Improving the specification of the target difference in the sample size calculation of a randomised trial of treatments for osteoarthritis

Copsey, B

Abstract:: The sample size of a clinical trial is the number of participants the trial aims to recruit. Sample size is a critical aspect of clinical trial design and has ethical and financial implications. The sample size depends on the target difference, the difference in outcome that the trial is powered to detect. This thesis aims to improve methods for specifying the target difference in randomised trials of osteoarthritis.

I conducted a systematic review of sample size calculations in hip and knee osteoarthritis trials published in 2016. It found that most sample size calculations were poorly reported and could not be reproduced. The target difference in the sample size calculation was commonly justified by a published minimum clinically important difference (MCID).

Several versions of the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) were commonly used in hip and knee osteoarthritis trials. It was often unclear which version was used, hindering interpretation of trial results.

I conducted a discrete choice experiment examining patient preferences when choosing between osteoarthritis medications. Duration of treatment effect was shown to be important to participants, viewed with similar importance to the amount of symptom relief provided and risks of the treatment.

I analysed a cohort of people with osteoarthritis and showed that MCID estimates for the WOMAC varied across different follow-up time points. However, there was no visual trend in the change in MCID estimates over time. Longitudinal methods were feasible to calculate MCID estimates, but did not improve precision.

A simulation study that I conducted found that the pattern of the treatment effect (its duration and consistency) affected the optimal statistical method of analysis for a randomised trial using the WOMAC as the primary outcome.

Future research is needed to examine whether the findings are generalisable to different datasets, outcome measures and health conditions.

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APA Style

Copsey, B. (2019). Improving the specification of the target difference in the sample size calculation of a randomised trial of treatments for osteoarthritis [PhD thesis]. University of Oxford.

MLA Style

Copsey, B. Improving the Specification of the Target Difference in the Sample Size Calculation of a Randomised Trial of Treatments for Osteoarthritis. 2019. University of Oxford, PhD thesis.

Chicago Style

Copsey, B. 2019. “Improving the Specification of the Target Difference in the Sample Size Calculation of a Randomised Trial of Treatments for Osteoarthritis.” PhD thesis, University of Oxford.
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Files:: FinalThesis_BethanCopsey_29Aug2019.pdf

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Authors

+ Copsey, B More by this author

Institution:: University of Oxford
Division:: MSD
Department:: NDORMS
Role:: Author

Contributors

+ Cook, J

Institution:: University of Oxford
Division:: MSD
Department:: NDORMS
Role:: Contributor, Supervisor

+ Buchanan, J

Department:: NDPH, University of Oxford
Role:: Supervisor

+ Fitzpatrick, R

Department:: NDPH, University of Oxford
Role:: Supervisor

+ Dutton, S

Institution:: University of Oxford
Division:: MSD
Department:: NDORMS
Role:: Supervisor

+ Lamb, S

Institution:: University of Oxford
Division:: MSD
Department:: NDORMS
Role:: Supervisor

More contributors...

+ Engineering and Physical Sciences Research Council More from this funder

Grant:: MR/K501256/1

+ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford More from this funder

DOI:: 10.5287/ora-mprrex7vx
Type of award:: DPhil
Level of award:: Doctoral
Awarding institution:: University of Oxford

Language:: English
Keywords:: target difference

systematic review

discrete choice experiment

simulation

minimum clinical important difference

MCID
Subjects:: Clinical trial

Randomised trial

Sample size

Osteoarthritis
UUID:: uuid:ba147e47-6c0f-477b-89c5-a700b467d84a
Deposit date:: 2019-11-11
ARK identifier:: ark:/29072/ora_ba147e476c0f477b89c5a700b467d84a

Related item:: Duration of Treatment Effect Should Be Considered in the Design and Interpretation of Clinical Trials: Results of a Discrete Choice Experiment
Description:: Objective: This study examined whether duration of treatment effect should be considered in a benefit-risk assessment using a case study of osteoarthritis medications. Study Design and Setting: A discrete choice experiment was completed by 300 residents of the United Kingdom with hip and/or knee osteoarthritis. In 16 choice tasks, participants selected their preferred option from 2 medications. Medications were described in terms of effect on pain, stiffness, and function; duration of treatment effect; and risk of heart attack and stomach ulcer bleeding. The analysis used mixed-effects logistic regression. Results: Pain, disease severity, and duration of treatment effect had the greatest influence on medication preferences, whereas stiffness did not significantly affect medication choice. Participants were willing to accept an increase in the risk of heart attack of 2.6% (95% confidence interval: 2.0% to 3.2%) to increase the duration of treatment effect from 1 month to 12 months. Reducing pain from moderate to mild was valued the same as increasing duration of effect from 1 month to 3 months; both were seen as equivalent to an absolute reduction of 1.2% in the risk of heart attack in the next year. Subgroup analysis suggested disease severity influenced patient preferences. Conclusions: Along with treatment benefits and risks, the results suggest that duration of treatment effect is an important factor in the medication choices of people with osteoarthritis. This could have implications for the design and interpretation of clinical trials, for example, incorporating longer-term surveillance of trial participants and accounting for duration of treatment effect in risk-benefit assessments. Future research is needed to assess whether these findings are generalizable to other samples, disease areas, and levels of duration of effect.
Related item:: Sample size calculations are poorly conducted and reported in many randomized trials of hip and knee osteoarthritis: results of a systematic review
Description:: OBJECTIVES: To review the methodology and reporting of sample size calculations in a contemporary sample of trials in osteoarthritis. STUDY DESIGN AND SETTING: Randomized trials in hip and/or knee osteoarthritis published in 2016 were identified by searching MEDLINE, Cochrane library, CINAHL, EMBASE, PsycINFO, PEDro, and AMED until March 31, 2017. Data were extracted on study characteristics, methods used to calculate the sample size, and the reporting and justification of components used in the sample size calculation. We attempted to replicate the sample size calculation using the reported information. RESULTS: This review included 116 trials. Seventy-eight (67%, n = 78/116) reported a power calculation. Less than a quarter reported all core components of the sample size calculation (21%, n = 16/78). The sample size calculation was only reproducible in 53% of the trials that reported a power calculation (n = 41/78). The replicated calculation produced a sample size over 10% larger than the reported value in 12% of trials (n = 9/78). Insufficient information was reported to allow the sample size calculation to be replicated in a quarter of trials (27%, n = 21/78). CONCLUSION: Sample size calculations in trials of hip and knee osteoarthritis are not adequately reported, and the calculation frequently cannot be reproduced.
Related item:: Current practice in methodology and reporting of the sample size calculation in randomised trials of hip and knee osteoarthritis: a protocol for a systematic review
Description:: BACKGROUND: A key aspect of the design of randomised controlled trials (RCTs) is determining the sample size. It is important that the trial sample size is appropriately calculated. The required sample size will differ by clinical area, for instance, due to the prevalence of the condition and the choice of primary outcome. Additionally, it will depend upon the choice of target difference assumed in the calculation. Focussing upon the hip and knee osteoarthritis population, this study aims to systematically review how the trial size was determined for trials of osteoarthritis, on what basis, and how well these aspects are reported. METHODS: Several electronic databases (Medline, Cochrane library, CINAHL, EMBASE, PsycINFO, PEDro and AMED) will be searched to identify articles on RCTs of hip and knee osteoarthritis published in 2016. Articles will be screened for eligibility and data extracted independently by two reviewers. Data will be extracted on study characteristics (design, population, intervention and control treatments), primary outcome, chosen sample size and justification, parameters used to calculate the sample size (including treatment effect in control arm, level of variability in primary outcome, loss to follow-up rates). Data will be summarised across the studies using appropriate summary statistics (e.g. n and %, median and interquartile range). The proportion of studies which report each key component of the sample size calculation will be presented. The reproducibility of the sample size calculation will be tested. DISCUSSION: The findings of this systematic review will summarise the current practice for sample size calculation in trials of hip and knee osteoarthritis. It will also provide evidence on the completeness of the reporting of the sample size calculation, reproducibility of the chosen sample size and the basis for the values used in the calculation. TRIAL REGISTRATION: As this review was not eligible to be registered on PROSPERO, the summary information was uploaded to Figshare to make it publicly accessible in order to avoid unnecessary duplication amongst other benefits ( https://doi.org/10.6084/m9.figshare.5009027.v1) ; Registered January 17, 2017.
Related item:: Problems persist in reporting of methods and results for the WOMAC measure in hip and knee osteoarthritis trials
Description:: PURPOSE: The Western Ontario and McMaster Universities Arthritis Index (WOMAC) is a commonly used outcome measure for osteoarthritis. There are different versions of the WOMAC (Likert, visual analogue or numeric scales). A previous review of trials published before 2010 found poor reporting and inconsistency in how the WOMAC was used. This review explores whether these problems persist. METHODS: This systematic review included randomised trials of hip and/or knee osteoarthritis published in 2016 that used the WOMAC. Data were extracted on the version used, score range, analysis and results of the WOMAC, and whether these details were clearly reported. RESULTS: This review included 62 trials and 41 reported the WOMAC total score. The version used and item range for the WOMAC total score were unclear in 44% (n = 18/41) and 24% (n = 10/41) of trials, respectively. The smallest total score range was 0-10 (calculated by averaging 24 items scored 0-10); the largest was 0-2400 (calculated by summing 24 items scored 0-100). All trials reported the statistical analysis methods but only 29% reported the between-group mean difference and 95% confidence interval. CONCLUSION: Details on the use and scoring of the WOMAC were often not reported. We recommend that trials report the version of the WOMAC and the score range used. The between-group treatment effect and corresponding confidence interval should be reported. If all the items of the WOMAC are collected, the total score and individual subscale scores should be presented. Better reporting would facilitate the interpretation, comparison and synthesis of the WOMAC score in trials.

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Improving the specification of the target difference in the sample size calculation of a randomised trial of treatments for osteoarthritis

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Improving the specification of the target difference in the sample size calculation of a randomised trial of treatments for osteoarthritis

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