HR 2.8; CI 1.3-5.9), massive hemoptysis (HR 2.1; CI 1.1-3.9), and relative drop in FEV1 ≥30% over 12 months (HR 1.7; CI 1.0-2.8) increased wait-list mortality risk; pulmonary exacerbation time 15-28 days (1.8; 1.1-2.9) increased post-transplant mortality risk. A relative drop in FEV1 ≥10% in chronic obstructive pulmonary disease (COPD) candidates was associated with increased wait-list mortality risk (HR 2.6; CI 1.2-5.4). Variability in LAS score and rank increased in patients with CF. Priority for transplant increased for COPD candidates. Access did not change for other diagnosis groups.Conclusions: Adding CF-specific variables improved discrimination among wait-listed CF candidates and benefited COPD candidates.

All bias analyses modify a conventional estimate of association to account for bias introduced by systematic error. These quantitative modifications revise the conventional estimate of association (e.g., a risk difference or a rate ratio) with equations that adjust it for the estimated impact of the systematic error. These equations have parameters, called bias parameters, that ultimately determine the direction and magnitude of the adjustment. For example: The proportions of all eligible subjects who participate in a study, simultaneously stratified into subgroups of persons with and without the disease outcome and within categories of the exposure variable of interest, are bias parameters. These parameters determine the direction and magnitude of selection bias. The sensitivity and specificity of exposure classification, within subgroups of persons with and without the disease outcome of interest, are bias parameters that affect the direction and magnitude of bias introduced by exposure misclassification. The strength of association between an unmeasured confounder and the exposure of interest and between the unmeasured confounder and the disease outcome of interest are bias parameters that affect the direction and magnitude of bias introduced by an unmeasured confounder.

Rationale: Referrals for lung transplant and transplant rates in the United States are lower than in Canada for patients with advanced cystic fibrosis (CF) lung disease. Further study of factors limiting access are needed to optimize referral and transplant for this population. Objectives: To determine the effect of socioeconomic position, while accounting for disease severity, on the likelihood of wait-listing for lung transplant in the United States. Methods: A case–control study of 3,110 patients (1,555 wait-listed, 1,555 never wait-listed) in the linked CF Foundation Patient Registry/Scientific Registry of Transplant Recipients was performed with 1:1 matching for age, forced expiratory volume in 1 second, and year. Logistic regression was performed with univariate and multivariate analyses accounting for eight clinical factors (sex, oxygen use, body mass index, hemoptysis, forced vital capacity, methicillin-resistant Staphylococcus aureus, multidrug-resistant Pseudomonas aeruginosa, and i.v. antibiotic days) and six socioeconomic factors (race, marital status, education, health insurance, median zip code income, and distance to transplant program). The CF Health Score and Socioeconomic Barrier Score were created based on summation of variables. Interactions between scores were calculated. Results: We found an inverse relationship between the probability of wait-listing and CF Health Score and Socioeconomic Barrier Score. As the CF Health Score decreased (less healthy), the probability of wait-listing increased by 69.3% from a score of 7 to 2. As the Socioeconomic Barrier Score decreased (fewer barriers), the probability of wait-listing increased by 31.7% from a score of ≥5 to 1). Regardless of illness severity, socioeconomic barriers presented an impediment to wait-listing. Individuals with higher Socioeconomic Barrier Scores accessed transplant about half as often as those with lower scores at the same level of medical severity. Analysis of interactions demonstrated a higher probability of wait-listing for individuals with moderate health severity and fewer social barriers compared with sicker individuals with more socioeconomic barriers. Conclusions: Accrual of socioeconomic barriers limits access to lung transplant irrespective of disease severity, a finding of substantial concern for patients with CF and for transplant providers. Future interventions can focus on this at-risk population early in the disease course.

Background The International Depression Epidemiological Study (TIDES) found elevated rates of screen positivity for depression and anxiety among individuals with cystic fibrosis (CF). Depression is associated with worse adherence and health-related quality of life in CF. We investigated the relationship with mortality. Methods Subjects were untransplanted participants in TIDES 12+ years of age receiving care at one of 45 collaborating US CF care centers who completed the Hospital Anxiety and Depression Scale and/or Center for Epidemiologic Studies Depression Scale during a stable visit between 2006 and 2010. Clinical characteristics and mortality data were obtained from the CF Foundation Patient Registry. The association of a positive screen with 5-year survival was evaluated using Cox Proportional Hazards modeling. Results Of 1005 eligible patients, 25% screened positive for depression and 34% screened positive for anxiety. Patients who screened positive for depression were more likely to be older, have a residual function mutation, public insurance, and more pulmonary exacerbations in the screening year. There were 96 deaths. The unadjusted 5-year Hazard Ratio (HR) for death among those with depression was 2.0; 95% CI (1.3, 3.0)]. When adjusted for predetermined potential confounders the HR for the entire population was 1.4; 95% CI (0.9, 2.2). The adjusted HR was higher in adults [1.6; 95% CI (1.0, 2.4)] and those screening in the severe range [2.0; 95% CI (1.2, 3.4)]. Anxiety was not associated with mortality. Conclusions A positive depression screen is associated with increased mortality among adults with CF. Research into the etiology of this relationship is needed.

BACKGROUND: The American Academy of Pediatrics does not recommend routine use of palivizumab prophylaxis for infants with cystic fibrosis (CF) but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain. METHODS: We used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary–related hospitalizations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. We created propensity scores to adjust for potential confounding by indication (ie, sicker infants were more likely to receive palivizumab). For each outcome, we performed regression analyses adjusted by propensity scores. RESULTS: The sample included 4267 infants; 1588 (37%) received palivizumab. Mean percent forced expiratory volume in 1 second predicted at 7 years old was similar among those who did (98.2; 95% confidence interval: 96.9–99.5) and did not (97.3; 95% confidence interval: 96.1–98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalization were similar among those who did and did not receive palivizumab. CONCLUSIONS: At the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.

Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians. Significant advances in therapies and outcomes have occurred for people with CF over the past 30 years. Many of these improvements have come about through the concerted efforts of the US CF Foundation and international CF societies, networks of CF care centers, and the worldwide community of care providers, researchers, and patients and families. Despite these gains, there are still hurdles to overcome to continue to improve the quality of life, reduce CF complications, prolong survival, and ultimately cure CF. This article reviews the epidemiology of CF, including trends in incidence and prevalence, clinical characteristics, common complications, and survival.

The Cystic Fibrosis Foundation Patient Registry (CFFPR) is an ongoing patient registry study that collects longitudinal demographic, clinical, and treatment information about persons with cystic fibrosis (CF) in the United States. CF is a life-shortening genetic disorder that occurs in approximately 1 in 3,500 births in the United States. High-quality observational data is important for clinical research, quality improvement, and clinical management.To describe the data collection, patient population, and key limitations of the CFFPR.Inclusion criteria for the CFFPR include diagnosis with CF or a CFTR-associated disorder, care at an accredited care center program, and provision of informed consent. Data from clinic visits and hospitalizations are collected through a secure website. Loss to follow-up and generalizability were examined using several methods. The accuracy of CFFPR data was evaluated with an audit of 2012 CFFPR data compared to the medical record.Since 1986, the CFFPR contains the records of 48,463 individuals with CF. Participation among individuals seen at accredited care centers is high, and loss to follow-up is low. An audit of 2012 CFFPR data suggests that the CFFPR contains 95% of clinic visits and 90% of hospitalizations found in the medical record for these patients, and nearly all of the audited fields were highly accurate.Registries such as the CFFPR are important tools for research, clinical care, and tracking incidence, mortality and population trends.

Objectives Our objective was to quantify the effect of different statistical techniques, inclusion/exclusion criteria, and missing data on the predicted median survival age. Study Design and Setting Using the Canadian cystic fibrosis registry (CCFR), the median age of survival was calculated using both the Cox proportional hazards (PH) and the life-table methods. Through simulations, we examined how the median age of survival would change when: (1) patients were excluded, (2) death dates were inaccurate, (3) patients were lost to follow-up, (4) entire years with no clinic visits were excluded even if the​ patient had a visit in subsequent years, and (5) censoring patients at their date of transplant. Simulations were run assuming 5–35% of data were affected by each scenario. Results Over the period 2009–2013, there were 4,666 individuals in the CCFR with 240 deaths. The observed median age of survival calculated by the Cox PH method was 50.9 [95% confidence interval (CI): 47.4, 54.3] and 50.5 from the life-table method (95% CI: 47.5, 53.5). Censoring patients at their transplant date overestimated the median age of survival by 7.2 years (58.1; 95% CI: 53.3, 64.7). Simulations determined that by missing just 15% of deaths, the median age of survival can be overestimated by 3.5 years (54.4; 95% CI: 54.2, 56.1), and having 25% of patients lost to follow-up can underestimate the median age of survival by 3.3 years (47.6; 95% CI: 46.8, 47.7). Conclusion We present several recommendations to assist national cystic fibrosis registries in calculating and reporting the median age of survival in a standardized fashion. It is imperative to state the statistical method used as well as the proportion lost to follow-up and the treatment of missing data and transplanted patients. Registries must be diligent in their data collection as incomplete data can lead to overestimation and underestimation of survival.

Background Monitoring potential changes in the epidemiology of cystic fibrosis (CF) pathogens furthers our understanding of the potential impact of interventions. Methods We performed a retrospective analysis using data reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) from 2006 to 2012 to determine the annual percent changes in the prevalence and incidence of selected CF pathogens. Pathogens included Pseudomonas aeruginosa , methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S aureus (MRSA), Haemophilus influenzae , Burkholderia cepacia complex, Stenotrophomonas maltophilia , and Achromobacter xylosoxidans . Changes in nontuberculous mycobacteria (NTM) prevalence were assessed from 2010 to 2012, when the CFFPR collected NTM species. Results In 2012, the pathogens of highest prevalence and incidence were MSSA and P aeruginosa , followed by MRSA. The prevalence of A xylosoxidans and B cepacia complex were relatively low. From 2006 to 2012, the annual percent change in overall (as well as in most age strata) prevalence and incidence significantly decreased for P aeruginosa and B cepacia complex, but significantly increased for MRSA. From 2010 to 2012, the annual percent change in overall prevalence of NTM and Mycobaterium avium complex increased. Conclusions The epidemiology of CF pathogens continues to change. The causes of these observations are most likely multifactorial and include improvements in clinical care and infection prevention and control. Data from this study will be useful to evaluate the impact of new therapies on CF microbiology.

BACKGROUND: Most studies of pulmonary exacerbations (PEx) in cystic fibrosis (CF) focus on intravenous (IV)-treated PEx, though most PEx are treated with oral antibiotics. Our objectives were to describe predictors of antibiotic choice and outcomes for PEx initially identified in clinic. METHODS: For each patient in the U.S. CF Foundation Patient Registry, we selected the first PEx recorded at a clinic visit in 2013-14 following a clinic visit without a PEx. We used multivariable logistic regression to determine associations between clinical characteristics and antibiotic treatment choice. We determined outcomes in the 90 days after the first PEx. RESULTS: Among 14,265 patients with a PEx initially identified in clinic, 21.4% received no antibiotics, 61.5% received new oral and/or inhaled antibiotics, and 17.0% had IV antibiotics within 14 days. Compared to IV antibiotics, patients more likely to receive new oral and/or inhaled antibiotics: were male, 10(th) percentile or 18.5 kg/m(2), >90 days between clinic visits, FEV(1) >70% predicted at the PEx, no prior-year IV-treated PEx, FEV1 decline

Rationale Lumacaftor-ivacaftor (LUM-IVA) was approved in the US in 2015 for patients with CF aged >12 homozygous for the delF508 mutation, and patients aged 6 to 12 in 2016. Objectives To examine the rate of initial LUM-IVA prescriptions following approval. Methods We compared patients eligible for LUM-IVA in the CF Foundation Patient Registry with and without prescriptions in 2015–2016. Results 5534 (53%) eligible patients had reported prescriptions. Prescription rate in children ages 6–11 was 19% and 61% among patients ≥12 years old. Individuals ≥12 with prescriptions more likely observed among those with private insurance, clinical trial participation, ages 18–30, FEV1 Conclusions LUM-IVA uptake was less rapid than what was previously observed for ivacaftor, a CFTR modulator approved for a different population. Age, insurance status, disease severity and use of other therapies differed in those prescribed LUM-IVA in the initial post-approval period.

Introduction The Cystic Fibrosis Foundation Patient Registry (CFFPR) contains clinical and demographic data from ∼85% of US cystic fibrosis (CF) patients across 120 care centers, but lacks robust inpatient hospitalization data. In contrast, the Pediatric Health Information System (PHIS) database includes inpatient clinical and resource utilization data from 49 US children's hospitals. The creation of a linked CFFPR-PHIS dataset can uniquely address questions related to in-hospital pediatric CF treatment and management. We assessed the feasibility of linking the CFFPR and PHIS databases and determined if successfully linked CF patients were generalizable to unlinked patients. Methods CF patients ≤21 years were eligible for linkage. The CFFPR and PHIS databases were linked at the patient level using indirect identifiers in a stepwise, deterministic, linkage approach. A validation cohort was created using a subset of patients to determine linkage accuracy. Clinical and demographic characteristics between linked and unlinked patients were compared to determine generalizability of the linked cohort. Results Of the 11 735 CF patients eligible for linkage from January 1st, 2005 through December 31st, 2016, 10 660 (91%) were successfully linked. Results of our single center validation cohort illustrated 100% accuracy. When compared to unlinked CF patients, fewer linked patients were born before 1990, more were Hispanic, and more were from West-affiliated PHIS hospitals. Otherwise, no clinically meaningful differences were seen between linked and unlinked CF patients. Conclusions We demonstrated successful linkage of the CFFPR and PHIS databases, and created a large generalizable pediatric CF cohort for use in CF-related research.

Cystic fibrosis is a life-threatening genetic disease that causes severe damage to the lungs. Ivacaftor, the first drug that targeted the underlying defect of the disease caused by specific mutations, is a sterling example of the potential of precision medicine. Clinical trial and registry studies showed that ivacaftor improved outcomes and reduced hospitalizations. Our study used US administrative claims data to assess the real-world effectiveness of ivacaftor. Comparing twelve-month rates before and after starting the use of ivacaftor among people who initiated therapy during 2012-2015, we found that overall and cystic fibrosis-related inpatient admissions fell by 55 percent and 81 percent, respectively. There was a comparable reduction in inpatient spending. Ivacaftor appears to be effective for multiple mutations that cause the disease, as suggested by the fact that during the study period, ivacaftor's use was extended to nine additional mutations in 2014. Examination of evidence from clinical trial, clinical care, and administrative data sources is important for understanding the real-world effectiveness of precision medicines such as ivacaftor.

Background & Aims Individuals with cystic fibrosis are at increased risk of colorectal cancer (CRC) compared with the general population, and risk is higher among those who received an organ transplant. We performed a cost-effectiveness analysis to determine optimal CRC screening strategies for patients with cystic fibrosis. Methods We adjusted the existing Microsimulation Screening Analysis-Colon model to reflect increased CRC risk and lower life expectancy in patients with cystic fibrosis. Modeling was performed separately for individuals who never received an organ transplant and patients who had received an organ transplant. We modeled 76 colonoscopy screening strategies that varied the age range and screening interval. The optimal screening strategy was determined based on a willingness to pay threshold of $100,000 per life-year gained. Sensitivity and supplementary analyses were performed, including fecal immunochemical test (FIT) as an alternative test, earlier ages of transplantation, and increased rates of colonoscopy complications, to assess if optimal screening strategies would change. Results Colonoscopy every 5 years, starting at an age of 40 years, was the optimal colonoscopy strategy for patients with cystic fibrosis who never received an organ transplant; this strategy prevented 79% of deaths from CRC. Among patients with cystic fibrosis who had received an organ transplant, optimal colonoscopy screening should start at an age of 30 or 35 years, depending on the patient's age at time of transplantation. Annual FIT screening was predicted to be cost-effective for patients with cystic fibrosis. However, the level of accuracy of the FIT in this population is not clear. Conclusions Using a Microsimulation Screening Analysis-Colon model, we found screening of patients with cystic fibrosis for CRC to be cost effective. Because of the higher risk of CRC in these patients, screening should start at an earlier age with a shorter screening interval. The findings of this study (especially those on FIT screening) may be limited by restricted evidence available for patients with cystic fibrosis.

Individuals with cystic fibrosis are at increased risk of colorectal cancer (CRC) compared to the general population, and risk is higher among those who received an organ transplant. We performed a cost-effectiveness analysis to determine optimal CRC screening strategies for patients with cystic fibrosis.We adjusted the existing Microsimulation Screening Analysis-Colon microsimulation model to reflect increased CRC risk and lower life expectancy in patients with cystic fibrosis. Modeling was performed separately for individuals who never received an organ transplant and patients who had received an organ transplant. We modeled 76 colonoscopy screening strategies that varied the age range and screening interval. The optimal screening strategy was determined based on a willingness to pay threshold of $100,000 per life-year gained. Sensitivity and supplementary analyses were performed, including fecal immunochemical test (FIT) as an alternative test, earlier ages of transplantation, and increased rates of colonoscopy complications, to assess whether optimal screening strategies would change.Colonoscopy every 5 years, starting at age 40 years, was the optimal colonoscopy strategy for patients with cystic fibrosis who never received an organ transplant; this strategy prevented 79% of deaths from CRC. Among patients with cystic fibrosis who had received an organ transplant, optimal colonoscopy screening should start at an age of 30 or 35 years, depending on the patient's age at time of transplantation. Annual FIT screening was predicted to be cost-effective for patients with cystic fibrosis. However, the level of accuracy of the FIT in population is not clear.Using a Microsimulation Screening Analysis-Colon microsimulation model, we found screening of patients with cystic fibrosis for CRC to be cost-effective. Due to the higher risk in these patients for CRC, screening should start at an earlier age with a shorter screening interval. The findings of this study (especially those on FIT screening) may be limited by restricted evidence available for patients with cystic fibrosis.

With improved survival into adulthood, the number of dedicated adult cystic fibrosis (CF) care programs has expanded in the United States over the past decade. Transfer from pediatric to adult CF programs represents a potential time for lapses in recommended health care.To describe variability in transfer between pediatric and adult CF care programs and to identify factors associated with prolonged gaps in care.Using the U.S. CF Foundation Patient Registry, we identified individuals with CF who transferred care from a pediatric to an adult CF care program during 2007 to 2013. A gap in care was defined as the time in days between the last recorded pediatric encounter and the first recorded adult encounter. A hierarchical multivariable regression model was applied to investigate the effect of program- and patient-level factors on gaps in care.There were 1,946 individuals at 155 pediatric CF programs who transferred to an adult CF program during the analytic period. The mean age at transfer was 21.1 years, with 68% transferring care between ages 18 and 21 years. The mean gap in care during transfer was 183 days (median, 106 d; range, 2-1,843 d); 47% had a less than 100-day gap, and 13% had a greater than or equal to 365-day gap (prolonged gap). Prolonged gaps in care were more likely to occur among those younger than age 18 years (odds ratio, 3.33; 95% confidence interval, 2.06-5.37) at the time of transfer and those who transferred to an adult program that was in a different city from their pediatric or affiliate program (odds ratio, 2.16; 95% confidence interval, 1.48-3.17). Having any health insurance coverage was associated with decreased likelihood of prolonged gaps (private insurance vs. no insurance [odds ratio, 0.15; 95% confidence interval, 0.09-0.23] or any government insurance versus no insurance [odds ratio, 0.11; 95% confidence interval, 0.07-0.18]). Lung function, nutritional status, and receipt of intravenous antibiotics in the final year of pediatric care were not associated with the length of gap in care during transfer.In the United States, the majority of individuals transferring from pediatric to adult CF care do so between ages 18 and 21 years. A minority had a gap greater than or equal to 365 days during transfer to adult care, suggesting that most did not have a disruption in recommended quarterly care visits during the transfer period. Risk factors for prolonged gaps in care include younger age at transfer, lack of health insurance, and relocation. Care coordination during transition in CF may minimize lapses in care by identifying and more closely addressing the needs of individuals at highest risk.

A 10-year gap in the median age of survival for patients with cystic fibrosis (CF) was reported between patients living in Canada compared with patients living in the United States.Because both malnutrition and poor lung function are associated with an increased risk of mortality in CF, we investigated the temporal and longitudinal trends in lung function and nutrition between Canada and the United States.This cohort study used Canadian CF Registry and U.S. CF Foundation Patient Registry data from 1990 to 2013. A unified dataset was created to harmonize the variables collected within the two registries for the purpose of comparing outcomes between the two countries.We conducted three analyses: survival differences by birth cohort; population trends for FEVThe reasons for the observed improvements, and catch-up in the United States, are likely multifactorial and include the introduction of high-fat, high-calorie diets; introduction of newborn screening; and/or improved access to care for CF children in the United States.

BACKGROUND AND OBJECTIVES: Cystic fibrosis transmembrane conductance regulator–related metabolic syndrome (CRMS) describes asymptomatic infants with a positive cystic fibrosis (CF) newborn screen (NBS) but inconclusive diagnostic testing for CF. Little is known about the epidemiology and outcomes of CRMS. The goal of this study was to determine the prevalence, clinical features, and short-term outcomes of infants with CRMS. METHODS: We analyzed data from the US CF Foundation Patient Registry (CFFPR) from 2010 to 2012. We compared demographic, diagnostic, anthropometric, health care utilization, microbiology, and treatment characteristics between infants with CF and infants with CRMS. RESULTS: There were 1983 infants diagnosed via NBS between 2010 and 2012 reported to the CFFPR. By using the CF Foundation guideline definitions, 1540 and 309 infants met the criteria for CF and CRMS, respectively (CF:CRMS ratio = 5.0:1.0). Of note, 40.8% of infants with CRMS were entered into the registry with a clinical diagnosis of CF. Infants with CRMS tended to have normal nutritional indices. However, 11% of infants with CRMS had a positive Pseudomonas aeruginosa respiratory tract culture in the first year of life. CONCLUSIONS: CRMS is a common outcome of CF NBS, and some infants with CRMS may develop features concerning for CF disease. A substantial proportion of infants with CRMS were assigned a clinical diagnosis of CF, which may reflect misclassification or clinical features not collected in the CFFPR.

Background In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias. Objective To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States. Design Population-based study. Setting 42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers. Patients Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013. Measurements Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival. Results Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 [95% CI, 0.54 to 0.81]). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively [standardized difference, 13.7]). Differences in survival between U.S. and Canadian patients varied according to U.S. patients' insurance status. Limitation Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results. Conclusion Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage. Primary Funding Source U.S. Cystic Fibrosis Foundation.

Purpose To identify novel variables associated with waitlist (WL) and posttransplant (PT) mortality for cystic fibrosis (CF) lung transplant patients. To analyze the impact of including new variables in the lung allocation score (LAS) system. Methods The Cystic Fibrosis Foundation Patient Registry (CFFPR) collects data for CF patients prior to listing and the US Scientific Registry of Transplant Recipients Registry collects broad data after listing. These databases were merged by a deterministic algorithm to represent CF patients pre- to posttransplant. The study included candidates and recipients, 1/1/2011-12/31/2014. CFFPR variables known to be important for mortality in CF were considered in Kaplan-Meier univariate time-to-event analyses; significant variables were considered in multivariable Cox proportional hazard regression analysis. LAS and rank, based on models including new variables, were calculated and compared by diagnosis. Results The study cohort consisted of 1020 WL candidates with CF and 677 transplant recipients. Relative drop in FEV1 ≥ 30%, presence of Burkholderia sp., 28-42 days hospitalized, and hemoptysis increased WL mortality. Pulmonary exacerbation time of 15-28 days increased risk of PT mortality. Relative change in FEV1 ≥ 10% increased mortality in chronic obstructive pulmonary disease (COPD) candidates. Including these new variables in the LAS calculation resulted in (1) CF candidates with increased variability in LAS and rank; (2) COPD candidates with higher LAS values and lower rank, indicating increased access to transplant; (3) minimal impact on candidates with other diagnoses. Conclusion Addition of CF-specific variables increased the predictive power of LAS for candidates with CF and COPD. Incorporating CF-specific variables could potentially decrease waitlist mortality for candidates with CF.

BACKGROUND: Previous studies demonstrated increased digestive tract cancers among individuals with cystic fibrosis (CF), particularly among lung transplant recipients. We describe cancer incidence among CF and non-CF lung recipients. METHODS: We used data from the US transplant registry and 16 cancer registries. Standardized incidence ratios (SIRs) compared cancer incidence to the general population, and competing risk methods were used for the cumulative incidence of colorectal cancer. RESULTS: We evaluated 10,179 lung recipients (1,681 with CF). Risk was more strongly increased in CF recipients than non-CF recipients for overall cancer (SIR 9.9 vs. 2.7) and multiple cancers including colorectal cancer (24.2 vs. 1.7), esophageal cancer (56.3 vs. 1.3), and non-Hodgkin lymphoma (61.8 vs. 9.4). At five years post-transplant, colorectal cancer was diagnosed in 0.3% of CF recipients aged

Death certificates are the source for mortality statistics and are used to set public health goals. Accurate death certificates are vital in tracking outcomes of cancer. Deaths may be certified by physicians or other medical professionals, coroners, or medical examiners. Idaho is one of 3 states that participated in a Centers for Disease Control and Prevention-funded study to assess the concordance between cancer-specific causes of death and primary cancer site among linked cancer registry/death certificate data. We investigated variability in the accuracy of cancer death certificates by characteristics of death certifiers, including certifier type (physician vs coroner), physician specialty, years of experience as death certifier, and number of deaths certified. This study showed significant differences by certifier type/physician specialty in the accuracy of cancer mortality measured by death certificates. Nonphysician coroners had lower accuracy rates compared with physicians. Although nonphysician coroners certified less than 5% of cancer deaths in Idaho, they were significantly less likely to match the primary site from the cancer registry. Results from this study may be useful in the future training of death certifiers to improve the accuracy of death certificates and cancer mortality statistics.

Background: Cancer mortality statistics, an important indicator for monitoring cancer burden, are traditionally restricted to instances when cancer is determined to be the underlying cause of death (UCD) based on information recorded on standard certificates of death. This study's objective was to determine the impact of using multiple causes of death codes to compute site-specific cancer mortality statistics. Methods: The state cancer registries of California, Colorado and Idaho provided linked cancer registry and death certificate data for individuals who died between 2002 and 2004, had at least one cancer listed on their death certificate and were diagnosed with cancer between 1993 and 2004. These linked data were used to calculate the site-specific proportion of cancers not selected as the UCD (non-UCD) among all cancer-related deaths (any mention on the death certificate). In addition, the retrospective concordance between the death certificate and the population-based cancer registry, measured as confirmations rates, was calculated for deaths with cancer as the UCD, as a non-UCD, and for any mention. Results: Overall, non-UCD deaths comprised 9.5 percent of total deaths; 11 of the 79 cancer sites had proportions greater than 3 standard deviations from 9.5 percent. The confirmation rates for UCD and for any mention did not differ significantly for any of the cancer sites. Conclusion and impact: The site-specific variation in proportions and rates suggests that for a few cancer sites, death rates might be computed for both UCD and any mention of the cancer site on the death certificate. Nevertheless, this study provides evidence that, in general, restricting to UCD deaths will not under report cancer mortality statistics.

One measure of the accuracy of cancer mortality statistics is the concordance between cancer defined as the underlying cause of death from death certificates and cancer diagnoses recorded in central, population-based cancer registries. Previous studies of such concordance are outdated.To characterize the accuracy of cancer mortality statistics from the concordance between cancer cause of death and primary cancer site at diagnosis.Central cancer registry records from California, Colorado, and Idaho in the U.S. were linked with state vital statistics data and evaluated by demographic and tumor information across 79 site categories. A retrospective arm (confirmation rate per 100 deaths) compared death certificate data from 2002 to 2004 with cancer registry diagnoses from 1993 to 2004, while a prospective arm (detection rate per 100 deaths) compared cancer registry diagnoses from 1993 to 1995 with death certificate data from 1993 to 2004 by International Statistical Classification of Diseases and Related Health Problems (ICD) version used to code deaths.With n=265,863 deaths where cancer was recorded as the underlying cause based on the death certificate, the overall confirmation rate for ICD-10 was 82.8% (95% confidence interval [CI], 82.6-83.0%), the overall detection rate for ICD-10 was 81.0% (95% CI, 80.4-81.6%), and the overall detection rate for ICD-9 was 85.0% (95% CI, 84.8-85.2%). These rates varied across primary sites, where some rates were50%, some were 95% or greater, and notable differences between confirmation and detection rates were observed.Important unique information on the quality of cancer mortality data obtained from death certificates is provided. In addition, information is provided for future studies of the concordance of primary cancer site between population-based cancer registry data and data from death certificates, particularly underlying causes of death coded in ICD-10.

Background Cystic fibrosis (CF) patients from Canada have better-reported post-lung transplant survival compared to patients from the United States. We hypothesized the clinical characteristics of CF patients prior to lung transplant differ between the two countries. Methods Population-based cohort study utilizing combined Canadian CF Registry and US CF Foundation Patient Registry data from 1986 to 2013. Demographic and clinical variables were analyzed prior to lung transplant. Results Between 1986 and 2013, 607 (10.2%) CF patients underwent lung transplantation in Canada and 3428 (7.5%) in the United States. A lower proportion of recipients had growth of B. cepacia complex prior to transplant in the United States compared to Canada (0.8% vs 4.3%). Lung function was similar between recipients from the two countries. The proportion of patients classified as underweight was significantly higher in the United States compared to Canada (39.8% vs 28.0%; SD 26.1) despite higher rates of feeding tube use (42.5% vs 28.6%; SD 29.0). Conclusions CF lung transplant recipients from the United States have similar lung function, lower rates of B. cepacia complex, and worse nutritional parameters prior to transplant compared to counterparts in Canada. Future studies are necessary to evaluate the impact of these differences on post-transplant survival.

Chronic cystic fibrosis (CF) therapies have variable rates of prescribed use, and therapies are rarely prescribed to more than 80% of eligible patients. Ivacaftor was approved in the United States in January 2012 for patients ages 6 years and older with a G551D mutation in their CF gene.To examine the rate of uptake and patterns of documented ivacaftor use among U.S. patients with CF during the first year after approval, to compare eligible patients with and without reported use, and to describe characteristics of early adopters of ivacaftor use.A cross-sectional study of patients in the U.S. Cystic Fibrosis Foundation Patient Registry in 2012 with at least one encounter in which ivacaftor use was documented. Ivacaftor-eligible patients were defined as any individual 6 years of age or older with a G551D mutation. We performed bivariate and multivariate regression analyses, stratified by age group, to compare clinical and demographic characteristics of (1) eligible patients with and without documented ivacaftor use in 2012 and (2) early (February-June) versus late (July-December) adopters in 2012.A total of 1,087 patients with CF with G551D mutations were in the U.S. Cystic Fibrosis Foundation Patient Registry in 2012. By June 2012, 64% of eligible patients had documented ivacaftor use, which increased to 81% by the end of 2012. Among eligible patients younger than 18 years of age, 85% were prescribed ivacaftor, with significantly lower odds among those with higher BMI percentile, fewer clinical encounters in 2011, and later age at diagnosis. Among eligible patients age 18 years or older, 79% were prescribed ivacaftor, with significantly lower odds in nonwhite patients and those with later age at diagnosis. Documented prescriptions of ivacaftor also varied by state of residence, with a range of 42-100% of eligible patients across states. The only association with early adoption of ivacaftor in 2012 was a decreased likelihood in adults with fewer than four encounters in 2011.Uptake of ivacaftor use among eligible patients in the United States was rapid, with the majority of use initiated within 4 months of regulatory approval. Differences in ivacaftor prescriptions appear to be related to patient age, older age at diagnosis, and less frequent clinical encounters. Nutritional status also appears to play a role in children, and race seems to have an association in adults.

Objective To determine whether severity of lung disease at age 6 years is associated with changes in nutritional status before age 6 within individual children with cystic fibrosis (CF). Study design Children with CF born between 1994 and 2005 and followed in the CF Foundation Patient Registry from age ≤2 through 7 years were assessed according to changes in annualized weight-for-length (WFL) percentiles between ages 0 and 2 years and body mass index (BMI) percentiles between ages 2 and 6 years. The association between growth trajectories before age 6 and forced expiratory volume in 1 second (FEV 1 )% predicted at age 6-7 years was evaluated using multivariable linear regression. Results A total of 6805 subjects met inclusion criteria. Children with annualized WFL-BMI always >50th percentile (N = 1323 [19%]) had the highest adjusted mean (95% CI) FEV 1 at 6-7 years (101.8 [100.1, 103.5]). FEV 1 at 6-7 years for children whose WFL-BMI increased >10 percentile points by age 6 years was 98.3 (96.6, 100.0). This was statistically significantly higher than FEV 1 for children whose WFL-BMI was stable (94.4 [92.6, 96.2]) or decreased >10 percentile points (92.9 [91.1, 94.8]). Among children whose WFL-BMI increased >10 percentile points, achieving and maintaining WFL-BMI >50th percentile at younger ages was associated with significantly higher FEV 1 at 6-7 years. Conclusions Within-patient changes in nutritional status in the first 6 years of life are significantly associated with FEV 1 at age 6-7 years. The establishment of a clear relationship between early childhood growth measurements and later lung function suggests that early nutritional interventions may impact on eventual lung health.

To estimate the proportion of older women who fail to complete 5 years of tamoxifen therapy and to identify predictors of non-adherence. We followed 462 women 65-years-old or older with stage I–IIIA breast cancer diagnosed in four US regions between 1996 and 1999 and who initiated tamoxifen therapy. We interviewed patients annually to assess tamoxifen adherence and collected information about predictors of adherence by medical record review, patient interview, and physician questionnaire. Thirty-one percent of patients who started tamoxifen failed to complete the recommended 5-year course. Patients who had initial severe side effects [hazard ratio (HR) per side effect=1.2, 95% confidence interval (CI) 0.97, 1.5] or developed them (HR per new side effect=1.3, 95% CI 1.0, 1.6) were more likely to discontinue. Patients with more prescription medications at baseline were less likely to discontinue (HR per baseline prescription equaled 0.90, 95% CI 0.81, 0.99), whereas patients who added a prescription were more likely to discontinue (HR per new prescription equaled 1.2, 95% CI 1.0, 1.4). Patients with positive views of tamoxifen at baseline (HR for a 10-point higher score=0.93, 95% CI 0.83, 1.0) and an improving view over follow-up (HR for a 10-point positive change=0.93, 95% CI 0.87, 1.0) were less likely to discontinue. Five years of tamoxifen confers a significant benefit beyond 1–2 years of tamoxifen, so physicians should ask patients about side effects, other prescriptions, and beliefs about tamoxifen and should educate them about the benefits of completing adjuvant therapy.

Objectives: The objectives of this study were to determine whether tamoxifen recommendation differs by physician specialty, to determine whether perception affects tamoxifen recommendation, and to investigate the association between the physician's specialty and the perception of risks and benefits of tamoxifen. Methods: We enrolled a cohort of geographically diverse women aged 65 and older with stage I through IIIa breast cancer in a prospective cohort study. We recruited their surgeons and, when applicable, their medical oncologists to provide patient-specific information about their perceptions of the risks and benefits of tamoxifen and whether they recommended tamoxifen. Each physician also completed a questionnaire regarding his or her demographic and practice characteristics. Patient data were collected through medical record review and a patient interview 3 months after definitive breast cancer surgery. Results: We collected physician treatment recommendation forms for 585 women. Oncologists were 2.5 times more likely to recommend tamoxifen, compared with surgeons, after adjusting for patient and tumor characteristics (95% confidence interval, 1.5–4.2). For both specialties, their perceptions of the risks and benefits of tamoxifen were strong predictors of tamoxifen recommendation. However, there were differences in perception by physician specialty. Distant metastases and tolerance of tamoxifen side effects were more important to oncologists, whereas local recurrence and risk of cataracts were more important to surgeons. Conclusion: Physicians’ perceptions of the risks and benefits of tamoxifen therapy for older women are important in their decision-making process.

Studies suggesting a positive association between pregnancy termination and breast cancer risk have often been of retrospective case-control design, so subject to selection and recall biases. We undertook a registry-based analysis with minimal selection bias and prospective record-based ascertainment of terminations. The source population comprised Massachusetts women with a record of giving birth between 1987 and 1999 in the Massachusetts Vital Statistics Registry. Primary breast cancer cases were 25-55 years old at diagnosis between 1988 and 2000 and had a record of the diagnosis in the Massachusetts Cancer Registry. We matched 3 controls to each case on maternal age, year of giving birth and birth facility. Information on terminations (induced and spontaneous) before the birth of record, the matched factors and potential confounders were collected from the birth certificate. After adjustment for the matched factors, age, parity and maternal and paternal education, the odds ratio associating any termination history with breast cancer risk equaled 0.91 (95% CI = 0.79-1.05). The marginally protective adjusted odds ratio largely derived from a protective effect among women with parity equaled to 1 (OR for any termination = 0.68; 95% CI = 0.45-1.03), suggesting a protective effect of terminated pregnancy among women with one live birth.

Published epidemiologic research usually provides a quantitative assessment of random error for effect estimates, but no quantitative assessment of systematic error. Sensitivity analysis can provide such an assessment.We describe a method to reconstruct epidemiologic data, accounting for biases, and to display the results of repeated reconstructions as an assessment of error. We illustrate with a study of the effect of less-than-definitive therapy on breast cancer mortality.We developed SAS code to reconstruct the data that would have been observed had a set of systematic errors been absent, and to convey the results. After 4,000 reconstructions of the example data, we obtained a median estimate of relative hazard equal to 1.5 with a 95% simulation interval of 0.8-2.8. The relative hazard obtained by conventional analysis equaled 2.0, with a 95% confidence interval of 1.2-3.4.Our method of sensitivity analysis can be used to quantify the systematic error for an estimate of effect and to describe that error in figures, tables, or text. In the example, the sources of error biased the conventional relative hazard away from the null, and that error was not accurately communicated by the conventional confidence interval.

Objective: An earlier investigation reported a five-fold increase in breast cancer risk among women who smoked during pregnancy. Using a similar design, we re-examined this hypothesis. Methods: The source population comprised Massachusetts residents who gave birth between 1987 and 1999 with a birth record in the Massachusetts Vital Statistics Registry. Cases were diagnosed with breast cancer between 1988 and 2000 at ages 25-55 with a record in the Massachusetts Cancer Registry. Three controls were matched to each case on maternal age, year of giving birth, and birth facility. Information on smoking, the matched factors, and potential confounders were collected from the birth certificate. The data were analyzed using conditional logistic regression. Results: After adjusting for potential confounders, women who smoked during pregnancy did not have an increased risk of breast cancer compared to women who did not smoke during pregnancy (relative risk = 1.0, 95% Confidence interval CI = 0.81-1.2). We observed no dose response relation between number of cigarettes smoked per day during pregnancy and breast cancer risk. There was no evidence that our results were biased by misclassification from women inaccurately reporting their smoking status. Conclusion: In contrast to the previous study, we did not observe an increased risk of breast cancer in women who smoked during pregnancy.

BACKGROUND Adjuvant tamoxifen is recommended for all women with estrogen receptor-positive breast carcinoma without regard for age. We investigated age-dependent variations in adjuvant tamoxifen prescription patterns in a cohort of women 80 years of age and older. METHODS We studied 92 women diagnosed at four U.S. sites with primary, early-stage breast carcinoma. Each woman consented to a medical record review and participated in two telephone interviews. We compared the proportion of tamoxifen prescriptions received by women 85–92 years of age with those received by women 80–84 years of age. Relative risks (RR) and 95% confidence intervals (95% CI) were generated using generalized estimating equations. Confounding by demographic, disease, and treatment characteristics was assessed. RESULTS Before adjustment, patients 85–92 years of age were 28% less likely to receive a tamoxifen prescription compared with patients 80–84 years of age (RR = 0.72, 95% CI 0.57–0.91). In this sample, patients not prescribed tamoxifen had substantially more comorbidity. After adjusting the crude finding for comorbidity, the RR was 0.74 (95% CI 0.58–0.93). In addition, the oldest patients and those not prescribed tamoxifen were significantly less likely to be married or have living children. After adjusting the crude finding for these two factors, the RR was 0.75 (95% CI 0.59–0.95). There was no confounding by the other demographic, disease, or treatment covariates assessed. CONCLUSION Given the increasing longevity of the oldest old, undertreatment with adjuvant tamoxifen may put older breast carcinoma patients at an increased risk of disease recurrence and breast carcinoma mortality. Cancer 2002;95:2465–72. © 2002 American Cancer Society. DOI 10.1002/cncr.10985

Background. Standard treatments for breast cancer can impair fertility. It is unknown how many U.S. survivors are at risk for infertility. We estimated the population at risk for infertility secondary to treatment among reproductive-aged breast cancer survivors. Methods. We combined data from three sources: the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results cancer registry data on incident breast cancers diagnosed in women aged 15–44 years between 2004 and 2006; treatment data from NPCR's 2004 Breast and Prostate Cancer Data Quality and Patterns of Care (PoC) study; and data on women's intentions to have children from the 2006–2010 National Survey of Family Growth (NSFG). Results. In the cancer registry data, an average of 20,308 women with breast cancer aged Conclusion. Nearly all young breast cancer survivors in the U.S. are at risk for infertility. Physicians should discuss the potential impact of treatment on fertility. A smaller but sizeable number of at-risk survivors may be interested in having children. Given the magnitude of potential infertility and its quality-of-life implications, these survivors should have access to and potential coverage for fertility services.

Background : In order to ensure accurate survival estimates, population-based cancer registries must ascertain all, or nearly all, patients diagnosed with cancer in their catchment area, and obtain complete follow-up information on all deaths that occurred among registered cancer patients. In the US, linkage with state death records may not be sufficient to ascertain all deaths. Since 1979, all state vital statistics offices have reported their death certificate information to the National Death Index (NDI). Objective : This study was designed to measure the impact of linkage with the NDI on population-based relative and cancer cause-specific survival rates in the US. Methods : Central cancer registry records for patients diagnosed 1993–1995 from California, Colorado, and Idaho were linked with death certificate information (deaths 1993–2004) from their individual state vital statistics offices and with the NDI. Two databases were created: one contained incident records with deceased patients linked only to state death records and the second database contained incident records with deceased patients linked to both state death records and the NDI. Survival estimates and 95% confidence intervals from each database were compared by state and primary site category. Results : At 60 months follow-up, 42.1–48.1% of incident records linked with state death records and an additional 0.7–3.4% of records linked with the NDI. Survival point estimates from the analysis without NDI were not contained within the corresponding 95% CIs from the NDI augmented analysis for all sites combined and colorectal, pancreas, lung and bronchus, breast, prostate, non-Hodgkin lymphoma, and Kaposi sarcoma cases in all 3 states using relative survival methods. Additional combinations of state and primary site had significant survival estimate differences, which differed by method (relative versus cause-specific survival). Conclusion : To ensure accurate population-based cancer survival rates, linkage with the National Death Index to ascertain out of state and late registered deaths is a necessary process for US central cancer registries.