Parameter identifiability of fundamental pharmacodynamic models

Issues of parameter identifiability of routinely used pharmacodynamics models are considered in this paper. The structural identifiability of 16 commonly applied pharmacodynamic model structures was analyzed analytically, using the input-output approach. Both fixed-effects versions (non-population, no between-subject variability) and mixed-effects versions (population, including between-subject variability) of each model structure were analyzed. All models were found to be structurally globally identifiable under conditions of fixing either one of two particular parameters. Furthermore, an example was constructed to illustrate the importance of sufficient data quality and show that structural identifiability is a prerequisite, but not a guarantee, for successful parameter estimation and practical parameter identifiability. This analysis was performed by generating artificial data of varying quality to a structurally identifiable model with known true parameter values, followed by re-estimation of the parameter values. In addition, to show the benefit of including structural identifiability as part of model development, a case study was performed applying an unidentifiable model to real experimental data. This case study shows how performing such an analysis prior to parameter estimation can improve the parameter estimation process and model performance. Finally, an unidentifiable model was fitted to simulated data using multiple initial parameter values, resulting in highly different estimated uncertainties. This example shows that although the standard errors of the parameter estimates often indicate a structural identifiability issue, reasonably “good” standard errors may sometimes mask unidentifiability issues

Which treatments are most effective for common tendinopathies? A systematic review and network meta-analysis protocol.

This is a preprint for a protocol. The purpose of the study described by the protocol was to compare the effectiveness of different treatment classes across a range of tendinopathies and outcomes, to better establish a treatment hierarchy. Where sufficient data were obtained, the potential for covariates - including patient demographics and condition specifics (e.g. symptom severity) - to explain statistical heterogeneity was explored

Comparison of exercise therapies across multiple tendinopathies: a systematic review and network meta-analysis protocol.

This is a preprint for a protocol. The study described by the protocol aimed to use network structures to compare exercise treatments and treatment classes in attempts to identify a treatment hierarchy. Additionally, the large amount of data synthesised was used to explore relevant factors that may explain statistical heterogeneity

The effect of dose components on resistance exercise therapies for tendinopathy management: a systematic review and meta-analysis.

The purpose of this study was to investigate potential moderating effects of resistance exercise dose components including intensity, volume and frequency, for the management of common tendinopathies. The research was undertaken through a systematic review and meta-analysis, comprising an extensive search of databases and trial registries. Eligibility criteria for selecting studies included randomised and non-randomised controlled trials investigating resistance exercise as the dominant treatment class and reporting sufficient information regarding at least two components of exercise dose (intensity, frequency, volume). Non-controlled standardised mean difference effect sizes were calculated across a range out outcome domains and combined with Bayesian hierarchical meta-analysis models for domains generating large (disability; function; pain) and small (range of motion; physical function capacity; and quality of life) effect size values. Meta-regressions were used to estimate differences in pooled mean values across categorical variables quantifying intensity, frequency and volume. Ninety-one studies presented sufficient data to be included in meta-analyses, comprising 126 treatment arms (TAs) and 2965 participants. Studies reported on five tendinopathy locations (Achilles: 39 TAs, 31.0%; rotator cuff: 39 TAs, 31.0%; lateral elbow: 25 TAs, 19.8%; patellar: 19 TAs, 15.1%; and gluteal: 4 TAs, 3.2%). Meta-regressions provided consistent evidence of greater pooled mean effect sizes for higher intensity therapies comprising additional external resistance compared to body mass only (large effect size domains: 0.39 [95% CrI: 0.00 to 0.82; p = 0.976]; small effect size domains (0.09 [95% CrI: -0.20 to 0.37; p = 0.723]) when data were combined across tendinopathy locations or analysed separately. Consistent evidence of greater pooled mean effect sizes was also identified for the lowest frequency (less than daily) compared with mid (daily) and high frequencies (more than daily) for both large effect size domain ( -0.66 [95% CrI: -1.2 to -0.19; p >0.999]; -0.54 [95% CrI:-0.99 to -0.10; p >0.999]) and small effect size domains ( -0.51 [95% CrI: -0.78 to -0.24; p >0.999]; -0.34 [95% CrI: -0.60 to -0.06; p = 0.992]) when data were combined across tendinopathy locations or analysed separately. Minimal and inconsistent evidence was obtained for differences for a moderating effect of training volume. The study concluded that resistance exercise dose is poorly reported within the tendinopathy management literature. However, this large meta-analysis identified some consistent patterns indicating greater efficacy on average with therapies prescribing higher intensities (through the inclusion of additional external loads) and lower frequencies, potentially creating stronger stimuli and facilitating adequate recovery

The effect of dose on resistance exercise therapies for tendinopathy: a systematic review and meta-analysis protocol.

This is a preprint for a protocol. The purpose of the study described by the protocol was to investigate the effect of resistance exercise dose across multiple common tendinopathies (rotator cuff, lateral elbow, patellar or Achilles), where the frequency, volume and intensity can be accurately quantified. By combining a large data set with contemporary meta-analysis and meta-regression approaches (including relevant covariates within models), the systematic review attempted to explore statistical heterogeneity and better assess potential dose-response relationships that may exist. Where placebo and no-treatment arms were included, these studies were used to reduce heterogeneity and provide sensitivity analyses to support or refute analyses with larger, but more complex data

Empirically derived guidelines for interpreting the effectiveness of exercise therapy for tendinopathies: a protocol.

This is a preprint for a protocol. The aim of the study described by the protocol was to perform a large synthesis of the available research investigating exercise therapy for tendinopathies, creating empirically derived thresholds to benchmark interventions and explore potential differences across tendinopathy types and outcome domains

Exercise therapy for tendinopathy: a scoping review mapping interventions and outcomes.

The aim of this research was to comprehensively map exercise interventions and outcomes across all tendinopathies. The study took the form of a scoping review. Eligibility criteria (PCC) included: 1) participants - any age or gender, with any tendinopathy; 2) concept - supervised or unsupervised exercise, of any type or format, delivered by any professional and any outcome used to evaluate any exercise intervention; 3) context - any setting in any country listed as very high on the human development index. The study used nine databases, four trial registries and six grey literature sources. At least two reviewers independently conducted title, abstract and full text screening. Data extraction was conducted using a bespoke tool developed for this review, informed by the TIDieR checklist and ICON health-related domains, to interpret exercise reporting and outcomes across included studies. Extracted data from 555 included studies from 31 countries incorporated 25,490 participants with mean study ages ranging from 15-65 years. A range of exercise interventions including strengthening, flexibility, aerobic, proprioceptive, and motor control were identified; showing rotator cuff-related shoulder pain, Achilles, patellar and lateral elbow tendinopathies were most studied. A range of health-related domains were measured by numerous outcome tools, with little consistency within domains or tendinopathies. Reporting of participant characteristics, interventions and adherence was highly variable. This first comprehensive map of exercise and outcomes for tendinopathy has identified four recommendations to be considered for future tendinopathy research: 1) Specific robust high quality research study designs; (2) Comprehensive research reporting; 3) Patient/practitioner lived experience; and 4) comprehensive high quality evidence synthesis

Effect of resistance exercise dose components for tendinopathy management: a systematic review with meta-analysis.

The objective of this study was to investigate potential moderating effects of resistance exercise dose components - including intensity, volume and frequency - for the management of common tendinopathies. The study was conducted through a systematic review with meta-analysis and meta-regressions, using sources that included (but were not limited to) MEDLINE, CINAHL, SPORTDiscus, ClinicalTrials.gov and the ISRCTN Registry. Selection criteria were based on randomised and non-randomised controlled trials investigating resistance exercise as the dominant treatment class, reporting sufficient information regarding two or more components of exercise dose. A total of 110 studies were included in meta-analyses (148 treatment arms (TAs), 3953 participants), reporting on five tendinopathy locations (rotator cuff: 48 TAs; Achilles: 43 TAs; lateral elbow: 29 TAs; patellar: 24 TAs; gluteal: 4 TAs). Meta-regressions provided consistent evidence of greater pooled mean effect sizes for higher intensity therapies comprising additional external resistance compared to body mass only (large effect size domains: βBodyMass:External = 0.50 [95% CrI: 0.15 to 0.84; p = 0.998]; small effect size domains βBodyMass:External = 0.04 [95% CrI: -0.21 to 0.31; p = 0.619]) when combined across tendinopathy locations or analysed separately. Greater pooled mean effect sizes were also identified for the lowest frequency (less than daily) compared with mid (daily) and high frequencies (more than once per day) for both effect size domains, when combined or analysed separately (p ≥ 0.976). Evidence for associations between training volume and pooled mean effect sizes was minimal and inconsistent. The study found that resistance exercise dose is poorly reported within tendinopathy management literature. However, this large meta-analysis identified some consistent patterns indicating greater efficacy on average with therapies prescribing higher intensities (through inclusion of additional loads) and lower frequencies, potentially creating stronger stimuli and facilitating adequate recovery

Which treatment classes and combinations are more effective for the management of common tendinopathies? A systematic review and network meta-analysis.

The aim of this research was to quantify the comparative effectiveness of treatment classes used for the management of the most common tendinopathies. The project studied network meta-analyses comparing combinations of exercise, non-exercise, and non-active treatments across a range of tendinopathy locations and outcome domains. The review covered randomised and quasi-randomised controlled trials including an exercise arm and persons with a tendinopathy diagnosis at any location, and of any severity or duration. Outcome measures included outcomes assessing disability, function, pain, shoulder range of motion, physical function capacity, or quality of life. Through network meta-analyses, broad (exercise/non-exercise/combined/non-active) and more specific (exercise/biomechanics/injection/electrotherapy/manual-therapy/non-active/surgery) treatment class models were fitted with hierarchical Bayesian models. Results were interpreted using pooled standardised mean difference effect sizes and ranking through Surface Under the Cumulative Ranking curves (SUCRA). Treatment hierarchies were assessed using the GRADE minimally contextualised framework. Two-hundred studies comprising 458 treatments arms were identified. Many comparisons were within the same class reducing data available to assess comparative effectiveness. Data from 85 studies generating 140 pairwise comparisons consistently identified the superiority of combining exercise and non-exercise treatment classes (SUCRA: 0.70 to 0.88). Central estimates indicated that combining exercise and non-exercise treatments increased effect sizes by ~0.1 to 0.3 compared with exercise alone. Analysis of more specific treatment classes identified with low/very low certainty the superiority of combining exercise with either biomechanical (e.g. taping, bracing or splinting; SUCRA: 0.73) or injection therapies (SUCRA: 0.72). The study concluded that clinicians should consider combining exercise and non-exercise therapies as a starting point for tendinopathy management. The most effective treatment combinations include exercise with the use of biomechanical or injection therapies

What are small, medium and large effect sizes for exercise treatments of tendinopathy? A systematic review and meta-analysis.

The objective of this study was to quantify and describe effect size distributions from exercise therapies across a range of tendinopathies and outcome domains, to inform future research and clinical practice through conducting a systematic review with meta-analysis. The review and meta-analysis explored moderating effects and context specific small, medium, and large thresholds. The study looked specifically at randomised and quasi-randomised controlled trials involving any persons with a diagnosis of rotator cuff, lateral elbow, patellar, Achilles or gluteal tendinopathy of any severity or duration. The study was conducted using common databases, six trial registries and six grey literature databases, which were searched on 18/01/21 (PROSPERO: CRD42020168187). Standardised mean difference (SMDpre) effect sizes were used with Bayesian hierarchical meta-analysis models to calculate the 0.25- (small), 0.5- (medium) and 0.75-quantiles (large), and to compare pooled means across potential moderators. Risk of bias was assessed with Cochrane's Risk of Bias tool. Data were obtained from 114 studies comprising 171 treatments and 4104 participants. SMDpre effect sizes were similar across tendinopathies but varied across outcome domains. Greater threshold values were obtained for self-reported measures of pain (small = 0.5; medium = 0.9; large = 1.4), disability (small = 0.6; medium = 1.0; large = 1.5) and function (small = 0.6; medium = 1.1; large = 1.8); and lower threshold values obtained for quality of life (small = -0.2; medium = 0.3; large = 0.7), and objective measures of physical function (small = 0.2; medium = 0.4; large = 0.7). Potential moderating effects of assessment duration, exercise supervision and symptom duration were also identified, with greater pooled mean effect sizes estimated for longer assessment durations, supervised therapies and studies comprising patients with shorter symptom durations. The study found that the effect size of exercise on tendinopathy is dependent on the type of outcome measure assessed. Threshold values presented here can be used to guide interpretation and assist with further research better establishing minimal important change