On-time denosumab dosing recovered rapidly during the COVID-19 pandemic, yet remains suboptimal.

Timely administration of denosumab every 6 mo is critical in osteoporosis treatment to avoid multiple vertebral fracture risk upon denosumab discontinuation or delay. This study aimed to estimate the immediate and prolonged impact of the COVID-19 pandemic on the timing of denosumab doses. We identified older adults (≥66 yr) residing in the community who were due to receive denosumab between January 2016 and December 2020 using Ontario Drug Benefit data. We completed an interrupted time-series analysis to estimate the impact of the COVID-19 pandemic (March 2020) on the monthly proportion of on-time denosumab doses (183 +/-30 d). Analyses were stratified by user type: patients due for their second dose (novice users), third or fourth dose (intermediate users), or ≥5th dose (established users). In additional analyses, we considered patients living in nursing homes, switching to other osteoporosis drugs, and reported trends until February 2022. We studied 148 554 patients (90.9% female, mean [SD] age 79.6 [8.0] yr) receiving 648 221 denosumab doses. The average pre-pandemic proportion of on-time therapy was steady in the community, yet differed by user type: 64.9% novice users, 72.3% intermediate users, and 78.0% established users. We identified an immediate overall decline in the proportion of on-time doses across all user types at the start of the pandemic: -17.8% (95% CI, -19.6, -16.0). In nursing homes, the pre-pandemic proportion of on-time therapy was similar across user types (average 83.5%), with a small decline at the start of the pandemic: -3.2% (95% CI, -5.0, -1.2). On-time therapy returned to pre-pandemic levels by October 2020 and was not impacted by therapy switching. Although on-time dosing remains stable as of February 2022, approximately one-fourth of patients in the community do not receive denosumab on-time. In conclusion, although pandemic disruptions to denosumab dosing were temporary, levels of on-time therapy remain suboptimal.

Methodological guidance for the use of real-world data to measure exposure and utilization patterns of osteoporosis medications.

Observational studies of osteoporosis medications can provide critical real-world evidence (RWE) that fills knowledge gaps left by clinical trials. However, careful consideration of study design is needed to yield reliable estimates of association. In particular, obtaining valid measurements of exposure to osteoporosis medications from real-world data (RWD) sources is complicated due to different medication classes, formulations, and routes of administration, each with different pharmacology. Extended half-lives of bisphosphonates and extended dosing of denosumab and zoledronic acid require particular attention. In addition, prescribing patterns and medication taking behavior often result in gaps in therapy, switching, and concomitant use of osteoporosis therapies. In this review, we present important considerations and provide specialized guidance for measuring osteoporosis drug exposures in RWD. First, we compare different sources of RWD used for osteoporosis drug studies and provide guidance on identifying osteoporosis medication use in these data sources. Next, we provide an overview of osteoporosis pharmacology and how it can influence decisions on exposure measurement within RWD. Finally, we present considerations for the measurement of osteoporosis medication exposure, adherence, switching, long-term exposures, and drug holidays using RWD. Ultimately, a thorough understanding of the differences in RWD sources and the pharmacology of osteoporosis medications is essential to obtain valid estimates of the relationship between osteoporosis medications and outcomes, such as fractures, but also to improve the critical appraisal of published studies.

Actualisation 2023 des lignes directrices de pratique clinique pour la prise en charge de l'ostéoporose et la prévention des fractures au Canada.

CONTEXTE: Au Canada, plus de 2 millions de personnes vivent avec l'ostéoporose, une maladie qui accroît le risque de fracture, ce qui fait augmenter la morbidité et la mortalité, et entraîne une perte de qualité de vie et d'autonomie. La présente actualisation des lignes directrices vise à accompagner les professionnelles et professionnels de la santé au Canada dans la prestation de soins visant à optimiser la santé osseuse et à prévenir les fractures chez les femmes ménopausées et les hommes de 50 ans et plus. MÉTHODES: Le présent document fournit une actualisation des lignes directrices de pratique clinique de 2010 d'Ostéoporose Canada sur le diagnostic et la prise en charge de l'ostéoporose au pays. Nous avons utilisé l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) et effectué l'assurance de la qualité conformément aux normes de qualité et de présentation des rapports de la grille AGREE II (Appraisal of Guidelines for Research & Evaluation). Les médecins de premier recours et les patientes et patients partenaires ont été représentés à tous les niveaux des comités et des groupes ayant participé à l'élaboration des lignes directrices, et ont participé à toutes les étapes du processus pour garantir la pertinence des informations pour les futurs utilisateurs et utilisatrices. Le processus de gestion des intérêts concurrents a été entamé avant l'élaboration des lignes directrices et s'est poursuivi sur toute sa durée, selon les principes du Réseau international en matière de lignes directrices. Dans la formulation des recommandations, nous avons tenu compte des avantages et des risques, des valeurs et préférences de la patientèle, des ressources, de l'équité, de l'acceptabilité et de la faisabilité; la force de chacune des recommandations a été déterminée en fonction du cadre GRADE. RECOMMANDATIONS: Les 25 recommandations et les 10 énoncés de bonne pratique sont répartis en sections : activité physique, alimentation, évaluation du risque de fracture, instauration du traitement, interventions pharmacologiques, durée et séquence du traitement, et monitorage. La prise en charge de l'ostéoporose devrait se fonder sur le risque de fracture, établi au moyen d'une évaluation clinique réalisée avec un outil d'évaluation du risque de fracture validé. L'activité physique, l'alimentation et la pharmacothérapie sont des éléments essentiels à la stratégie de prévention des fractures, qui devraient être personnalisés. INTERPRÉTATION: Les présentes lignes directrices ont pour but d'outiller les professionnelles et professionnels de la santé et la patientèle afin qu'ensemble ils puissent parler de l'importance de la santé osseuse et du risque de fracture tout au long de la vie adulte avancée. La détection et la prise en charge efficace de la fragilité osseuse peuvent contribuer à réduire les fractures et à préserver la mobilité, l'autonomie et la qualité de vie.

Clinical practice guideline for management of osteoporosis and fracture prevention in Canada: 2023 update.

BACKGROUND: In Canada, more than 2 million people live with osteoporosis, a disease that increases the risk for fractures, which result in excess mortality and morbidity, decreased quality of life and loss of autonomy. This guideline update is intended to assist Canadian health care professionals in the delivery of care to optimize skeletal health and prevent fractures in postmenopausal females and in males aged 50 years and older. METHODS: This guideline is an update of the 2010 Osteoporosis Canada clinical practice guideline on the diagnosis and management of osteoporosis in Canada. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework and quality assurance as per Appraisal of Guidelines for Research and Evaluation (AGREE II) quality and reporting standards. Primary care physicians and patient partners were represented at all levels of the guideline committees and groups, and participated throughout the entire process to ensure relevance to target users. The process for managing competing interests was developed before and continued throughout the guideline development, informed by the Guideline International Network principles. We considered benefits and harms, patient values and preferences, resources, equity, acceptability and feasibility when developing recommendations; the strength of each recommendation was assigned according to the GRADE framework. RECOMMENDATIONS: The 25 recommendations and 10 good practice statements are grouped under the sections of exercise, nutrition, fracture risk assessment and treatment initiation, pharmacologic interventions, duration and sequence of therapy, and monitoring. The management of osteoporosis should be guided by the patient's risk of fracture, based on clinical assessment and using a validated fracture risk assessment tool. Exercise, nutrition and pharmacotherapy are key elements of the management strategy for fracture prevention and should be individualized. INTERPRETATION: The aim of this guideline is to empower health care professionals and patients to have meaningful discussions on the importance of skeletal health and fracture risk throughout older adulthood. Identification and appropriate management of skeletal fragility can reduce fractures, and preserve mobility, autonomy and quality of life.

Implementation of the appointment-based model in community pharmacies: An analysis of refills and adherence.

BACKGROUND: Traditionally, much of community pharmacy practice relies on patients to request their own medication refills. These refills are often not aligned, which has been shown to decrease adherence and workflow efficiencies. The appointment-based model (ABM) is designed to proactively synchronize refills and schedule patient-pharmacist appointments. OBJECTIVES: To describe the characteristics of patients enrolled in the ABM; and to compare the number of distinct refill dates, number of refills, and adherence for antihypertensives, oral antihyperglycemics, and statins 6-months and 12-months pre-post ABM implementation. METHODS: In September 2017, the ABM was implemented across independent community pharmacies within a pharmacy banner in Ontario, Canada. In December 2018, a convenience sample of three pharmacies was extracted. Demographic and clinical characteristics were collected on program enrollment (index) date for individual patients and their medication fill histories were used to investigate adherence measures including distinct number of refill dates, number of refills, and proportion of days covered. Descriptive statistics were analyzed using StataCorp. RESULTS: Analysis of 131 patients (48.9% male; mean age 70.8 years ± 10.5 SD) filled on average 5.1 ± 2.7 medications with 73 (55.7%) experiencing polypharmacy. Patients had a significant reduction in mean number of refill dates (6.8 ± 3.8 SD six-months pre-enrollment, 4.9 ± 3.1 SD six-months post-enrollment, p < 0.0001). Adherence to chronic medications remained high (PDC ≥95%). CONCLUSION: The ABM was implemented for a cohort of established users, already highly adherent to their chronic medications. Results demonstrate reduced filling complexity and fewer refill dates while also sustaining the high baseline adherence across all chronic medications studied. Future studies should investigate patient perspectives and potential clinical benefits of the ABM.

Comparison of Fracture Identification Using Different Definitions in Healthcare Administrative (Claims) Data.

We identified inconsistency in fracture definitions in a prior review of studies that utilized claims data. Here, we aimed to compare fracture rates estimated using thirteen hip and seven radius/ulna fracture definitions. Our primary analysis compared results in a cohort of 120,363 older adults treated with oral bisphosphonates for ≥3 years. The most inclusive definition (hip: inpatient or emergency diagnosis; radius/ulna: inpatient, emergency, or outpatient diagnosis) served as a referent to compare the number and proportion of fractures captured. In sensitivity analyses, we considered a 180-day washout, excluded fractures associated with trauma; and hip only, excluded: (1) subtrochanteric fractures, and (2) hip replacement procedures. Hip fractures varied by definition in number (52-8058) and incidence (0.7-111.8/10,000 person-years). The second most inclusive definition required one inpatient diagnosis and identified 8% fewer hip fractures than the referent. Excluding hip replacements missed 33% of hip fractures relative to the primary analysis. Radius/ulna fractures also ranged in number (1589-6797) and incidence (22.0-94.3/10,000 person-years). Outpatient data were important, when restricted to inpatient or emergency data, only 78% of radius/ulna fractures were identified. Other than hip replacement procedures, sensitivity analyses had minimal impact on fracture identification. Analyses were replicated in a cohort of patients treated with long-term glucocorticoids. This study highlights the importance and impact of coding decisions on fracture outcome definitions. Further research is warranted to inform best practice in fracture outcome identification.

Comparative Fracture Risk During Osteoporosis Drug Holidays After Long-Term Risedronate Versus Alendronate Therapy : A Propensity Score-Matched Cohort Study.

BACKGROUND: An osteoporosis drug holiday is recommended for most patients after 3 to 5 years of therapy. Risedronate has a shorter half-life than alendronate, and thus the residual length of fracture protection may be shorter. OBJECTIVE: To examine the comparative risks of drug holidays after long-term (≥3 years) risedronate versus alendronate therapy. DESIGN: Population-based, matched, cohort study. SETTING: Province-wide health care administrative databases providing comprehensive coverage to Ontario residents aged 65 years or older between November 2000 and March 2020. PATIENTS: Persons aged 66 years or older who had long-term risedronate therapy and a drug holiday were matched 1:1 on propensity score to those who had long-term alendronate therapy and a drug holiday. MEASUREMENTS: The primary outcome was hip fracture within 3 years after a 120-day ascertainment period. Secondary analyses included shorter follow-up and sex-specific estimates. Cox proportional hazards models were used to estimate hazard ratios (HRs) for fracture risk between groups. RESULTS: A total of 25 077 propensity score-matched pairs were eligible (mean age, 81 years; 81% women). Hip fracture rates were higher among risedronate than alendronate drug holidays (12.4 and 10.6 events, respectively, per 1000 patient-years; HR, 1.18 [95% CI, 1.04 to 1.34]; 915 total hip fractures). The association was attenuated when any fracture was included as the outcome (HR, 1.07 [CI, 1.00 to 1.16]) and with shorter drug holidays (1 year: HR, 1.03 [CI, 0.85 to 1.24]; 2 years: HR, 1.14 [CI, 0.96 to 1.32]). LIMITATION: Analyses were limited to health care administrative data (potential unmeasured confounding), and some secondary analyses contained few events. CONCLUSION: Drug holidays after long-term therapy with risedronate were associated with a small increase in risk for hip fracture compared with alendronate drug holidays. Future research should examine how best to mitigate this risk. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Fracture outcome definitions in observational osteoporosis drug effects studies: a scoping review protocol.

OBJECTIVE: The objective of this review is to describe fracture outcome definitions in observational osteoporosis drug effects studies from Canada and the United States. INTRODUCTION: Health care administrative data are commonly utilized in pharmacoepidemiologic studies. These data are used to define outcomes, such as fractures, and are critical to determining real-world safety and effectiveness of medications. However, there is no current standard for fracture outcome definitions in observational studies. As a result, fractures are inconsistently defined. To inform future research, a synthesis of how fractures are defined in observational studies using health care administrative claims data is needed. Providing clarity on how fractures are defined will provide guidance for future research. INCLUSION CRITERIA: We will include observational studies from the United States and Canada that consider the impact of osteoporosis pharmacotherapies on fracture risk and leverage health care administrative data. METHODS: This review will follow the three-step JBI methodology for scoping reviews. We will search MEDLINE, Embase, and CINAHL for studies published in English from 2000 to the present. Following de-duplication, titles and abstracts will be screened independently by two reviewers. We will then conduct full-text screening for eligible studies. In addition, Canadian and US government pharmacovigilance websites will be searched to identify gray literature. Data extraction will be completed by two reviewers. Results will be presented in figures and in tabular format.

Observational study methods used to assess pharmacotherapy effects of type 2 diabetes on fracture risk: a scoping review protocol.

OBJECTIVE: The objective of this review is to summarize observational research methods employed to study fracture risk and the use of type 2 diabetes mellitus medications. The methods summary will be used as a case study to illustrate current practices in the study of medication effects on fracture risk. INTRODUCTION: Observational studies examining drug effects on fracture risk fill knowledge gaps left by clinical trials but require specific design considerations. In recent years, several pharmacoepidemiologic studies have examined fracture risk as a possible adverse effect of type 2 diabetes mellitus medications using varying methodologies; these studies can illustrate design considerations for studies of fracture risk. INCLUSION CRITERIA: This scoping review will consider peer-reviewed observational studies that examine the effects of type 2 diabetes mellitus medications on fracture risk. Primary literature comprising empirical pharmacoepidemiologic studies, such as cohort, case-control, case-crossover, self-controlled, case series, and case-cohort designs, that evaluate fracture risk associated with at least one type 2 diabetes mellitus medication will be eligible. Studies without use of an administrative database and those with an experimental, cross-sectional, or time-series design will be excluded. METHODS: This scoping review will follow JBI methodology for scoping reviews. MEDLINE (Ovid), Embase (Ovid), and CINAHL Plus with Full Text (EBSCO) will be searched from January 1, 2000 (to capture recent methodologies) to the present to identify eligible articles. After de-duplication, titles and abstracts will be screened independently by two reviewers, then full texts will be reviewed. Data on study methods will be extracted from eligible texts using a piloted form developed by the authors, and study methods will be aggregated in tabular format.

Duration of Bisphosphonate Drug Holidays in Osteoporosis Patients: A Narrative Review of the Evidence and Considerations for Decision-Making.

Bisphosphonates are first-line therapy for osteoporosis, with alendronate, risedronate, and zoledronate as the main treatments used globally. After one year of therapy, bisphosphonates are retained in bone for extended periods with extended anti-fracture effects after discontinuation. Due to this continued fracture protection and the potential for rare adverse events associated with long-term use (atypical femoral fractures and osteonecrosis of the jaw), a drug holiday of two to three years is recommended for most patients after long-term bisphosphonate therapy. The recommendation for a drug holiday up to three years is derived primarily from extensions of pivotal trials with alendronate and zoledronate and select surrogate marker studies. However, certain factors may modify the duration of bisphosphonate effects on a drug holiday and warrant consideration when determining an appropriate time off-therapy. In this narrative review, we recall what is currently known about drug holidays and discuss what we believe to be the primary considerations and areas for future research regarding drug holiday duration: total bisphosphonate exposure, type of bisphosphonate used, bone mineral density and falls risk, and patient sex and body weight.

The Use of Active Comparators in Self-Controlled Designs.

For self-controlled studies of medication-related effects, time-varying confounding by indication can occur if the indication varies over time. We describe how active comparators might mitigate such bias, using an empirical example. Approaches to using active comparators are described for case-crossover design, case-time-control design, self-controlled case-series, and sequence symmetry analyses. In the empirical example, we used Danish data from 1996-2018 to study the association between penicillin and venous thromboembolism (VTE), using roxithromycin, a macrolide antibiotic, as comparator. Upper respiratory infection is a transient risk factor for VTE, thus representing time-dependent confounding by indication. Odds ratios for case-crossover analysis were 3.35 (95% confidence interval: 3.23, 3.49) for penicillin and 3.56 (95% confidence interval: 3.30, 3.83) for roxithromycin. We used a Wald-based method or an interaction term to estimate the odds ratio for penicillin with roxithromycin as comparator. These 2 estimates were 0.94 (95% confidence interval: 0.87, 1.03) and 1.03 (95% confidence interval: 0.95, 1.13). Results were similar for the case-time-control analysis, but both the self-controlled case-series and sequence symmetry analysis suggested a weak protective effect of penicillin, seemingly explained by VTE affecting future exposure exclusively for penicillin. The strong association of antibiotics with VTE suggests presence of confounding by indication. Such confounding can be mitigated by using an active comparator.

Control yourself: ISPE-endorsed guidance in the application of self-controlled study designs in pharmacoepidemiology.

PURPOSE: Consensus is needed on conceptual foundations, terminology and relationships among the various self-controlled "trigger" study designs that control for time-invariant confounding factors and target the association between transient exposures (potential triggers) and abrupt outcomes. The International Society for Pharmacoepidemiology (ISPE) funded a working group of ISPE members to develop guidance material for the application and reporting of self-controlled study designs, similar to Standards of Reporting Observational Epidemiology (STROBE). This first paper focuses on navigation between the types of self-controlled designs to permit a foundational understanding with guiding principles. METHODS: We leveraged a systematic review of applications of these designs, that we term Self-controlled Crossover Observational PharmacoEpidemiologic (SCOPE) studies. Starting from first principles and using case examples, we reviewed outcome-anchored (case-crossover [CCO], case-time control [CTC], case-case-time control [CCTC]) and exposure-anchored (self-controlled case-series [SCCS]) study designs. RESULTS: Key methodological features related to exposure, outcome and time-related concerns were clarified, and a common language and worksheet to facilitate the design of SCOPE studies is introduced. CONCLUSIONS: Consensus on conceptual foundations, terminology and relationships among SCOPE designs will facilitate understanding and critical appraisal of published studies, as well as help in the design, analysis and review of new SCOPE studies. This manuscript is endorsed by ISPE.

Strategies for measuring prescription medication switching with pharmacy claims data: a scoping review protocol.

OBJECTIVE: This scoping review will aim to compare strategies for measuring prescription medication switching with pharmacy claims data, with a focus on psychotropic vs non-psychotropic medications. INTRODUCTION: Medication switching (ie, the replacement of one medication for another) is common and occurs due to several factors (such as adverse effects to a specific medication). In pharmacoepidemiology studies that use pharmacy claims data, it is important to identify and account for switches; however, due to data limitations and lack of a methodological standard, this can be challenging. The aim of this scoping review is to describe how studies have previously measured medication switching with pharmacy claims data in order to create a repository of common strategies and highlight areas for future research. INCLUSION CRITERIA: This review will include studies that have used pharmacy claims data to measure medication switching as their primary independent or dependent variable. Studies conducted at the individual level (ie, not ecological), published between January 1, 1980, and October 31, 2020, and investigating orally administered, non-anti-infective medications will be considered. No age, population, or context restrictions are specified as inclusion criteria. METHODS: JBI methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews were used for this protocol. MEDLINE (PubMed), Embase (Ovid), Central (Cochrane Library), CINAHL (EBSCO), and Google Scholar will be searched with the assistance of a health sciences research librarian. Two reviewers will independently screen titles, abstracts, and full-text articles. Strategies for measuring medication switching will be narratively described and summarized overall and by broad medication class.

Temporal Trends and Factors Associated with Bisphosphonate Discontinuation and Restart.

Adverse events related to long-term use of bisphosphonates have raised interest in temporary drug discontinuation. Trends in bisphosphonate discontinuation and restart, as well factors associated with these decisions, are not fully understood at a population level. We investigated temporal trends of bisphosphonate discontinuation from 2010 to 2015 and identified factors associated with discontinuation and restart of osteoporosis therapy. Our cohort consisted of long-term bisphosphonate users identified from 2010 to 2015 Medicare data. We defined discontinuation as ≥12 months without bisphosphonate prescription claims. We used conditional logistic regression to compare factors associated with alendronate discontinuation or osteoporosis therapy restart in the 120-day period preceding discontinuation or restart referent to the 120-day preceding control periods. Among 73,800 long-term bisphosphonate users, 59,251 (80.3%) used alendronate, 6806 (9.2%) risedronate, and 7743 (10.5%) zoledronic acid, exclusively. Overall, 26,281 (35.6%) discontinued bisphosphonates for at least 12 months. Discontinuation of bisphosphonates increased from 1.7% in 2010, reaching a peak of 14% in 2012 with levels plateauing through 2015. The factors most strongly associated with discontinuation of alendronate were: benzodiazepine prescription (adjusted odds ratio [aOR] = 2.5; 95% confidence interval [CI] 2.1, 3.0), having a dual-energy X-ray absorptiometry (DXA) scan (aOR = 1.8; 95% CI 1.7, 2.0), and skilled nursing facility care utilization (aOR = 1.8; 95% CI 1.6, 2.1). The factors most strongly associated with restart of osteoporosis therapy were: having a DXA scan (aOR = 9.9; 95% CI 7.7, 12.6), sustaining a fragility fracture (aOR = 2.8; 95% CI 1.8, 4.5), and an osteoporosis or osteopenia diagnosis (aOR = 2.5; 95% CI 2.0, 3.1). Our national evaluation of bisphosphonate discontinuation showed that an increasing proportion of patients on long-term bisphosphonate therapy discontinue medications. The factors associated with discontinuation of alendronate were primarily related to worsening of overall health status, whereas traditional factors associated with worsening bone health were associated with restarting osteoporosis medication. © 2019 American Society for Bone and Mineral Research.

External validation of clinical prediction rules for complications and mortality following Clostridioides difficile infection.

BACKGROUND: Several clinical prediction rules (CPRs) for complications and mortality of Clostridioides difficile infection (CDI) have been developed but only a few have gone through external validation, and none is widely recommended in clinical practice. METHODS: CPRs were identified through a systematic review. We included studies that predicted severe or complicated CDI (cCDI) and mortality, reported at least an internal validation step, and for which data were available with minimal modifications. Data from a multicenter prospective cohort of 1380 adults with confirmed CDI were used for external validation. In this cohort, cCDI occurred in 8% of the patients and 30-day all-cause mortality occurred in 12%. The performance of each tool was assessed using individual outcomes, with the same cut-offs and standard parameters. RESULTS: Seven CPRs were assessed. Three predictive scores for cCDI showed low sensitivity (25-61%) and positive predictive value (PPV; 9-31%), but moderate specificity (54-90%) and negative predictive value (NPV; 82-95%). One model [using age, white blood cell count (WBC), narcotic use, antacids use, and creatinine ratio > 1.5× the normal level as covariates] showed a probability of 25% of cCDI at the optimal cut-off point with 36% sensitivity and 84% specificity. Two scores for mortality had low sensitivity (4-55%) and PPV (25-31%), and moderate specificity (71-78%) and NPV (87-92%). One predictive model for 30-day all-cause mortality [Charlson comorbidity index, WBC, blood urea nitrogen (BUN), diagnosis in ICU, and delirium] showed an AUC-ROC of 0.74. All other CPRs showed lower AUC values (0.63-0.69). Errors in calibration ranged from 12%- 27%. CONCLUSIONS: Included CPRs showed moderate performance for clinical use in a large validation cohort with a majority of patients infected with ribotype 027 strains and a low rate of cCDI and mortality. These data show that better CPRs need to be developed and validated.

Design choices for observational studies of the effect of exposure on disease incidence.

The purpose of this paper is to help readers choose an appropriate observational study design for measuring an association between an exposure and disease incidence. We discuss cohort studies, sub-samples from cohorts (case-cohort and nested case-control designs), and population-based or hospital-based case-control studies. Appropriate study design is the foundation of a scientifically valid observational study. Mistakes in design are often irremediable. Key steps are understanding the scientific aims of the study and what is required to achieve them. Some designs will not yield the information required to realise the aims. The choice of design also depends on the availability of source populations and resources. Choosing an appropriate design requires balancing the pros and cons of various designs in view of study aims and practical constraints. We compare various cohort and case-control designs to estimate the effect of an exposure on disease incidence and mention how certain design features can reduce threats to study validity.