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Shawn D Aaron,1 Andrea S Gershon,2 Yuan Gao,1 Jenna Yang,1 GA Whitmore1,3 On behalf of the Canadian Respiratory Research Network 1Ottawa Hospital Research Institute, University of Ottawa, Ottawa, 2Sunnybrook Research Institute, University of Toronto, ON, 3Desautels Faculty of Management, McGill University, Montreal, QC, Canada Purpose: Studies suggest that COPD prevalence may vary between countries. We conducted an ecological study of data from COPD prevalence articles to assess the influence of differences in country-level risk factors on COPD prevalence. Patients and methods: Our study covered English language articles published during 2003–2014. Qualified articles used spirometry to assess COPD prevalence and used representative samples from national or subnational populations. Stepwise binomial regression was used to analyze associations between study- and country-level factors and COPD prevalence. Results: Eighty articles provided 1,583 measures of COPD prevalence for subjects in different sex, age, and smoking categories for 112 districts in 41 countries. Adjusted prevalence rates for COPD were significantly lower for Australia/New Zealand and the Mediterranean and significantly higher for Latin America, compared to North America, Southeast Asia, and Northern Europe. Country-level socioeconomic development variables had an uneven and mixed association with COPD prevalence. High elevation above sea level was shown to be a protective factor for COPD. Study-level variables for the established risk factors of sex, age, and smoking explained 64% of variability in COPD prevalence. Country-level risk factors raised the explanatory power to 72%. Approximately 28% of worldwide variability in COPD prevalence remained unexplained. Conclusion: Our study suggests that COPD prevalence varies across world regions, even after adjustment for established risk factors. Major country-level risk factors contributing to the worldwide epidemic of COPD remain to be investigated. Keywords: country effects, ecological study, epidemiology, lung disease, risk factors, spirometry

Background: Some patients with asthma demonstrate normal spirometry and remain undiagnosed without further testing., Objective: To determine clinical predictors of asthma in symptomatic adults with normal spirometry, and to generate a tool to help clinicians decide who should undergo bronchial challenge testing (BCT)., Methods: Using random-digit dialling and population-based case-finding, we recruited adults from the community with respiratory symptoms and no previous history of diagnosed lung disease. Participants with normal pre- and post-bronchodilator spirometry subsequently underwent BCT. Asthma was diagnosed in those with symptoms and a methacholine provocative concentration (PC 20 ) of < 8 mg/ml. Sputum and blood eosinophils, and exhaled nitric oxide were measured. Univariate analyses identified potentially predictive variables, which were then used to construct a multivariable logistic regression model to predict asthma. Model sensitivity, specificity, and area under the receiver operating curve (AUC) were calculated., Results: Of 132 symptomatic individuals with normal spirometry, 34 (26%) had asthma. Of those ultimately diagnosed with asthma, 33 (97%) answered 'yes' to a question asking whether they experienced cough, chest tightness or wheezing provoked by exercise or cold air. Other univariate predictors of asthma included female sex, pre-bronchodilator FEV1 percentage predicted, and percent positive change in FEV1 post bronchodilator. A multivariable model containing these predictive variables yielded an AUC of 0.82 (95% CI: 0.72-0.91), a sensitivity of 82%, and a specificity of 66%. The model was used to construct a nomogram to advise clinicians which patients should be prioritized for BCT., Conclusions: Four readily available patient characteristics demonstrated a high sensitivity and AUC for predicting undiagnosed asthma in symptomatic adults with normal pre- and post-bronchodilator spirometry. These characteristics can potentially help clinicians to decide which individuals with normal spirometry should be investigated with bronchial challenge testing. However, further prospective validation of our decision tool is required., (© 2023. The Author(s).)

Background: It remains unclear why some symptomatic individuals with asthma or COPD remain undiagnosed. Here, we compare patient and physician characteristics between symptomatic individuals with obstructive lung disease (OLD) who are undiagnosed and individuals with physician-diagnosed OLD., Methods: Using random-digit dialling and population-based case finding, we recruited 451 participants with symptomatic undiagnosed OLD and 205 symptomatic control participants with physician-diagnosed OLD. Data on symptoms, quality of life and healthcare utilisation were analysed. We surveyed family physicians of participants in both groups to elucidate differences in physician practices that could contribute to undiagnosed OLD., Results: Participants with undiagnosed OLD had lower mean pre-bronchodilator forced expiratory volume in 1 s percentage predicted compared with those who were diagnosed (75.2% versus 80.8%; OR 0.975, 95% CI 0.963-0.987). They reported greater psychosocial impacts due to symptoms and worse energy and fatigue than those with diagnosed OLD. Undiagnosed OLD was more common in participants whose family physicians were practising for >15 years and in those whose physicians reported that they were likely to prescribe respiratory medications without doing spirometry. Undiagnosed OLD was more common among participants who had never undergone spirometry (OR 10.83, 95% CI 6.18-18.98) or who were never referred to a specialist (OR 5.92, 95% CI 3.58-9.77). Undiagnosed OLD was less common among participants who had required emergency department care (OR 0.44, 95% CI 0.20-0.97)., Conclusions: Individuals with symptomatic undiagnosed OLD have worse pre-bronchodilator lung function and present with greater psychosocial impacts on quality of life compared with their diagnosed counterparts. They were less likely to have received appropriate investigations and specialist referral for their respiratory symptoms., Competing Interests: Conflict of interest: M. Cherian reports no conflict of interest. K.M.A. Magner reports no conflict of interest. G.A. Whitmore reports no conflict of interest. K.L. Vandemheen reports no conflict of interest. C. Bergeron reports grants, contracts or honoraria from Novartis, Biohaven, AstraZeneca, Sanofi, Valeo and Grifols; and advisory board participation Sanofi, AstraZeneca, GlaxoSmithKline, Takeda and Valeo. L-P. Boulet reports grants, contracts, consulting fees or honoraria from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Sanofi-Regeneron, Covis and Novartis; royalties or licences from UptoDate and Taylor & Francis; leadership roles with the Global Initiative for Asthma (GINA), Global Asthma Association (INTERASMA) and Canadian Thoracic Society; and holds the Laval University Chair on Knowledge Transfer, Prevention and Education in Respiratory and Cardiovascular Health. A. Cote reports grants, contracts, consulting fees or honoraria from GlaxoSmithKline, AstraZeneca, Valeo, Sanofi-Regeneron and Covis; and advisory board participation with AstraZeneca, Sanofi and Valeo. S.K. Field reports grants, contracts, consulting fees or honoraria from Bayer, Insmed, Merck, Valeo and GlaxoSmithKline. E. Penz reports grants, contracts, consulting fees or honoraria from the Saskatchewan Health Research Foundation, CIHR, Respiratory Research Centre, SCPOR, AstraZeneca, Saskatchewan Cancer Agency, GlaxoSmithKline, Sanofi, Genzyme, ICBEM and Boehringer Ingelheim; and leadership roles with the Canadian Thoracic Society COPD Assembly, CIHR Institute Advisory Board and Youth4Change. R.A. McIvor reports no conflict of interest. C. Lemière repots grants, contracts, consulting fees or honoraria from GlaxoSmithKline, AstraZeneca, Sanofi and Novartis; and royalties or licences from UptoDate. S. Gupta reports no conflict of interest. I. Mayers reports no conflict of interest. M. Bhutani reports grants, contracts, consulting fees, support for travel or honoraria from the CIHR, AstraZeneca, GlaxoSmithKline, Novartis, Grifols, Sanofi, Covis, Valeo, Lung Association of Saskatchewan, Canadian Thoracic Society and Lung Association of Alberta and Northwest Territories; and leadership roles with the Canadian Thoracic Society and Alberta Health Services. P. Hernandez reports grants, contracts, support for travel or honoraria from the CIHR, Cyclomedia, Boehringer Ingelheim, Vertex, Grifols, AstraZeneca, Boehringer Ingelheim, Janssen and Canadian Thoracic Society; advisory board participation with Acceleron, AstraZeneca, Boehringer Ingelheim, Covis, GlaxoSmithKline, Grifols, Janssen, Novartis, Sanofi, Takeda and Valeo; and leadership roles with the Canadian Thoracic Society. M.D. Lougheed reports grants, contracts or honoraria from the CIHR, AstraZeneca, GlaxoSmithKline, Canadian Thoracic Society and MDBriefcase; advisory board participation with AstraZeneca; leadership roles with the Canadian Thoracic Society, Health Quality Ontario and the Lung Association. C.J. Licskai reports no conflict of interest. T. Azher reports no conflict of interest. M. Ainslie reports no conflict of interest. N. Ezer reports grants, contracts or honoraria from the CIHR, Rossy Cancer Network, Covis Pharma, GlaxoSmithKline, AstraZeneca, Fédération des Omnipracticiens du Québec and Médecin du Québec Magazine; advisory board participation with GlaxoSmithKline; leadership role with the Quebec Ministry of Health Lung Cancer Screening Implementation Committee; and receipt of study drug from Covis. S. Mulpuru reports no conflict of interest. S.D. Aaron reports honoraria from AstraZeneca, Sanofi and GlaxoSmithKline; and advisory board participation with AstraZeneca, GlaxoSmithKline and Sanofi., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Many people with asthma and COPD remain undiagnosed. We developed and validated a new case-finding questionnaire to identify symptomatic adults with undiagnosed obstructive lung disease., Methods: Adults in the community with no prior history of physician-diagnosed lung disease who self-reported respiratory symptoms were contacted via random-digit dialling. Pre- and post-bronchodilator spirometry was used to confirm asthma or COPD. Predictive questions were selected using multinomial logistic regression with backward elimination. Questionnaire performance was assessed using sensitivity, predictive values and area under the receiver operating characteristic curve (AUC). The questionnaire was assessed for test-retest reliability, acceptability and readability. External validation was prospectively conducted in an independent sample and predictive performance re-evaluated., Results: A 13-item Undiagnosed COPD and Asthma Population Questionnaire (UCAP-Q) case-finding questionnaire to predict undiagnosed asthma or COPD was developed. The most appropriate risk cut-off was determined to be 6% for either disease. Applied to the derivation sample (n=1615), the questionnaire yielded a sensitivity of 92% for asthma and 97% for COPD; specificity of 17%; and an AUC of 0.69 (95% CI 0.64-0.74) for asthma and 0.82 (95% CI 0.78-0.86) for COPD. Prospective validation using an independent sample (n=471) showed sensitivities of 93% and 92% for asthma and COPD, respectively; specificity of 19%; with AUCs of 0.70 (95% CI 0.62-0.79) for asthma and 0.81 (95% CI 0.74-0.87) for COPD. AUCs for UCAP-Q were higher compared to AUCs for currently recommended case-finding questionnaires for asthma or COPD., Conclusions: The UCAP-Q demonstrated high sensitivities and AUCs for identifying undiagnosed asthma or COPD. A web-based calculator allows for easy calculation of risk probabilities for each disease., Competing Interests: Conflict of interest: C. Huynh reports no conflicts of interest. G.A. Whitmore reports no conflicts of interest. K.L. Vandemheen reports no conflicts of interest. J.M. FitzGerald reports no conflicts of interest. C. Bergeron reports no conflicts of interest. L-P. Boulet reports receiving grants, consulting fees or honoraria from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis and Sanofi-Regeneron. A. Cote reports receiving honoraria from GlaxoSmithKline, AstraZeneca, Sanofi and Covis. S.K. Field reports receiving consulting fees or honoraria from Merck, GlaxoSmithKline, Novartis and Boehringer Ingelheim. E. Penz reports receiving honoraria from AstraZeneca, GlaxoSmithKline, Novartis, ICEBM and Boehringer Ingelheim. R.A. McIvor reports no conflicts of interest. C. Lemière reports receiving consulting fees or honoraria from Sanofi, TEVA, GlaxoSmithKline and AstraZeneca. S. Gupta reports no conflicts of interest. I. Mayers reports no conflicts of interest. M. Bhutani reports payments or honoraria from AZ, GSK, Novartis, Grifols, Sanofi, Covis and Valeo. P. Hernandez reports payments or honoraria from AZ, GSK, Novartis and Valeo. M.D. Lougheed reports receiving grants from AZ and GSK. C.J. Licskai reports receiving honoraria from AstraZeneca, GlaxoSmithKline, Novartis and Boehringer Ingelheim. T. Azher reports no conflicts of interest. M. Ainslee reports receiving honoraria from Boehringer Ingelheim. I. Fraser reports no conflicts of interest. M. Mahdavian reports no conflicts of interest. G.G. Alvarez reports no conflicts of interest. T. Kendzerska reports speaker honoraria from AstraZeneca. S.D. Aaron reports sitting on advisory boards and honoraria payments from GlaxoSmithKline, Sanofi and AstraZeneca., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: The actual burden of COPD and asthma may be much higher than appreciated, since a large proportion of individuals are not diagnosed. Our study objective was to compare health care utilization, burden of symptoms and quality of life in subjects with self-reported respiratory symptoms who were subsequently found to have undiagnosed airflow obstruction compared to those having no airflow obstruction., Methods: This cross-sectional case-finding study used data from the Undiagnosed COPD and Asthma Population (UCAP) study. Adult subjects with respiratory symptoms who had no history of diagnosed lung disease were recruited in a two-step case-finding process using random digit-dialling of land lines and cell phones located within a 90-min radius of 16 Canadian study sites. Participants were assessed for COPD, asthma or no airflow obstruction using pre- and post-bronchodilator spirometry based on American Thoracic Society diagnostic criteria., Results: 1660 participants were recruited, of these 1615 had adequate spirometry and 331 (20.5%) subjects met spirometry criteria for undiagnosed asthma or COPD. Subjects with undiagnosed asthma or COPD had increased respiratory symptoms as assessed by the COPD Assessment Test (CAT), and higher St. George's Respiratory Questionnaire (SGRQ) scores indicating worse health-related quality of life, compared to subjects with no airflow obstruction. No between-group differences were found in health care utilization or work or school absenteeism., Conclusion: Undiagnosed asthma and COPD are common in Canadian adults experiencing breathing problems and are associated with a greater burden of symptoms and poorer health-related quality of life. These results suggest that patients may benefit from early identification and treatment of undiagnosed asthma and COPD., Competing Interests: Declaration of competing interest All authors in this paper declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: ∼5-10% of adults may have undiagnosed airflow obstruction. The objective of this study was to develop a population-based case-finding strategy to assess the prevalence of undiagnosed airflow obstruction (asthma or COPD) amongst adults with respiratory symptoms in Canada., Methods: Adults without a previous history of asthma, COPD or lung disease were recruited using random digit-dialling and asked if they had symptoms of dyspnoea, cough, sputum or wheeze within the past 6 months. Those who answered affirmatively completed the Asthma Screening Questionnaire (ASQ), COPD-Diagnostic Questionnaire (COPD-DQ) and COPD Assessment Test (CAT). Those with an ASQ score of ≥6 or a COPD-DQ score of ≥20 underwent pre- and post-bronchodilator spirometry to diagnose asthma or COPD., Results: 12 117 individuals were contacted at home and assessed for study eligibility. Of the 1260 eligible individuals, 910 (72%) enrolled and underwent spirometry. Ultimately, 184 subjects (20% of those enrolled) had obstructive lung disease (73 asthma and 111 COPD). Individuals found to have undiagnosed asthma or COPD had more severe respiratory symptoms and impaired quality of life compared with those without airflow obstruction. The ASQ, COPD-DQ, and CAT had ROC areas for predicting undiagnosed asthma or COPD of 0.49, 0.64 and 0.56, respectively. Four descriptive variables (age, BMI, sex and pack-years smoked) produced better receiver operating characteristic (ROC) values than the questionnaires (ROC area=0.68)., Conclusion: 20% of randomly selected individuals who report respiratory symptoms in Canada have undiagnosed airflow obstruction due to asthma or COPD. Questionnaires could exclude subjects at low risk but lack the ability to accurately find subjects with undiagnosed disease., Competing Interests: Conflict of interest: M. Preteroti has nothing to disclose. Conflict of interest: G.A. Whitmore has nothing to disclose. Conflict of interest: K.L. Vandemheen has nothing to disclose. Conflict of interest: J.M. FitzGerald has nothing to disclose. Conflict of interest: C. Lemiere reports grants and personal fees for advisory board work, consultancy and lectures from AstraZeneca, grants and personal fees for advisory board work and lectures from TEVA Innovation, personal fees for advisory board work and consultancy from GlaxoSmithKline, personal fees for advisory board work from Sanofi, outside the submitted work. Conflict of interest: L-P. Boulet reports research grants for participation in multicentre studies from AstraZeneca, Boston Scientific, GlaxoSmithKline, Hoffman La Roche, Novartis, Ono Pharma, Sanofi and Takeda, support for research projects introduced by the investigator from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck and Takeda, fees for consulting and advisory boards from AstraZeneca, Novartis and Methapharm, nonprofit grants for production of educational materials from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck and Novartis, conference fees from AstraZeneca, GlaxoSmithKline, Merck and Novartis, support for participation in conferences and meetings from Novartis and Takeda. Conflict of interest: E. Penz reports CIHR funding of UCAP study, during the conduct of the study; grants, personal fees for advisory board work, consultancy and lectures, and non-financial (travel) support from AstraZeneca, personal fees for advisory board work and non-financial (travel) support from GlaxoSmithKline and Boehringer Ingelheim, outside the submitted work. Conflict of interest: S.K. Field reports grants from GSK, InsMed, Novartis and Boehringer Ingelheim, outside the submitted work. Conflict of interest: S. Gupta has nothing to disclose. Conflict of interest: R.A. McIvor has nothing to disclose. Conflict of interest: I. Mayers has nothing to disclose. Conflict of interest: P. Hernandez reports grants from CIHR, during the conduct of the study; personal fees for consultancy from Actelion, GlaxoSmithKline, Novartis, Sanofi and Teva, personal fees for consultancy and educational activities from AstraZeneca, grants and personal fees for consultancy and educational activities from Boehringer Ingelheim, grants from Cyclomedica, Grifols and Prometic, outside the submitted work. Conflict of interest: D. Lougheed reports grants from AstraZeneca, GlaxoSmithKline, Hoffman LaRoche Ltd, Novartis, Government of Ontario's Innovation Fund, Allergen NCE, Janssen, Canadian Institutes of Health Research, Manitoba Workers Compensation Board and Ontario Lung Association/Canada Health Infoway, grants and honoraria for educational activities from Ontario Lung Association, honoraria for educational activities from Canadian Thoracic Society, honoraria for advisory board work from AstraZeneca PRECISION Program, outside the submitted work; and is the nominated Canadian Thoracic Society representative on the Canadian Lung Association's Board of Directors. Conflict of interest: M. Ainslie has nothing to disclose. Conflict of interest: C. Licskai reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis and Pfizer, personal fees from GSK, outside the submitted work. Conflict of interest: T. Azher has nothing to disclose. Conflict of interest: I. Fraser has nothing to disclose. Conflict of interest: M. Madavian reports personal fees for lectures from AstraZeneca, personal fees for lectures and non-financial (drug sample) support from Novartis and Boehringer Ingelheim, non-financial (drug sample) support from GSK, outside the submitted work. Conflict of interest: S.D. Aaron has nothing to disclose., (Copyright ©ERS 2020.)

Introduction: We aimed to develop a clinical tool for predicting 1- and 2-year risk of death for patients with cystic fibrosis (CF). The model considers patients' overall health status as well as risk of intermittent shock events in calculating the risk of death., Methods: Canadian CF Registry data from 1982 to 2015 were used to develop a predictive risk model using threshold regression. A 2-year risk of death estimated conditional probability of surviving the second year given survival for the first year. UK CF Registry data from 2007 to 2013 were used to externally validate the model., Results: The combined effect of CF chronic health status and CF intermittent shock risk provided a simple clinical scoring tool for assessing 1-year and 2-year risk of death for an individual CF patient. At a threshold risk of death of ≥20%, the 1-year model had a sensitivity of 74% and specificity of 96%. The area under the receiver operating curve (AUC) for the 2-year mortality model was significantly greater than the AUC for a model that predicted survival based on forced expiratory volume in 1 s <30% predicted (AUC 0.95 versus 0.68 respectively, p<0.001). The Canadian-derived model validated well with the UK data and correctly identified 79% of deaths and 95% of survivors in a single year in the UK., Conclusions: The prediction models provide an accurate risk of death over a 1- and 2-year time horizon. The models performed equally well when validated in an independent UK CF population., Competing Interests: Conflict of interest: S. Stanojevic has nothing to disclose. Conflict of interest: J. Sykes has nothing to disclose. Conflict of interest: A.L. Stephenson has nothing to disclose. Conflict of interest: S.D. Aaron has nothing to disclose. Conflict of interest: G.A. Whitmore has nothing to disclose., (Copyright ©ERS 2019.)

Rationale: Chronic obstructive pulmonary disease (COPD) is a chronic, progressive disease, and reversal of COPD diagnosis is thought to be uncommon., Objectives: To determine whether a spirometric diagnosis of mild or moderate COPD is subject to variability and potential error., Methods: We examined two prospective cohort studies that enrolled subjects with mild to moderate post-bronchodilator airflow obstruction. The Lung Health Study (n = 5,861 subjects; study duration, 5 yr) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study (n = 1,551 subjects; study duration, 4 yr) were examined to determine frequencies of (1) diagnostic instability, represented by how often patients initially met criteria for a spirometric diagnosis of COPD but then crossed the diagnostic threshold to normal and then crossed back to COPD over a series of annual visits, or vice versa; and (2) diagnostic reversals, defined as how often an individual's COPD diagnosis at the study outset reversed to normal by the end of the study., Measurements and Main Results: Diagnostic instability was common and occurred in 19.5% of the Lung Health Study subjects and 6.4% of the CanCOLD subjects. Diagnostic reversals of COPD from the beginning to the end of the study period occurred in 12.6% and 27.2% of subjects in the Lung Health Study and CanCOLD study, respectively. The risk of diagnostic instability was greatest for subjects whose baseline FEV 1 /FVC value was closest to the diagnostic threshold, and the risk of diagnostic reversal was greatest for subjects who quit smoking during the study., Conclusions: A single post-bronchodilator spirometric assessment may not be reliable for diagnosing COPD in patients with mild to moderate airflow obstruction at baseline.

Previously established predictors of survival may no longer apply in the current era of cystic fibrosis (CF) care. Our objective was to identify risk factors associated with survival in a contemporary CF population. We used the Canadian CF Registry, a population-based cohort, to calculate median age of survival and summarise patient characteristics from 1990 to 2012. Clinical, demographic and geographical factors, and survival were estimated for a contemporary cohort (2000-2012) using Cox proportional hazards models. There were 5787 individuals in the registry between 1990 and 2012. Median survival age increased from 31.9 years (95% CI 28.3-35.2 years) in 1990 to 49.7 years (95% CI 46.1-52.2 years) in the most current 5-year window ending in 2012. Median forced expiratory volume in 1 s improved (p=0.04) and fewer subjects were malnourished (p<0.001) over time. Malnourished patients (hazard ratio (HR) 2.1, 95% CI 1.6-2.8), those with multiple exacerbations (HR 4.5, 95% CI 3.2-6.4) and women with CF-related diabetes (HR 1.8, 95% CI 1.2-2.7) were at increased risk of death. Life expectancy in Canadians with CF is increasing. Modifiable risk factors such as malnutrition and pulmonary exacerbations are associated with an increased risk of death. The sex gap in CF survival may be explained by an increased hazard for death in women with CF-related diabetes., (Copyright ©ERS 2015.)

In epidemiological and clinical studies, time-to-event data often violate the assumptions of Cox regression due to the presence of time-dependent covariate effects and unmeasured risk factors. An alternative approach, which does not require proportional hazards, is to use a first hitting time model which treats a subject's health status as a latent stochastic process that fails when it reaches a threshold value. Although more flexible than Cox regression, existing methods do not account for unmeasured covariates in both the initial state and the rate of the process. To address this issue, we propose a Bayesian methodology that models an individual's health status as a Wiener process with subject-specific initial state and drift. Posterior inference proceeds via a Markov chain Monte Carlo methodology with data augmentation steps to sample the final health status of censored observations. We apply our method to data from melanoma patients with nonproportional hazards and find interesting differences from a similar model without random effects. In a simulation study, we show that failure to account for unmeasured covariates can lead to inaccurate estimates of survival probabilities.

There is considerable scientific interest in knowing the probability that a site-specific transcription factor will bind to a given DNA sequence. Microarray methods provide an effective means for assessing the binding affinities of a large number of DNA sequences as demonstrated by Bulyk et al. (2001, Proceedings of the National Academy of Sciences, USA 98, 7158-7163) in their study of the DNA-binding specificities of Zif268 zinc fingers using microarray technology. In a follow-up investigation, Bulyk, Johnson, and Church (2002, Nucleic Acid Research 30, 1255-1261) studied the interdependence of nucleotides on the binding affinities of transcription proteins. Our article is motivated by this pair of studies. We present a general statistical methodology for analyzing microarray intensity measurements reflecting DNA-protein interactions. The log probability of a protein binding to a DNA sequence on an array is modeled using a linear ANOVA model. This model is convenient because it employs familiar statistical concepts and procedures and also because it is effective for investigating the probability structure of the binding mechanism.

We present statistical methods for analyzing replicated cDNA microarray expression data and report the results of a controlled experiment. The study was conducted to investigate inherent variability in gene expression data and the extent to which replication in an experiment produces more consistent and reliable findings. We introduce a statistical model to describe the probability that mRNA is contained in the target sample tissue, converted to probe, and ultimately detected on the slide. We also introduce a method to analyze the combined data from all replicates. Of the 288 genes considered in this controlled experiment, 32 would be expected to produce strong hybridization signals because of the known presence of repetitive sequences within them. Results based on individual replicates, however, show that there are 55, 36, and 58 highly expressed genes in replicates 1, 2, and 3, respectively. On the other hand, an analysis by using the combined data from all 3 replicates reveals that only 2 of the 288 genes are incorrectly classified as expressed. Our experiment shows that any single microarray output is subject to substantial variability. By pooling data from replicates, we can provide a more reliable analysis of gene expression data. Therefore, we conclude that designing experiments with replications will greatly reduce misclassification rates. We recommend that at least three replicates be used in designing experiments by using cDNA microarrays, particularly when gene expression data from single specimens are being analyzed.

Serial dilution assays are widely employed for estimating substance concentrations and minimum inhibitory concentrations. The Poisson-Bernoulli model for such assays is appropriate for count data but not for continuous measurements that are encountered in applications involving substance concentrations. This paper presents practical inference methods based on a log-normal model and illustrates these methods using a case application involving bacterial toxins.

Count data often show overdispersion compared to the Poisson distribution. Overdispersion is typically modeled by a random effect for the mean, based on the gamma distribution, leading to the negative binomial distribution for the count. This paper considers a larger family of mixture distributions, including the inverse Gaussian mixture distribution. It is demonstrated that it gives a significantly better fit for a data set on the frequency of epileptic seizures. The same approach can be used to generate counting processes from Poisson processes, where the rate or the time is random. A random rate corresponds to variation between patients, whereas a random time corresponds to variation within patients.

Properties of the inverse gaussian distribution are presented with comments on fitting the distribution to lentgh-of-stay data. A conceptual framework for the hospitalization process is described; it suggests that the inverse gaussian distribution has considerable potential as both a descriptive and prescriptive model of length of stay, especially in the setting of psychiatric hospitals.

The mortality component of contemporary health indexes is discussed. Since these indexes reduce to mortality indexes when only life and death states enter the analysis, they share the conceptual weaknesses of mortality indexes. Also, they do not incorporate consumption variables explicity and therefore provide no structure for relating health status and living standard. Some attention is devoted to methodological problems of assessing survival probabilities, either from survey or experimental data or from beliefs of experts or individuals who are affected directly. The final section deals with individual preferences for survival lotteries. Conceptual weaknesses of common indexes are discussed, several canonical models for survival preferences are presented, the interdependence of individual utilities is discussed, and methods for eliciting individual survival preferences are considered, along with some illustrative empirical results.