Chronic opioid use and complication risks in women with endometriosis: A cohort study in US administrative claims.

BACKGROUND: Women with endometriosis are prescribed opioids for pain relief but may be vulnerable to chronic opioid use given their comorbidity profile. METHODS: A cohort study was conducted in the Clinformatics™ DataMart database between 2006 and 2017 comparing women aged 18-50 years with endometriosis (N = 36 373) to those without (N = 2 172 936) in terms of risk of chronic opioid use, opioid dependence diagnosis, and opioid overdose. Chronic opioid use was defined as ≥120 days' supply dispensed or ≥10 fills of an opioid during any 365-day interval. Among women with endometriosis, we evaluated factors associated with higher risk of chronic opioid use and quantified the risk of complications associated with the use of opioids. RESULTS: Women with endometriosis were at greater risk for chronic opioid use (OR: 3.76; 95%CI: 3.57-3.96), dependence (OR: 2.73, 95%CI: 2.38-3.13) and overdose (OR: 4.34, 95%CI: 3.06-6.15) compared to women without. Chronic users displayed dose escalation and increase in days supplied over time, as well as co-prescribing with benzodiazepines and sedatives. Approximately 34% of chronic users developed constipation, 20% experienced falls, and 8% reported dizziness. Among endometriosis patients, women in younger age groups, those with other comorbidities associated with pain symptoms, as well as those with depression or anxiety were at a higher risk of developing chronic opioid use. CONCLUSIONS: Women with endometriosis had a four times greater risk of chronic opioid use compared to women without. Multimorbidity among these patients was associated with the elevated risk of chronic opioid use and should be taken into account during treatment selection.

Immunogenicity of Current and Next-Generation Pneumococcal Conjugate Vaccines in Children: Current Challenges and Upcoming Opportunities.

Global use of pneumococcal conjugate vaccines (PCVs) with increasingly broader serotype coverage has helped to reduce the burden of pneumococcal disease in children and adults. In clinical studies comparing PCVs, higher-valency PCVs have met noninferiority criteria (based on immunoglobulin G geometric mean concentrations and response rates) for most shared serotypes. A numeric trend of declining immunogenicity against shared serotypes with higher-valency PCVs has also been observed; however, the clinical relevance is uncertain, warranting additional research to evaluate the effectiveness of new vaccines. Novel conjugation processes, carriers, adjuvants, and vaccine platforms are approaches that could help maintain or improve immunogenicity and subsequent vaccine effectiveness while achieving broader protection with increasing valency in pneumococcal vaccines.

Extending the vision of adaptive point-of-care platform trials to improve targeted use of drug therapy regimens: An agile approach in the learning healthcare system toolkit.

OBJECTIVES: Improving the targeted use of drug regimens requires robust real-world evidence (RWE) to address the uncertainties that remain regarding their real-world performance following market entry. However, challenges in the current state of RWE production limit its impact on clinical decisions, as well as its operational scalability and sustainability. We propose an adaptive point-of-care (APoC) platform trial as an approach to RWE production that improves both clinical and operational efficiencies. METHODS AND FINDINGS: We explored design innovations, operational challenges, and infrastructure needs within a multi-stakeholder consortium to evaluate the potential of an APoC platform trial for studying chronic disease treatment regimens using rheumatoid arthritis as a case study. The concept integrates elements from adaptive clinical trials (dynamic treatment regimen strategies) and point-of-care trials (research embedded into routine clinical care) under a perpetual platform infrastructure. The necessary components to implement an APoC platform trial within outpatient settings exist, and present an opportunity for a cross-disciplinary, multi-stakeholder approach. Effective engagement of key stakeholders involved in and impacted by the platform is critical to success. Our collaborative design process identified three high-impact stakeholder-engagement areas: (1) focus on research question(s), (2) design and implementation planning such that it is feasible and fit-for-purpose, and (3) measurement, or meaningful metrics for both clinical (patient outcomes) and system (operational efficiencies) impact. CONCLUSIONS: An APoC platform trial for rheumatoid arthritis integrating innovative design elements in a scalable infrastructure has the potential to reduce important uncertainties about the real-world performance of biomedical innovations and improve clinical decisions.

Risk of Guillain-Barré syndrome after meningococcal conjugate vaccination.

PURPOSE: A new meningococcal conjugate vaccine (MCV4) was introduced in 2005. Shortly after, case reports of Guillain-Barré syndrome (GBS), a serious demyelinating disease, began to be reported to the Vaccine Adverse Event Reporting System. In 2006, the Centers for Disease Control and Prevention and the Food and Drug Administration requested the evaluation of GBS risk after MCV4 vaccination. We conducted a study to assess the risk of GBS after MCV4 vaccination using health plan administrative and claims data together with the review of primary medical records of potential cases. METHODS: Retrospective cohort study among 12.6 million 11- to 21-year-old members of five US health plans with a total membership of 50 million. Automated enrollment and medical claims data from March 2005 through August 2008 were used to identify the population, the vaccinations administered, and the medical services associated with possible GBS. Medical records were reviewed and adjudicated by a neurologist panel to confirm cases of GBS. The study used distributed data analysis methods that minimized sharing of protected health information. RESULTS: We confirmed 99 GBS cases during 18,322,800 person-years (5.4/1,000,000 person-years). More than 1.4 million MCV4 vaccinations were observed. No confirmed cases of GBS occurred within 6 weeks after vaccination. The upper 95% CI for the attributable risk of GBS associated with MCV4 is estimated as 1.5 cases per 1,000,000 doses. CONCLUSIONS: Among members of five US health plans, MCV4 vaccination was not associated with increased GBS risk.

ACE inhibitor or ARB treatment among patients with diabetes and chronic kidney disease.

OBJECTIVES: Many patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) experience a delay in treatment or fail to initiate treatment with guideline-recommended angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) after CKD diagnosis. This study aimed to describe treatment patterns and treatment initiation after initial CKD diagnosis among patients with T2D. STUDY DESIGN: Retrospective analysis using data from the Optum Clinformatics Data Mart administrative claims database (January 2014-September 2018). METHODS: Adult patients with T2D entered the cohort if they met the criteria for CKD, defined as 2 laboratory test results 90 to 365 days apart (January 2014-September 2017) indicating CKD. Included were patients with no prior use of ACEis or ARBs or evidence of kidney disease in the 365 days prior to cohort entry (baseline). Patients were followed for a maximum of 365 days and were censored on death, disenrollment, or end of data. Patient demographics, comorbidities, and medication use were assessed at baseline, and treatments were assessed over a 1-year followup period. Multivariate logistic regression was used to identify factors associated with ACEi or ARB initiation. RESULTS: Among 15,400 eligible patients without prior ACEi or ARB treatment, only 17% initiated such therapy within a year after meeting CKD criteria. Patients who were White, resided in the northeastern United States, had more comorbidities, had less advanced albuminuria, or used sodium-glucose cotransporter 2 inhibitors were less likely to initiate treatment. CONCLUSIONS: A large proportion of patients with T2D meeting criteria for CKD do not initiate the recommended therapy within 1 year of CKD diagnosis, highlighting a need for new therapies that can slow the progression of CKD.

Cardiovascular and Renal Outcomes in Patients with Type-2 Diabetes and Chronic Kidney Disease Identified in a United States Administrative Claims Database: A Population Cohort Study.

INTRODUCTION: CKD, a common complication of type-2 diabetes (T2D), causes considerable disease burden. Patients with T2D and CKD are considered high-risk for complications; however, studies describing patients with T2D and incident CKD identified from real-world data using the diagnostic gold-standard criteria - estimated glomerular filtration rate and urine albumin-to-creatinine ratio (UACR) - are scarce. METHODS: In this population-based cohort study, we sought to estimate the rates of cardiovascular and renal outcomes among patients with T2D and CKD by comorbidity subgroups and CKD severity. Patients were sampled between 2008 and 2017 from de-identified US administrative claims enriched with laboratory data. Analyses were stratified by prevalent heart failure (HF), anemia, and resistant hypertension and the KDIGO categories at index. RESULTS: We identified 106,369 patients with T2D and incident CKD. The rate of all-cause hospitalization was 189 [95% CI: 187, 191] per 1,000 person-years with cardiovascular-related hospitalizations being more frequent than kidney-related outcomes. The rate of acute kidney failure was 77.3 [95% CI: 76.2, 78.5] per 1,000 person-years. Patients with HF experienced a 4-times higher rate for cardiovascular events compared to those without. Rates of hospitalization increased from 5- to 6-fold with increasing KDIGO severity. CONCLUSIONS: Multimorbidity and advance stages of CKD increase the risk of cardiovascular and renal complications among patients with T2D diabetes. Earlier CKD diagnosis as well as interventions and coordinated care addressing other comorbid conditions present at diagnosis may reduce the overall disease burden in this population.

Chronic kidney disease progression among patients with type 2 diabetes identified in US administrative claims: a population cohort study.

BACKGROUND: Chronic kidney disease (CKD), one of the most common complications of type 2 diabetes (T2D), is associated with poor health outcomes and high healthcare expenditures. As the CKD population increases, a better understanding of the prevalence and progression of CKD is critical. However, few contemporary studies have explored the progression of CKD relative to its onset in T2D patients using established markers derived from real-world care settings. METHODS: This retrospective, population-based cohort study assessed CKD progression among adults with T2D and with newly recognized CKD identified from US administrative claims data between 1 January 2008 and 30 September 2018. Included were patients with T2D and laboratory evidence of CKD as indicated by the established estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) criteria. Disease progression was described as transitions across the eGFR- and UACR-based stages. RESULTS: A total of 65 731 and 23 035 patients with T2D contributed to the analysis of eGFR- and UACR-based CKD stage progression, respectively. CKD worsening was observed in approximately 10-17% of patients over a median follow-up of 2 years. Approximately one-third of patients experienced an increase in eGFR values or a decrease in UACR values during follow-up. CONCLUSIONS: A relatively high proportion of patients were observed with disease progression over a short period of time, highlighting the need for better identification of patients at risk of rapidly progressive CKD. Future studies are needed to determine the clinical characteristics of these patients to inform earlier diagnostic and therapeutic interventions aimed at slowing disease progression.

Outcomes Associated With Oral Anticoagulants Plus Antiplatelets in Patients With Newly Diagnosed Atrial Fibrillation.

Importance: Patients with nonvalvular atrial fibrillation at risk of stroke should receive oral anticoagulants (OAC). However, approximately 1 in 8 patients in the Global Anticoagulant Registry in the Field (GARFIELD-AF) registry are treated with antiplatelet (AP) drugs in addition to OAC, with or without documented vascular disease or other indications for AP therapy. Objective: To investigate baseline characteristics and outcomes of patients who were prescribed OAC plus AP therapy vs OAC alone. Design, Setting, and Participants: Prospective cohort study of the GARFIELD-AF registry, an international, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation and at least 1 risk factor for stroke enrolled between March 2010 and August 2016. Data were extracted for analysis in October 2017 and analyzed from April 2018 to June 2019. Exposure: Participants received either OAC plus AP or OAC alone. Main Outcomes and Measures: Clinical outcomes were measured over 3 and 12 months. Outcomes were adjusted for 40 covariates, including baseline conditions and medications. Results: A total of 24 436 patients (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) were analyzed. Among eligible patients, those receiving OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including acute coronary syndromes (22.0% vs 4.3%), coronary artery disease (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). Over 1 year, patients treated with OAC plus AP had significantly higher incidence rates of stroke (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) than those treated with OAC alone. These patients did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51). Risk of acute coronary syndrome was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Patients treated with OAC plus AP also had higher rates of all clinical outcomes than those treated with OAC alone over the short term (3 months). Conclusions and Relevance: This study challenges the practice of coprescribing OAC plus AP unless there is a clear indication for adding AP to OAC therapy in newly diagnosed atrial fibrillation.

Implementation of the uterine fibroids Option Grid patient decision aids across five organizational settings: a randomized stepped-wedge study protocol.

BACKGROUND: Uterine fibroids are non-cancerous overgrowths of the smooth muscle in the uterus. As they grow, some cause problems such as heavy menstrual bleeding, pelvic pain, discomfort during sexual intercourse, and rarely pregnancy complications or difficulty becoming pregnant. Multiple treatment options are available. The lack of comparative evidence demonstrating superiority of any one treatment means that choosing the best option is sensitive to individual preferences. Women with fibroids wish to consider treatment trade-offs. Tools known as patient decision aids (PDAs) are effective in increasing patient engagement in the decision-making process. However, the implementation of PDAs in routine care remains challenging. Our aim is to use a multi-component implementation strategy to implement the uterine fibroids Option Grid™ PDAs at five organizational settings in the USA. METHODS: We will conduct a randomized stepped-wedge implementation study where five sites will be randomized to implement the uterine fibroid Option Grid PDA in practice at different time points. Implementation will be guided by the Consolidated Framework for Implementation Research (CFIR) and Normalization Process Theory (NPT). There will be a 6-month pre-implementation phase, a 2-month initiation phase where participating clinicians will receive training and be introduced to the Option Grid PDAs (available in text, picture, or online formats), and a 6-month active implementation phase where clinicians will be expected to use the PDAs with patients who are assigned female sex at birth, are at least 18 years of age, speak fluent English or Spanish, and have new or recurrent symptoms of uterine fibroids. We will exclude postmenopausal patients. Our primary outcome measure is the number of eligible patients who receive the Option Grid PDAs. We will use logistic and linear regression analyses to compare binary and continuous quantitative outcome measures (including survey scores and Option Grid use) between the pre- and active implementation phases while adjusting for patient and clinician characteristics. DISCUSSION: This study may help identify the factors that impact the implementation and sustained use of a PDA in clinic workflow from various stakeholder perspectives while helping patients with uterine fibroids make treatment decisions that align with their preferences. TRIAL REGISTRATION: Clinicaltrials.gov , NCT03985449. Registered 13 July 2019, https://clinicaltrials.gov/ct2/show/NCT03985449.

Life expectancy in Gaucher disease type 1.

We estimated life expectancy at birth for Gaucher disease type 1 (GD1) patients by comparing survival data from GD1 patients enrolled in ICGG Gaucher Registry to the U.S. population using standard life table methods. 2,876 GD1 patients had 102 reported deaths in 13,509 person-years of follow-up. Estimated life expectancy at birth was 68 y, compared with 77 y in reference population; splenectomized patients, 64 y; nonsplenectomized, 72 y. Causes of death for 63/102 patients were malignancy (17/63), cardiovascular (11/63), and cerebrovascular (8/63). Estimated life expectancy at birth for GD1 patients was approximately 9 y less than reference population. Malignancies did not contribute to shortened life expectancy.

A distributed research network model for post-marketing safety studies: the Meningococcal Vaccine Study.

PURPOSE: We describe a multi-center post-marketing safety study that uses distributed data methods to minimize the need for covered entities to share protected health information (PHI). Implementation has addressed several issues relevant to creation of a large scale post-marketing drug safety surveillance system envisioned by the FDA's Sentinel Initiative. METHODS: This retrospective cohort study of Guillain-Barré syndrome (GBS) following meningococcal conjugate vaccination incorporates the data and analytic expertise of five research organizations closely affiliated with US health insurers. The study uses administrative claims data, plus review of full text medical records to adjudicate the status of individuals with a diagnosis code for GBS (ICD9 357.0). A distributed network approach is used to create the analysis files and to perform most aspects of the analysis, allowing nearly all of the data to remain behind institutional firewalls. Pooled analysis files transferred to a central site will contain one record per person for approximately 0.2% of the study population, and contain PHI limited to the month and year of GBS onset for cases or the index date for matched controls. RESULTS: The first planned data extraction identified over 9 million eligible adolescents in the target age range of 11-21 years. They contributed an average of 14 months of eligible time on study over 27 months of calendar time. MCV4 vaccination coverage levels exceeded 20% among 17-18-year olds and 16% among 11-13 and 14-16-year-old age groups by the second quarter of 2007. CONCLUSION: This study demonstrates the feasibility of using a distributed data network approach to perform large scale post-marketing safety analyses and is scalable to include additional organizations and data sources. We believe these results can inform the development of a large national surveillance system.

Comparative effectiveness of uterine fibroids procedures using linked medical record and claims data.

AIMS: To compare durability of uterus-conserving procedures for symptomatic fibroids in terms of incidence and time to subsequent procedures. PATIENTS & METHODS: We conducted a retrospective database study of 2648 patients having a uterus-conserving procedure for uterine fibroids from 2005 to 2011 with a minimum of 2 years follow-up. RESULTS: Patients with myomectomy or uterine artery embolization as their index procedure had lower risk of a subsequent procedure during the study compared with patients who underwent endometrial ablation. CONCLUSION: While subject to known limitations of using electronic medical record and administrative claims data, this research provides additional evidence regarding expectations for time to subsequent procedures that may be helpful for women and their healthcare providers to consider when making treatment choices.

The GRACE Checklist: A Validated Assessment Tool for High Quality Observational Studies of Comparative Effectiveness.

BACKGROUND: Recognizing the growing need for robust evidence about treatment effectiveness in real-world populations, the Good Research for Comparative Effectiveness (GRACE) guidelines have been developed for noninterventional studies of comparative effectiveness to determine which studies are sufficiently rigorous to be reliable enough for use in health technology assessments. OBJECTIVE: To evaluate which aspects of the GRACE Checklist contribute most strongly to recognition of quality. METHODS: We assembled 28 observational comparative effectiveness articles published from 2001 to 2010 that compared treatment effectiveness and/or safety of drugs, medical devices, and medical procedures. Twenty-two volunteers from academia, pharmaceutical companies, and government agencies applied the GRACE Checklist to those articles, providing 56 assessments. Ten senior academic and industry experts provided assessments of overall article quality for the purpose of decision support. We also rated each article based on the number of annual citations and impact factor of the journal in which the article was published. To identify checklist items that were most predictive of quality, classification and regression tree (CART) analysis, a binary, recursive, partitioning methodology, was used to create 3 decision trees, which compared the 56 article assessments with 3 external quality outcomes: (1) expert assessment of overall quality, (2) citation frequency, and (3) impact factor. A fourth tree looked at the composite outcome of all 3 quality indicators. RESULTS: The best predictors of quality included the following: use of concurrent comparators, limiting the study to new initiators of the study drug, equivalent measurement of outcomes in study groups, collecting data on most if not all known confounders or effect modifiers, accounting for immortal time bias in the analysis, and use of sensitivity analyses to test how much effect estimates depended on various assumptions. Only sensitivity analyses appeared consistently as a predictor of quality in all 4 trees. When a composite outcome of the 3 quality measures was used, the GRACE Checklist showed high sensitivity and specificity (71.43% and 80.95%, respectively). CONCLUSIONS: The GRACE Checklist stands out from other consensus-driven and expert guidance documents because of its extensive validation efforts. This most recent work shows that the checklist has strong sensitivity and specificity, increasing its utility as a screening tool to identify high-quality observational comparative effectiveness research worthy of in-depth review and applicability for decision support. DISCLOSURES: No outside funding supported this research. All authors are full-time employees of Quintiles, which provides research and consulting services to the biopharmaceutical industry. The authors have no other disclosures to report. Two of the 3 CART trees were presented at the International Society of Pharmacepidemiology in 2015 ("Article Citations per Year" and "Journal Impact Factor"). The original validation study was published in the March 2014 issue of the Journal of Managed Care & Specialty Pharmacy. The checklist questions and scoring were included using a table that was originally published by this journal in 2014. Study concept and design were primarily contributed by Dreyer and Velentgas, along with Bryant. Bryant took the lead in data collection and analysis, along with Dreyer and Velentgas, and data interpretation was performed by Dreyer, Velentgas, and Bryant. The manuscript was written and revised primarily by Dreyer, along with Bryant and Velentgas.

Impact of treatment strategies for open angle glaucoma on intraocular pressure: the RiGOR study.

AIMS: The RiGOR study's primary outcome measure was a 15% reduction in intraocular pressure (IOP) for patients with open-angle glaucoma at 1 year. METHODS: Patients received treatment according to the ophthalmologist's usual practice. RESULTS: A higher proportion of patients in the incisional and other surgery group achieved a 15% reduction in IOP than in the laser surgery or additional medication groups (82, 57, and 57% respectively). In multivariate regression analyses, incisional surgery patients were 2.7-times as likely as patients treated with additional medication to achieve a 15% reduction in IOP (odds ratio: 2.67; 95% CI: 2.01-3.57). CONCLUSION: Incisional and other surgical procedures are effective treatments. There were no differences in treatment response by race or ethnicity.

Quality of life and visual acuity outcomes in the Registry in Glaucoma Outcomes Research study.

AIMS: The RiGOR study evaluated the association of treatment and patient-reported outcomes for open-angle glaucoma patients. METHODS: The Glaucoma Symptom Scale (National Eye Institute-Visual Function Questionnaire (NEI-VFQ) and visual acuity (VA) were collected as quality of life measures. RESULTS: The proportion of patients with improvement of at least two lines of vision was highest in the incisional surgery group (14.2% compared with 9.9% for laser surgery and 10.9% for additional medication). CONCLUSION: No clinically relevant differences were seen in benefit for the laser surgery or incisional surgery groups compared with additional medications for the Glaucoma Symptom Scale or NEI-VFQ measures or subscales. Differences in quality of life by race need to be explored in further studies.

RiGOR: a prospective observational study comparing the effectiveness of treatment strategies for open-angle glaucoma.

AIMS: The RigOR study was designed to assess comparative effectiveness of medications, laser trabeculoplasty and incisional surgery in patients with open-angle glaucoma (OAG) in the community initiating a new or additional course of therapy as judged necessary by their ophthalmologist. This paper focuses specifically on demographic and clinical characteristics of OAG patients at enrollment. PATIENTS & METHODS: A total of 2597 with OAG already on medical therapy were enrolled from 45 community and academic practices throughout the USA. RESULTS: Overall, 784 (30%) patients were treated with laser surgery, 436 with other surgical procedures (17%), and 1377 with additional medication (53%). Patients had mild (35%) or moderate (31%) glaucoma, with 28% with severe glaucoma. CONCLUSION: The RiGOR study enrolled a diverse population and will provide valuable information regarding visual function and treatment patterns among different racial/ethnic populations. African-American and Hispanic patients entered the study with poorer visual acuity and more severe glaucoma.

Practice patterns and treatment changes for open-angle glaucoma: the RiGOR study.

AIMS: The RiGOR study provides a current picture of the types of glaucoma treatment over 12 months. METHODS: Patients were identified and enrolled at the time of decision to proceed with laser surgery procedure or other procedure such as incisional surgery or drainage device implantation, or initiation of a new or additional course of therapy with medication for glaucoma treatment. RESULTS: The most frequent type of treatments were prostaglandin analogues (60%) among patients with additional medication, selective laser trabeculoplasty (87%) among patients with laser surgery and trabeculectomy (57%) among patients with incisional surgery. CONCLUSION: For 36% of patients, a treatment cascade involves two or more therapies over a year. This demonstrates the complex nature of open-angle glaucoma treatment.

A call for comparative effectiveness research to learn whether routine clinical care decisions can protect from dementia and cognitive decline.

Common diseases like diabetes, hypertension, and atrial fibrillation are probable risk factors for dementia, suggesting that their treatments may influence the risk and rate of cognitive and functional decline. Moreover, specific therapies and medications may affect long-term brain health through mechanisms that are independent of their primary indication. While surgery, benzodiazepines, and anti-cholinergic drugs may accelerate decline or even raise the risk of dementia, other medications act directly on the brain to potentially slow the pathology that underlies Alzheimer's and other dementia. In other words, the functional and cognitive decline in vulnerable patients may be influenced by the choice of treatments for other medical conditions. Despite the importance of these questions, very little research is available. The Alzheimer's Drug Discovery Foundation convened an advisory panel to discuss the existing evidence and to recommend strategies to accelerate the development of comparative effectiveness research on how choices in the clinical care of common chronic diseases may protect from cognitive decline and dementia.

Association of sweat chloride concentration at time of diagnosis and CFTR genotype with mortality and cystic fibrosis phenotype.

BACKGROUND: The extent to which sweat chloride concentration predicts survival and clinical phenotype independently of CFTR genotype in cystic fibrosis is not well understood. METHODS: We analyzed the US Cystic Fibrosis Foundation Patient Registry data using Cox regression to examine the relationship between sweat chloride concentration (<60, 60-<80, ≥80mmol/L), CFTR genotype (high and lower risk for lung function decline), and survival and mixed linear regression to examine the relationship between sweat chloride, CFTR genotype, and measures of lung function and growth. RESULTS: When included in the same model, CFTR genotype, but not sweat chloride, was independently associated with survival and with lung function, height, and BMI. Among patients with unclassified CFTR genotype, sweat chloride was an independent predictor of survival (<60 HR 0.53 [0.37, 0.77], 60-<80 0.51 [0.42, 0.63]). CONCLUSIONS: Sweat chloride concentration may be a useful predictor of mortality and clinical phenotype when CFTR genotype functional class is unclassified.

Characterization of Missing Data in Clinical Registry Studies.

Patterns of missing data are seldom well-characterized in observational research. This study examined the magnitude of, and factors associated with, missing data across multiple observational studies. Missingness was evaluated for demographic, clinical, and patient-reported outcome (PRO) data from a procedure registry (TOPS), a rare disease (cystic fibrosis) registry (Port-CF), and a comparative effectiveness registry (glaucoma, RiGOR). Generalized linear mixed effects models were fit to assess whether patient characteristics or follow-up methods predicted missingness. Data from 156,707 surgical procedures, 32,118 cystic fibrosis patients, and 2373 glaucoma patients were analyzed. Data were rarely missing for demographics, treatments, and outcomes. Missingness for clinical variables varied by registry and measure and depended on whether a variable was required. Within RiGOR, PRO forms were missing more often when collected by e-mail compared with office-based paper data collection. In Port-CF, missingness varied based on insurance status and sex. Strategic consideration of operational approaches affecting missing data should be performed prior to data collection and assessed periodically during study conduct.