ABSTRACT
Uses of real-world data in drug safety and effectiveness studies are often challenged by various sources of bias. We undertook a systematic search of the published literature through September 2020 to evaluate the state of use and utility of negative controls to address bias in pharmacoepidemiologic studies. Two reviewers independently evaluated study eligibility and abstracted data. Our search identified 184 eligible studies for inclusion. Cohort studies (115, 63%) and administrative data (114, 62%) were, respectively, the most common study design and data type used. Most studies used negative control outcomes (91, 50%), and for most studies the target source of bias was unmeasured confounding (93, 51%). We identified 4 utility domains of negative controls: 1) bias detection (149, 81%), 2) bias correction (16, 9%), 3) P-value calibration (8, 4%), and 4) performance assessment of different methods used in drug safety studies (31, 17%). The most popular methodologies used were the 95% confidence interval and P-value calibration. In addition, we identified 2 reference sets with structured steps to check the causality assumption of the negative control. While negative controls are powerful tools in bias detection, we found many studies lacked checking the underlying assumptions. This article is part of a Special Collection on Pharmacoepidemiology.
Subject(s)
Pharmacoepidemiology , Humans , Bias , Pharmacoepidemiology/methodsABSTRACT
Undertreatment of depression is common among children and adolescents, but evidence of the impact of undertreatment of depression on risk of suicide is limited due to the low base rate of suicide in the population and lack of sufficient data sources. We developed a microsimulation model that uses evidence from multiple sources to study the impact of different durations of antidepressant treatment on suicide risk in a synthesized sample that is nationally representative of children and adolescents with major depressive disorder. Compared with receiving no treatment, suicide rate and risk of suicide attempt both decreased with increasing duration of antidepressant treatment (for 12 weeks, suicide rate ratios = 0.78 (95% credible interval (CrI): 0.58, 1.15), 36 weeks, 0.65 (95% CrI: 0.44, 0.90), and 52 weeks, 0.63 (95% CrI: 0.45, 0.72); for suicide attempt: 12 weeks, suicide risk ratios = 0.68 (95% CrI: 0.62, 0.69), 36 weeks, 0.56 (95% CrI: 0.52, 0.57), and 52 weeks, 0.55 (95% CrI: 0.51, 0.56). The suicide rate and risk of suicide attempt were lower in children than in adolescents. Males had a lower risk of suicide attempt but higher suicide rate than females. The findings from the microsimulation model show that completion of 12-36 weeks of antidepressant treatment may reduce suicide attempt and suicide among children and adolescents with major depressive disorder.
Subject(s)
Depressive Disorder, Major , Male , Female , Adolescent , Child , Humans , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/epidemiology , Depression , Antidepressive Agents/therapeutic use , Suicide, Attempted , Risk , Disease SusceptibilityABSTRACT
OBJECTIVE: Airborne infection from aerosolized SARS-CoV-2 poses an economic challenge for businesses without existing heating, ventilation, and air conditioning (HVAC) systems. The Environmental Protection Agency notes that standalone units may be used in areas without existing HVAC systems, but the cost and effectiveness of standalone units has not been evaluated. STUDY DESIGN: Cost-effectiveness analysis with Monte Carlo simulation and aerosol transmission modeling. METHODS: We built a probabilistic decision-analytic model in a Monte Carlo simulation that examines aerosol transmission of SARS-CoV-2 in an indoor space. As a base case study, we built a model that simulated a poorly ventilated indoor 1000 square foot restaurant and the range of Covid-19 prevalence of actively infectious cases (best-case: 0.1%, base-case: 2%, and worst-case: 3%) and vaccination rates (best-case: 90%, base-case: 70%, and worst-case: 0%) in New York City. We evaluated the cost-effectiveness of improving ventilation rate to 12 air changes per hour (ACH), the equivalent of hospital-grade filtration systems used in emergency departments. We also provide a customizable online tool that allows the user to change model parameters. RESULTS: All 3 scenarios resulted in a net cost-savings and infections averted. For the base-case scenario, improving ventilation to 12 ACH was associated with 54 [95% Credible Interval (CrI): 29-86] aerosol infections averted over 1 year, producing an estimated cost savings of $152,701 (95% CrI: $80,663, $249,501) and 1.35 (95% CrI: 0.72, 2.24) quality-adjusted life years (QALYs) gained. CONCLUSIONS: It is cost-effective to improve indoor ventilation in small businesses in older buildings that lack HVAC systems during the pandemic.
ABSTRACT
Few studies have quantified the multimorbidity burden in older adults with chronic obstructive pulmonary disease (COPD) using large and generalizable data. Such evidence is essential to inform evidence-based research, clinical care, and resource allocation. This retrospective cohort study used a nationally representative sample of Medicare beneficiaries aged 65 years or older with COPD and 1:1 matched (on age, sex, and race) non-COPD beneficiaries to: (1) quantify the prevalence of multimorbidity at COPD onset and one-year later; (2) quantify the rates [per 100 person-years (PY)] of newly diagnosed multimorbidity during in the year prior to and in the year following COPD onset; and (3) compare multimorbidity prevalence in beneficiaries with and without COPD. Among 739,118 eligible beneficiaries with and without COPD, the average number of multimorbidity was 10.0 (SD = 4.7) and 1.0 (SD = 3.3), respectively. The most prevalent multimorbidity at COPD onset and at one-year after, respectively, were hypertension (70.8% and 80.2%), hyperlipidemia (52.2% and 64.8%), anemia (42.1% and 52.0%), arthritis (39.8% and 47.7%), and congestive heart failure (CHF) (31.3% and 38.8%). Conditions with the highest newly diagnosed rates before and following COPD onset, respectively, included hypertension (39.8 and 32.3 per 100 PY), hyperlipidemia (22.8 and 27.6), anemia (17.8 and 20.3), CHF (16.2 and 13.2), and arthritis (12.9 and 13.2). COPD was significantly associated with increased odds of all measured conditions relative to non-COPD controls. This study updates existing literature with more current, generalizable findings of the substantial multimorbidity burden in medically complex older adults with COPD-necessary to inform patient-centered, multidimensional care.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1968815 .
Subject(s)
Multimorbidity , Pulmonary Disease, Chronic Obstructive , Aged , Humans , Medicare , Prevalence , Pulmonary Disease, Chronic Obstructive/epidemiology , Retrospective Studies , United States/epidemiologyABSTRACT
BACKGROUND: Asthma diagnosis in the community is often made without objective testing. OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of implementing a stepwise objective diagnostic verification algorithm among patients with community-diagnosed asthma in the United States. METHODS: We developed a probabilistic time-in-state cohort model that compared a stepwise asthma verification algorithm on the basis of spirometry testing and a methacholine challenge test against the current standard of care over 20 years. Model input parameters were informed from the literature and with original data analyses when required. The target population was US adults (≥15 years old) with physician-diagnosed asthma. The final outcomes were costs (in 2018 dollars) and quality-adjusted life years (QALYs), discounted at 3% annually. Deterministic and probabilistic analyses were undertaken to examine the effect of alternative assumptions and uncertainty in model parameters on the results. RESULTS: In a simulated cohort of 10,000 adults with diagnosed asthma, the stepwise algorithm resulted in removal of the diagnosis of 3,366. This was projected to be associated with savings of $36.26 million in direct costs and a gain of 4,049.28 QALYs over 20 years. Extrapolating these results to the US population indicated an undiscounted potential savings of $56.48 billion over 20 years. The results were robust against alternative assumptions and plausible changes in values of input parameters. CONCLUSION: Implementation of a simple diagnostic testing algorithm to verify asthma diagnosis might result in substantial savings and improvement in patients' quality of life.
Subject(s)
Algorithms , Asthma/diagnosis , Asthma/economics , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Asthmatic Agents/economics , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Asthma/physiopathology , Cost-Benefit Analysis , Decision Trees , Female , Forced Expiratory Volume , Humans , Male , Middle Aged , Models, Statistical , Quality of Life , Quality-Adjusted Life Years , Spirometry/economics , United States , Young AdultABSTRACT
Shifts in migration and border control policies may increase the likelihood of trauma exposure related to child-parent separation and result in costs to the health system and society. In the present study, we estimated direct and indirect costs per child as well as overall cohort costs of border control policies on migrant children and adolescents who were separated from their parents, detained, and placed in the custody of the United States following the implementation of the 2018 Zero Tolerance Policy. Economic modeling techniques, including a Markov process and Monte Carlo simulation, based on data from the National Child Traumatic Stress Network's Core Data Set (N = 458 migrant youth) and published studies were used to estimate economic costs associated with three immigration policies: No Detention, Family Detention, and Zero Tolerance. Clinical evaluation data on mental health symptoms and disorders were used to estimate the initial health state and risks associated with additional trauma exposure for each scenario. The total direct and indirect costs per child were conservatively estimated at $33,008, $33,790, and $34,544 after 5 years for No Detention, Family Detention, and Zero Tolerance, respectively. From a health system perspective, annual estimated spending increases ranged from $1.5 million to $14.9 million for Family Detention and $2.8 million to $29.3 million for Zero Tolerance compared to baseline spending under the No Detention scenario. Border control policies that increase the likelihood of child and adolescent trauma exposure are not only morally troubling but may also create additional economic concerns in the form of direct health care costs and indirect societal costs.
Subject(s)
Emigration and Immigration/legislation & jurisprudence , Family Separation , Mental Disorders/epidemiology , Psychological Trauma/epidemiology , Refugees/psychology , Adolescent , Adolescent Health/economics , Adolescent Health/statistics & numerical data , Child , Child Health/economics , Child Health/statistics & numerical data , Female , Humans , Jails/statistics & numerical data , Male , Mental Disorders/economics , Psychological Trauma/economics , Psychological Trauma/etiology , Refugees/statistics & numerical data , United States/epidemiologyABSTRACT
OBJECTIVE: To demonstrate the landscape of model-based economic studies in asthma and highlight where there is room for improvement in the design and reporting of studies. DESIGN: A systematic review of the methodologies of model-based, cost-effectiveness analyses of asthma-related interventions was conducted. Models were evaluated for adherence to best-practice modeling and reporting guidelines and assumptions about the natural history of asthma. METHODS: A systematic search of English articles was performed in MEDLINE, EMBASE, and citations within reviewed articles. Studies were summarized and evaluated based on their adherence to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). We also studied the underlying assumptions about disease progression, heterogeneity in disease course, comorbidity, and treatment effects. RESULTS: Forty-five models of asthma were included (33 Markov models, 10 decision trees, 2 closed-form equations). Novel biological treatments were evaluated in 12 studies. Some of the CHEERS' reporting recommendations were not satisfied, especially for models published in clinical journals. This was particularly the case for the choice of the modeling framework and reporting on heterogeneity. Only 13 studies considered any subgroups, and 2 explicitly considered the impact of comorbidities. Adherence to CHEERS requirements and the quality of models generally improved over time. CONCLUSION: It would be difficult to replicate the findings of contemporary model-based evaluations of asthma-related interventions given that only a minority of studies reported the essential parameters of their studies. Current asthma models generally lack consideration of disease heterogeneity and do not seem to be ready for evaluation of precision medicine technologies.
Subject(s)
Anti-Asthmatic Agents/economics , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Cost-Benefit Analysis/methods , Decision Support Techniques , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/adverse effects , Asthma/physiopathology , Comorbidity , Decision Making , Economics, Medical , Health Care Rationing/organization & administration , Humans , Models, Economic , Quality-Adjusted Life YearsABSTRACT
BACKGROUND: Using the 140 speed cameras in New York City (NYC) as a case study, we explore how to optimise the number of cameras such that the most lives can be saved at the lowest cost. METHODS: A Markov model was built to explore the economic and health impacts of speed camera installations in NYC as well as the optimal number and placement. Both direct and indirect medical savings associated with speed cameras are weighed against their cost. Health outcomes are measured in terms of quality-adjusted life years (QALYs). RESULTS: Over the lifetime of an average NYC resident, the existing 140 speed cameras increase QALYs by 0.00044 units (95% credible interval (CrI) 0.00027 to 0.00073) and reduce costs by US$70 (95% CrI US$21 to US$131) compared with no speed cameras. The return on investment would be maximised where the number of cameras more than doubled to 300. This would further increase QALY gains per resident by 0.00083 units (95% CrI 0.00072 to 0.00096) while reducing medical costs by US$147 (95% CrI US$70 to US$221) compared with existing speed cameras. Overall, this increase in cameras would save 7000 QALYs and US$1.2 billion over the lifetime of the current cohort of New Yorkers. CONCLUSION: Speed cameras rank among the most cost-effective social policies, saving both money and lives.
Subject(s)
Accidents, Traffic/economics , Automobile Driving/legislation & jurisprudence , Law Enforcement/methods , Public Health/economics , Wounds and Injuries/prevention & control , Accidents, Traffic/prevention & control , Accidents, Traffic/statistics & numerical data , Automobile Driving/statistics & numerical data , Cost-Benefit Analysis , Environment Design , Health Promotion , Humans , Markov Chains , New York City/epidemiology , Public Health/legislation & jurisprudence , Quality-Adjusted Life Years , Wounds and Injuries/economics , Wounds and Injuries/epidemiologyABSTRACT
We examined the association between sexually transmitted disease (STD) and depressive symptoms. Our analysis utilized the 2015 cross-sectional Washington Heights Community Survey. Multivariable binary logistic regression analysis was used to examine the primary association between having a history of STD and patient health questionnaire-9 (PHQ-9) score while adjusting for potential confounders. Then in separate models, we adjusted for the interaction of social factors with PHQ-9 score to test for modification effect on the primary association. In this low-income neighborhood, STD history was not significantly associated with PHQ-9 score in the overall logistic regression model for the primary association. However, in interaction models, STD and depressive symptoms were associated in sub-groups defined by social factors, namely being Hispanic [odds ratio (OR) 1.08; 95% confidence interval (CI) 1.02-1.15], foreign-born (OR 1.08; 95% CI 1.02-1.15), and having low to moderate social support (OR 1.09; 95% CI 1.02-1.15). Our results demonstrate a need for targeted interventions to be applied to vulnerable subgroups identified.
Subject(s)
Depression/psychology , Sexually Transmitted Diseases/psychology , Adolescent , Adult , Cross-Sectional Studies , Female , Humans , Logistic Models , Male , Middle Aged , New York City/epidemiology , Poverty , Residence Characteristics , Risk Factors , Sexually Transmitted Diseases/epidemiology , Social Support , Young AdultABSTRACT
OBJECTIVES: To examine health benefits and cost-effectiveness of implementing a freeway deck park to increase urban green space. METHODS: Using the Cross-Bronx Expressway in New York City as a case study, we explored the cost-effectiveness of implementing deck parks. We built a microsimulation model that included increased exercise, fewer accidents, and less pollution as well as the cost of implementation and maintenance of the park. We estimated both the quality-adjusted life years gained and the societal costs for 2017. RESULTS: Implementation of a deck park over sunken parts of Cross-Bronx Expressway appeared to save both lives and money. Savings were realized for 84% of Monte Carlo simulations. CONCLUSIONS: In a rapidly urbanizing world, reclaiming green space through deck parks can bring health benefits alongside economic savings over the long term. Public Health Implications. Policymakers are seeking ways to create cross-sectorial synergies that might improve both quality of urban life and health. However, such projects are very expensive, and there is little information on their return of investment. Our analysis showed that deck parks produce exceptional value when implemented over below-grade sections of road.
Subject(s)
Cost-Benefit Analysis/economics , Environment Design/economics , Exercise , Parks, Recreational , Public Health/economics , Quality-Adjusted Life Years , Accidents, Traffic/economics , Accidents, Traffic/prevention & control , Adult , Humans , New York CityABSTRACT
Although recent declines in life expectancy among non-Hispanic Whites, coined "deaths of despair," grabbed the headlines of most major media outlets, this is neither a recent problem nor is it confined to Whites. The decline in America's health has been described in the public health literature for decades and has long been hypothesized to be attributable to an array of worsening psychosocial problems that are not specific to Whites. To test some of the dominant hypotheses, we show how various measures of despair have been increasing in the United States since 1980 and how these trends relate to changes in health and longevity. We show that mortality increases among Whites caused by the opioid epidemic come on the heels of the crack and HIV syndemic among Blacks. Both occurred on top of already higher mortality rates among all Americans relative to people in other nations, and both occurred among declines in measures of well-being. We believe that the attention given to Whites is distracting researchers and policymakers from much more serious, longer-term structural problems that affect all Americans.
Subject(s)
Health Status , Life Expectancy/ethnology , Mental Health/ethnology , Opioid-Related Disorders/ethnology , Public Health , Black or African American/statistics & numerical data , Cause of Death , Drug Overdose/ethnology , Economics , Female , Health Behavior/ethnology , Health Expenditures , Health Status Disparities , Humans , Male , Socioeconomic Factors , United States , White People/statistics & numerical dataABSTRACT
The "Citi Bike" bike share program in New York City is the largest bike share program in the USA. We ask whether expanding this program to lower-income communities is cost-effective means of encouraging exercise and reducing pollution in New York City. We built a stochastic Markov model to evaluate the cost-effectiveness of the Citi Bike expansion program, an effort to extend bike share to areas with higher costs and risks over a 10-year time horizon. We used one-way sensitivity analyses and Monte Carlo simulation to test the model uncertainty. The incremental cost-effectiveness ratio of the Citi Bike expansion program relative to the current program (status quo) was $7869/quality-adjusted life year gained. The Citi Bike expansion program in New York City offers good value relative to most health interventions.
Subject(s)
Bicycling/economics , Bicycling/statistics & numerical data , Cost-Benefit Analysis/statistics & numerical data , Poverty/statistics & numerical data , Urban Population/statistics & numerical data , Adult , Age Factors , Aged , Female , Humans , Male , Middle Aged , New York City , Quality-Adjusted Life Years , Sex Factors , Socioeconomic FactorsABSTRACT
BACKGROUND: A significant minority of asthma patients remain uncontrolled despite the use of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA). A number of add-on therapies, including monoclonal antibodies (namely omalizumab) and more recently tiotropium bromide have been recommended for this subgroup of patients. The purpose of this study was to assess the cost-effectiveness of tiotropium versus omalizumab as add-on therapies to ICS + LABA for patients with uncontrolled allergic asthma. METHODS: A probabilistic Markov model of asthma was created. Total costs (in 2013 US $) and health outcomes of three interventions including standard therapy (ICS + LABA), add-on therapy with tiotropium, and add-on therapy with omalizumab, were calculated over a 10-year time horizon. Future costs and quality-adjusted life years (QALYs) were discounted at the rate of 3%. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at willingness-to-pay value of $50,000. RESULTS: The 10-year discounted costs and QALYs for standard therapy were $38,432 and 6.79, respectively. The corresponding values for add-on therapy with tiotropium and with omalizumab were $41,535 and 6.88, and $217,847 and 7.17, respectively. The incremental cost-effectiveness ratios (ICER) of add-on therapy with tiotropium versus standard therapy, and omalizumab versus tiotropium were $34,478/QALY, and $593,643/QALY, respectively. The model outcomes were most sensitive to the costs of omalizumab but were robust against other assumptions. CONCLUSIONS: Although omalizumab had the best health outcomes, add-on therapy with tiotropium was a cost-effective alternative to omalizumab and standard therapy for uncontrolled allergic asthma at willingness-to-pay of $50,000/QALY.
ABSTRACT
BACKGROUND: Many decision-analytic models with varying structures have been developed to inform resource allocation in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To review COPD models for their adherence to the best practice modeling recommendations and their assumptions regarding important aspects of the natural history of COPD. METHODS: A systematic search of English articles reporting on the development or application of a decision-analytic model in COPD was performed in MEDLINE, Embase, and citations within reviewed articles. Studies were summarized and evaluated on the basis of their adherence to the Consolidated Health Economic Evaluation Reporting Standards. They were also evaluated for the underlying assumptions about disease progression, heterogeneity, comorbidity, and treatment effects. RESULTS: Forty-nine models of COPD were included. Decision trees and Markov models were the most popular techniques (43 studies). Quality of reporting and adherence to the guidelines were generally high, especially in more recent publications. Disease progression was modeled through clinical staging in most studies. Although most studies (n = 43) had incorporated some aspects of COPD heterogeneity, only 8 reported the results across subgroups. Only 2 evaluations explicitly considered the impact of comorbidities. Treatment effect had been mostly modeled (20) as both reduction in exacerbation rate and improvement in lung function. CONCLUSIONS: Many COPD models have been developed, generally with similar structural elements. COPD is highly heterogeneous, and comorbid conditions play an important role in its burden. These important aspects, however, have not been adequately addressed in most of the published models.
Subject(s)
Models, Economic , Pulmonary Disease, Chronic Obstructive/economics , Comorbidity , Cost-Benefit Analysis , Decision Support Techniques , Disease Progression , Economics, Medical , Guideline Adherence , Humans , Markov Chains , Practice Guidelines as Topic , Pulmonary Disease, Chronic Obstructive/physiopathology , Quality of Life , Quality-Adjusted Life YearsABSTRACT
PURPOSE: Medulloblastoma is the most prevalent childhood brain cancer. Children with medulloblastoma typically receive a combination of surgery, radiation, and chemotherapy. The survival rate is high but survivors often have sequelae from radiotherapy of the entire developing brain and spinal cord. Ongoing genetic studies have suggested that decreasing the dose of radiation might be possible among children with favorable molecular variants; however, this may result in an increased disease recurrence. As such, there is a need to investigate the nature of trade-offs that individuals are willing to make regarding the treatment of medulloblastoma. METHOD: We used best-worst scaling to estimate the importance of attributes affecting the general public's decision making around the treatment of medulloblastoma. After conducting focus groups, we selected three relevant attributes: (1) the accuracy of the genetic test; (2) the probability of serious adverse effects of the treatment(s); and (3) the survival rate. Using the paired method, we applied a conditional logit model to estimate preferences. RESULTS: In total, 3,006 respondents (51.3% female) with an average age of 43 years answered the questionnaires. All coefficients were statistically significantly different from zero and the attribute levels of adverse effects and the survival rate had the most impact on individuals' stated decision making. CONCLUSION: Overall, respondents showed high sensitivity to children experiencing disability particularly in the setting of a good prognosis. However, among children with poor prognostic molecular variants, participants showed tolerance about having a child with mild and partial disability compared to a low rate of survival.
Subject(s)
Brain Neoplasms , Medulloblastoma , Quality of Life , Adult , Age Factors , Brain Neoplasms/mortality , Brain Neoplasms/physiopathology , Brain Neoplasms/therapy , Disease-Free Survival , Female , Humans , Male , Medulloblastoma/mortality , Medulloblastoma/physiopathology , Medulloblastoma/therapy , Middle Aged , Risk Factors , Socioeconomic Factors , Survival RateABSTRACT
BACKGROUND: Medication management (MM) services are being provided by pharmacists across Canada in various forms, but pharmacist-physician collaboration is still not a routine practice in most jurisdictions. This survey aimed to gather pharmacists' and physicians' opinions and preferences for MM provision. METHODS: Two parallel, cross-sectional online surveys, including best-worst scaling tasks, were designed for pharmacists and physicians in British Columbia to capture and compare their preferences for a number of attributes of MM. RESULTS: Surveys were completed by 119 pharmacists and 146 physicians. Results indicate that pharmacists and physicians had similar opinions on many aspects of MM. Ninety-five percent of pharmacists and 69% of physicians believed that additional health services are needed to help patients optimize the use of their medications. However, the majority of each group felt that they were the most important health care professional in providing this service. Most pharmacists (79%) and some physicians (25%) thought that optimizing use of medications would result in both decreased costs and utilization to the health care system. Both pharmacists and physicians felt that the best attribute of an MM service would be if the services resulted in improved health and medication use for patients. Both groups were motivated by increased remuneration for MM; however, the relative strength of preference for this was higher among physicians. Interestingly, physicians valued improved medication adherence as a result of MM more highly than pharmacists did. DISCUSSION AND CONCLUSION: Most pharmacists and physicians agreed that improving patients' health and medication use would be the best attribute of MM and that there is a need for such services. However, physicians also had strong preferences for being remunerated for participating in MM provision.
ABSTRACT
Exacerbations are a hallmark of chronic obstructive pulmonary disease (COPD). Evidence suggests the presence of substantial between-individual variability (heterogeneity) in exacerbation rates. The question of whether individuals vary in their tendency towards experiencing severe (versus mild) exacerbations, or whether there is an association between exacerbation rate and severity, has not yet been studied. We used data from the MACRO Study, a 1-year randomized trial of the use of azithromycin for prevention of COPD exacerbations (United States and Canada, 2006-2010; n = 1,107, mean age = 65.2 years, 59.1% male). A parametric frailty model was combined with a logistic regression model, with bivariate random effects capturing heterogeneity in rate and severity. The average rate of exacerbation was 1.53 episodes/year, with 95% of subjects having a model-estimated rate of 0.47-4.22 episodes/year. The overall ratio of severe exacerbations to total exacerbations was 0.22, with 95% of subjects having a model-estimated ratio of 0.04-0.60. We did not confirm an association between exacerbation rate and severity (P = 0.099). A unified model, implemented in standard software, could estimate joint heterogeneity in COPD exacerbation rate and severity and can have applications in similar contexts where inference on event time and intensity is considered. We provide SAS code (SAS Institute, Inc., Cary, North Carolina) and a simulated data set to facilitate further uses of this method.
Subject(s)
Azithromycin/therapeutic use , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/drug therapy , Aged , Anti-Bacterial Agents/therapeutic use , Disease Progression , Humans , Logistic Models , Male , Middle Aged , Multicenter Studies as Topic , North America , Proportional Hazards Models , Randomized Controlled Trials as Topic/statistics & numerical data , Severity of Illness IndexABSTRACT
BACKGROUND: Severe asthma is associated with disproportionately high morbidity, but little is known about its natural history and how risk factors at first year of diagnosis modify its subsequent development. METHODS: Using administrative health data, we retrospectively followed patients 14-55â years of age with newly diagnosed severe asthma in British Columbia, Canada. Based on intensity of resource use (drug therapy) and occurrence of exacerbations, each patient-year was classified into mild, moderate, or severe asthma. We estimated the probability of transition between severity levels or to death over the study period using a four-state Markov model, and used this to assess the 10-year trajectory of severe asthma and the influence of baseline risk factors. RESULTS: We followed 13,467 patients. Ten years after incident severe asthma, 83% had transitioned to a less severe level (mild: 43%, moderate: 40%). Low socioeconomic status, high comorbidity burden, and high adherence (proportion of days covered (PDC) by asthma controller therapy) in the first year were independently associated with, respectively, 10%, 24% and 35% more time in severe asthma over the next 10â years. Sex was not associated with the clinical course. CONCLUSIONS: Most patients with incident severe asthma used fewer resources over time, indicating a long-term transition to milder asthma. Potentially modifiable risk factors for poor prognosis of severe asthma include low socioeconomic status and high comorbidity burden. The association between PDC and future asthma severity is likely due to residual confounding by disease severity.
Subject(s)
Asthma/etiology , Population Surveillance/methods , Risk Assessment/methods , Adolescent , Adult , Asthma/diagnosis , Asthma/epidemiology , British Columbia/epidemiology , Disease Progression , Female , Follow-Up Studies , Humans , Male , Middle Aged , Morbidity/trends , Prognosis , Retrospective Studies , Risk Factors , Severity of Illness Index , Socioeconomic Factors , Time Factors , Young AdultABSTRACT
BACKGROUND: The rate of lung-function decline in chronic obstructive pulmonary disease (COPD) varies substantially among individuals. We sought to develop and validate an individualized prediction model for forced expiratory volume at 1 second (FEV1) in current smokers with mild-to-moderate COPD. METHODS: Using data from a large long-term clinical trial (the Lung Health Study), we derived mixed-effects regression models to predict future FEV1 values over 11 years according to clinical traits. We modelled heterogeneity by allowing regression coefficients to vary across individuals. Two independent cohorts with COPD were used for validating the equations. RESULTS: We used data from 5594 patients (mean age 48.4 yr, 63% men, mean baseline FEV1 2.75 L) to create the individualized prediction equations. There was significant between-individual variability in the rate of FEV1 decline, with the interval for the annual rate of decline that contained 95% of individuals being -124 to -15 mL/yr for smokers and -83 to 15 mL/yr for sustained quitters. Clinical variables in the final model explained 88% of variation around follow-up FEV1. The C statistic for predicting severity grades was 0.90. Prediction equations performed robustly in the 2 external data sets. INTERPRETATION: A substantial part of individual variation in FEV1 decline can be explained by easily measured clinical variables. The model developed in this work can be used for prediction of future lung health in patients with mild-to-moderate COPD. TRIAL REGISTRATION: Lung Health Study - ClinicalTrials.gov, no. NCT00000568; Pan-Canadian Early Detection of Lung Cancer Study - ClinicalTrials.gov, no. NCT00751660.
Subject(s)
Individuality , Lung/physiopathology , Pulmonary Disease, Chronic Obstructive/physiopathology , Smoking Cessation , Smoking/physiopathology , Adult , Canada , Disease Progression , Female , Forced Expiratory Volume , Humans , Longitudinal Studies , Male , Middle AgedABSTRACT
AIMS/HYPOTHESIS: The evidence on the association between pioglitazone use and bladder cancer is contradictory, with many studies subject to allocation bias. The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts. The potential for allocation bias was minimised by focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach. METHODS: Prescription, cancer and mortality data from people with type 2 diabetes were obtained from six populations across the world (British Columbia, Finland, Manchester, Rotterdam, Scotland and the UK Clinical Practice Research Datalink). A discrete time failure analysis using Poisson regression was applied separately to data from each centre to model the effect of cumulative drug exposure on bladder cancer incidence, with time-dependent adjustment for ever use of pioglitazone. These were then pooled using fixed and random effects meta-regression. RESULTS: Data were collated on 1.01 million persons over 5.9 million person-years. There were 3,248 cases of incident bladder cancer, with 117 exposed cases and a median follow-up duration of 4.0 to 7.4 years. Overall, there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men (rate ratio [RR] per 100 days of cumulative exposure, 1.01; 95% CI 0.97, 1.06) or women (RR 1.04; 95% CI 0.97, 1.11) after adjustment for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone. No association was observed between rosiglitazone and bladder cancer in men (RR 1.01; 95% CI 0.98, 1.03) or women (RR 1.00; 95% CI 0.94, 1.07). CONCLUSIONS/INTERPRETATION: The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large, pooled multipopulation analysis.