Purpose
The weighted cumulative exposure (WCE) method has been used in a number of fields including pharmacoepidemiology where it can account for intensity, duration and timing of exposures on the ...risk of an outcome. The method uses a data driven approach with flexible cubic B‐splines to assign weights to past doses and select an aetiologically appropriate time window. Predictions of risk are possible for common exposure patterns encountered in real‐world studies. The purpose of this study was to describe applications of the WCE method to pharmacoepidemiology and assess the strengths and limitations of the method.
Method
A literature search was undertaken to find studies applying the WCE method to the study of medicines. Articles published in PubMed using the search term ‘weighted cumulative exposure’ and articles citing Sylvestre et al. (2009) in Google Scholar or Scopus up to March 2023 were subsequently reviewed. Articles were selected based on title and review of s.
Results
Seventeen clinical applications using the data‐driven WCE method with flexible cubic splines were identified in the review. These included 3 case–control studies and 14 cohort studies, of which 12 were analysed with Cox proportional hazards models and 2 with logistic regression. Thirteen studies used time windows of 1 year or longer. Of 11 studies which compared conventional models with the WCE method, 10 (91%) studies found a better fit with WCE models while one had an equivalent fit. The freely available ‘WCE’ software package has facilitated the applications of the WCE method with flexible cubic splines.
Conclusions
The WCE method allows additional insights into the effect of cumulative exposure on outcomes, including the timing and intensity (dose) of the exposure on the risk. The flexibility of the method is particularly well suited to studies with long‐term exposures that vary over time or where the current risk of an event is affected by how far the exposure is in the past, which is difficult to model with conventional definitions of exposure. Interpretation of the results can be more complex than for conventional models and would be facilitated by a standardised reporting framework.
Abstract
The case-crossover study design has been proposed as a suitable design for use when a brief exposure causes a transient change in risk of an acute-onset disease. In pharmacoepidemiology, the ...condition of “brief exposure” is rarely satisfied because medication use is often chronic or successive, which may result in bias due to within-subject exposure dependency. Here we describe a simulation of a case-crossover study conducted within a cohort, where patients successively used a drug for 60 or more days and the rate ratio for the outcome occurrence was 4.0. Standard conditional logistic regression for the analysis produced overestimated odds ratios ranging up to 7.8. This bias due to within-subject exposure dependency from chronic use can be removed by the Mantel-Haenszel method or by our recently proposed weighting method. We also show that when some patients are censored after switching to another drug, a lack of pairwise exchangeability causes bias which is similar to bias due to an exposure time trend. This bias can be removed by using the case–time-control study design. We show that bias due to within-subject exposure dependency and lack of pairwise exchangeability occur independently and can occur separately or simultaneously, and we demonstrate how to detect and remove them.
Girardeau, Ravaud and Donner in 2008 presented a formula for sample size calculations for cluster randomised crossover trials, when the intracluster correlation coefficient, interperiod correlation ...coefficient and mean cluster size are specified in advance. However, in many randomised trials, the number of clusters is constrained in some way, but the mean cluster size is not. We present a version of the Girardeau formula for sample size calculations for cluster randomised crossover trials when the number of clusters is fixed. Formulae are given for the minimum number of clusters, the maximum cluster size and the relationship between the correlation coefficients when there are constraints on both the number of clusters and the cluster size. Our version of the formula may aid the efficient planning and design of cluster randomised crossover trials.
Objective measures for screening, prioritizing, and planning care for frail individuals are essential for appropriate aged care provision. This study evaluates metrics derived from actigraphy ...measures (captured by wrist accelerometer) as a digital biomarker to identify frail individuals at risk of adverse outcomes, including death, hospitalization, and cognitive decline.
This was a secondary study using data from a randomized controlled trial assessing the effectiveness of an ongoing pharmacist service in residential aged care facilities. Three metrics are studied and compared: the Frailty Index, the daily time spent in light time activity, and the temporal correlation of the actigraphy signal, measured by detrended fluctuation analysis. The association between actigraphy-derived metrics at baseline and adverse events within 12 months (death, cognitive decline, and hospitalizations) was assessed using logistic regression.
Actigraphy records were available for 213 participants living in aged-care, median age of 85 years. Individuals with higher temporal correlation (activity is less random) were at lower risk of death (Standardized OR: 0.49; 95% CI 0.34, 0.7, p < 0.001) and hospitalization (Standardized OR: 0.57; 95% CI 0.42, 0.77, p < 0.001) in 12 months, but there was no difference in cognitive decline (Standardized OR: 1; 95% CI 0.74, 1.35, p = 0.98). The predictive model that included temporal correlation had an area under the curve of 0.70 (CI 0.60-0.80) for death and 0.64 (CI 0.54-0.72) for hospitalization.
Temporal correlation of the actigraphy signal from aged care residents was strongly associated with death and hospitalization, but not cognitive decline. Digital biomarkers may have a place as an objective, accurate, and low-cost patient metric to support risk stratification and clinical planning.
KRAS and BRAF testing is currently recommended in metastatic colorectal cancer. There is evidence that KRAS and BRAF mutation status may act as a prognostic biomarker in patients with non-metastatic ...colorectal cancer. Data is limited on whether KRAS and BRAF mutation status impacts recurrence and mortality in patients with non-metastatic colorectal cancer.
A retrospective cohort study was conducted in a tertiary hospital examining outcomes in patients who had KRAS and BRAF testing for colorectal cancer in 2017. Primary outcomes were all-cause mortality and recurrence. Multivariable analysis for both outcomes, used cause specific Cox proportional hazards models with KRAS/BRAF status as exposure. For time to recurrence, a sensitivity analysis was performed with a weighted Fine-Grey model with death as a competing risk.
KRAS mutation status was not associated with all-cause mortality (average Hazard Ratio (aHR) = 0.78, 95% CI 0.28-2.21) or recurrence (aHR = 0.96, 95% CI 0.32-2.86). BRAF mutation status was not associated with time to all-cause mortality (aHR = 3.06, 95% CI 0.79-11.8) or recurrence (aHR = 0.94, 95% CI 0.13-6.57). Increased risk of recurrence was significantly associated with large bowel obstruction (aHR = 2.73, 95% CI 1.16-6.45) and anaemia (aHR = 3.39, 95% CI 1.06-10.8) at time of surgery.
This study did not demonstrate an association between KRAS and BRAF mutations and all-cause mortality or recurrence. A significantly increased risk of cancer recurrence was found in patients with large bowel obstruction and in patients with anaemia at time of surgery. Anaemia should be promptly investigated and corrected prior to colorectal cancer surgery.
Objective
To test the equivalence of two doses of intravenous iron (ferric carboxymaltose) in pregnancy.
Design
Parallel, two‐arm equivalence randomised controlled trial with an equivalence margin of ...5%.
Setting
Single centre in Australia.
Population
278 pregnant women with iron deficiency.
Methods
Participants received either 500 mg (n = 152) or 1000 mg (n = 126) of intravenous ferric carboxymaltose in the second or third trimester.
Main outcome measures
The proportion of participants requiring additional intravenous iron (500 mg) to achieve and maintain ferritin >30 microg/L (diagnostic threshold for iron deficiency) at 4 weeks post‐infusion, and at 6 weeks, and 3‐, 6‐ and 12‐months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth and safety outcomes.
Results
The two doses were not equivalent within a 5% margin at any time point. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500‐mg group compared with 5/67 (8%) in the 1000‐mg group: difference in proportions, 0.283 (95% confidence interval CI 0.177–0.389). Overall, participants in the 500‐mg arm received twice the repeat infusion rate (0.81 SD = 0.824 versus 0.40 SD = 0.69, rate ratio 2.05, 95% CI 1.45–2.91).
Conclusions
Administration of 1000 mg ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions. A 500‐ mg dose requires ongoing monitoring to ensure adequate iron stores are reached and sustained.
The carbon footprint of nitrous oxide use for birth Froessler, Bernd; Malek, Michaela; Jila, Mathonsi ...
BJOG : an international journal of obstetrics and gynaecology,
2024-May-28, 2024-05-28, 20240528
Journal Article
Purpose
Medicine dispensing data require extensive preparation when used for research and decisions during this process may lead to results that do not replicate between independent studies. We ...conducted an experiment to examine the impact of these decisions on results of a study measuring discontinuation, intensification, and switching in a cohort of patients initiating metformin.
Methods
Four Australian sites independently developed a HARmonized Protocol template to Enhance Reproducibility (HARPER) protocol and executed their analyses using the Australian Pharmaceutical Benefits Scheme 10% sample dataset. Each site calculated cohort size and demographics and measured treatment events including discontinuation, switch to another diabetes medicine, and intensification (addition of another diabetes medicine). Time to event and hazard ratios for associations between cohort characteristics and each event were also calculated. Concordance was assessed by measuring deviations from the calculated median of each value across the sites.
Results
Good agreement was found across sites for the number of initiators (median: 53 127, range: 51 848–55 273), gender (56.9% female, range: 56.8%–57.1%) and age group. Each site employed different methods for estimating days supply and used different operational definitions for the treatment events. Consequently, poor agreement was found for incidence of discontinuation (median 55%, range: 34%–67%), switching (median 3.5%, range: 1%–7%), intensification (median 8%, range: 5%–12%), time to event estimates and hazard ratios.
Conclusions
Differences in analytical decisions when deriving exposure from dispensing data affect replicability. Detailed analytical protocols, such as HARPER, are critical for transparency of operational definitions and interpretations of key study parameters.
Abstract
Background
Case-crossover studies have been widely used in various fields including pharmacoepidemiology. Vines and Farrington indicated in 2001 that when within-subject exposure dependency ...exists, conditional logistic regression can be biased. However, this bias has not been well studied.
Methods
We have extended findings by Vines and Farrington to develop a weighting method for the case-crossover study which removes bias from within-subject exposure dependency. Our method calculates the exposure probability at the case period in the case-crossover study which is used to weight the likelihood formulae presented by Greenland in 1999. We simulated data for the population with a disease where most patients receive a cyclic treatment pattern with within-subject exposure dependency but no time trends while some patients stop and start treatment. Finally, the method was applied to real-world data from Japan to study the association between celecoxib and peripheral edema and to study the association between selective serotonin reuptake inhibitor (SSRI) and hip fracture in Australia.
Results
When the simulated rate ratio of the outcome was 4.0 in a case-crossover study with no time-varying confounder, the proposed weighting method and the Mantel-Haenszel odds ratio reproduced the true rate ratio. When a time-varying confounder existed, the Mantel-Haenszel method was biased but the weighting method was not. When more than one control period was used, standard conditional logistic regression was biased either with or without time-varying confounding and the bias increased (up to 8.7) when the study period was extended. In real-world analysis with a binary exposure variable in Japan and Australia, the point estimate of the odds ratio (around 2.5 for the association between celecoxib and peripheral edema and around 1.6 between SSRI and hip fracture) by our weighting method was equal to the Mantel-Haenszel odds ratio and stable compared with standard conditional logistic regression.
Conclusion
Case-crossover studies may be biased from within-subject exposure dependency, even without exposure time trends. This bias can be identified by comparing the odds ratio by the Mantel-Haenszel method and that by standard conditional logistic regression. We recommend using our proposed method which removes bias from within-subject exposure dependency and can account for time-varying confounders.
The Birmingham Hip Resurfacing (BHR) prosthesis is the most commonly used metal-on-metal hip resurfacing arthroplasty device. The current manufacturer-recommended target demographic for the BHR is ...male patients, younger than 65 years requiring a femoral head size of ≥ 50 mm. Female patients, older patients, and individuals with smaller femoral-head diameter (≤ 50 mm) are known to have higher revision rates. Prior studies suggest that the survivorship of the BHR when used in the target demographic is comparable with that of primary conventional THA, but comparing survivorship of the most durable hip resurfacing arthroplasty device to the survivorship of all conventional THA prostheses is not ideal because the THA group comprises a large number of different types of prostheses that have considerable variation in prosthesis survival. A more informative comparison would be with the THA implants with the best survivorship, as this might help address the question of whether survivorship in the BHR target population can be improved by using a well-performing conventional THA.
We compared the difference in cumulative percent revision, reasons for revision and types of revision for procedures reported to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) using the BHR prosthesis (femoral-head size > 50 mm) and three conventional THA prostheses identified as having the lowest 10-year cumulative percent revision in the currently recommended BHR target population to ask: (1) Does the BHR have a lower cumulative revision rate than the group of three conventional THA prostheses? (2) Is there a difference in the revision diagnosis between the BHR and the three best conventional THA prostheses? (3) What is the difference in the components used for a revision of a BHR compared with the three best conventional THA prostheses?
Data reported to the AOANJRR between September 1, 1999 and December 31, 2018 was used for this analysis. This study period includes almost the entire use of the BHR in Australia. The AOANJRR is a large national joint registry with almost 100% completeness, high accuracy, rigorous validation, and little to no loss to follow-up. The study population included males younger than 65 years that had received one hip replacement procedure for osteoarthritis. All patients with bilateral procedures, no matter the time interval between hips, were excluded. Only BHR prostheses with a femoral-head size ≥ 50 mm and conventional THA prostheses with femoral head sizes ≥ 32 mm and either ceramic-on-ceramic or metal, ceramic, ceramicized metal-on-crosslinked polyethylene (XLPE) bearings were included. These femoral head sizes and bearings were selected because they reflect modern conventional THA practice. There is no difference in the revision rate of these bearings in the AOANJRR. There were 4790 BHR procedures and 2696 conventional THA procedures in the study group. The mean (± SD) age for BHR procedures was 52 ± 7.8 years and 56 ± 7.1 years for conventional THA procedures. All comparative analyses were adjusted for age. Other demographics data including American Society Anesthesiologists (ASA) score and BMI were only included in AOANJRR data collection since 2012 and 2015, respectively, and have not been included in this analysis because of the low use of BHR in Australia since that time. The maximum follow-up was 18.7 years for both groups and mean follow-up of 11.9 years for the BHR and 9.3 years for the conventional THA group. Revision rates were determined using Kaplan-Meier estimates of survivorship to describe the time to the first revision, with censoring at the time of death or closure of the database at the time of analysis. A revision was defined as removal, replacement or addition of any component of a joint replacement. Revisions can be further classified as major revisions (removal of a component articulating with bone-usually the stem and/or the shell) or minor revisions (removal of other components-usually the head and/or the liner). The unadjusted cumulative percent revision after the primary arthroplasty (with 95% confidence intervals) was calculated and compared using Cox proportional hazard models adjusted for age.
The BHR prosthesis had a statistically higher rate of all-cause revision at 17 years than the selected conventional THA prostheses (HR 2.77 95% CI 1.78 to 4.32; p < 0.001). The revision diagnoses differed between the groups, with the BHR demonstrating a higher revision rate for loosening after 2 years than the conventional THA protheses (HR 4.64 95% CI 1.66 to 12.97; p = 0.003), as well as a higher fracture rate during the entire period (HR 2.57 95% CI 1.24 to 5.33; p = 0.01). There was a lower revision rate for infection for the BHR compared with the THA group in the first 5 years, with no difference between the two groups after this time. All revisions of the BHR were major revisions (such as, removal or exchange of the femoral and/or acetabular components) and this occurred in 4.5% of the primary BHR procedures. Major revision was the most common type of revision for primary THA accounting for 1.7% of all primary THA procedures. Minor revisions (head, inset or both) were undertaken in a further 0.6% of primary THA procedures.
Given the increasing revision risk of the BHR compared with better-performing conventional THA prostheses in the target population, we recommend that patients be counseled about this risk. We suggest that a THA with proven low revision rates might be the better choice, particularly for patients who are concerned about implant durability. Well-controlled prospective studies that show appreciable clinically important differences in patient-reported outcomes and functional results favoring the BHR over conventional THA prostheses using modern bearings are needed to justify the use of the BHR in view of this revision risk.
Level III, therapeutic study.
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