Patient reported outcomes (PROs) are becoming increasingly important in cancer studies, particularly with the emphasis on patient centered outcome research. However, multiple PROs, using different scales, with different directions of favorability are often used within a trial, making interpretation difficult. To enhance interpretability, we propose the use of a standardized effect size graph, which shows all PROs from a study on the same figure, on the same scale. Plotting standardized effects with their 95% confidence intervals (CIs) on a single graph clearly showing the null value conveys a comprehensive picture of trial results. We demonstrate how to create such a graph using data from a randomized controlled trial that measured 12 PROs at two time points. The 24 effect sizes and CIs are shown on one graph and clearly indicate that the intervention is effective and sustained.

Les données rapportées par les patients sont maintenant fréquemment utilisées en recherche biomédicale. Ces instruments permettent la mesure de concepts subjectifs tels que la qualité de vie, les niveaux d’anxiété, de douleur, de fatigue. L’interprétation d’une différence de score au cours du temps était basée sur l’hypothèse que le sens des concepts et échelles restai stable au cours du temps dans l’esprit des individus. Cette hypothèse semble aujourd’hui dépassée. L’auto-évaluation d’un concept est maintenant comprise comme contingente de la représentation subjective qu’à un sujet du dit concept, cette représentation pouvant changer au cours du temps, surtout après avoir vécu un évènement de santé : ce phénomène est connu comme le « response shift ». Depuis la fin des années 1990s, l’investigation de ce phénomène est devenue un sujet d’intérêt majeur en psychométrie. Si des développements ont vu le jour, ce sujet reste récent et donc accompagné de débats variés que ce soit sur le plan théorique ou méthodologique. Aussi, l’objectif général de cette thèse est d’investiguer certaines problématiques méthodologiques et statistiques liées au response shift. Ce manuscrit est composé de trois travaux principaux : un état de l’art et une synthèse des travaux conduits à un niveau international depuis que le response shift est étudié, une étude pilote des performances de la procédure d’Oort (une méthode populaire de détection de response shift) par simulations et un travail théorique sur les liens entre response shift et complexité sémantique des concepts mesurés et items utilisés. / Patient-Reported Outcomes are increasingly used in health-related research. These instruments allow the assessment of subjective concepts such as Health-Related Quality of Life, anxiety level, pain or fatigue. Initially, the interpretation of a difference in score over time was based on the assumption that the meaning of concepts and measurement scales remains stable in individuals’ minds over time. This assumption has been challenged. Indeed, the self-assessment of a concept is now understood as a contingency of the subjective meaning a subject has of this concept, which can change over time especially as a result of a salient medical event: the “response shift” phenomenon. Since the end of the 1990s, researches on response shift phenomenon has become of prime interest in the field of health-related research. If developments have been made, it is still a young field with various scientific debates on a theoretical, methodological and statistical level. Thus, the broad objective of this thesis is to investigate some methodological and statistical issues regarding response shift concept, detection and integration into PRO data analyses. The manuscript is composed of three main works: a state of the art and synthesis of the works conducted at an international level since response shift phenomenon is investigated, a pilot study investigating the statistical performances of the Oort’s Procedure (a popular method of response shift detection using Structural Equation Modeling) by simulations and a theoretical work about the links between response shift occurrence and semantic complexity of concepts measured and items used.

INTRODUCTION: Immune checkpoint inhibitors are a new form of immunotherapy that has transformed the treatment landscape for an ever-increasing number of malignancies. While these medications utilize and enhance the immune system to treat malignancies, they can also have significant side effects, termed immune related adverse events, that in many ways resemble autoimmune disease states. One such example is inflammatory arthritis, which has been found to resemble a number of different presentations, including rheumatoid arthritis and seronegative spondyloarthropathies. In addition to these traditional inflammatory arthritis phenotypes, worsening of pre-existing arthritis is another subgroup of inflammatory arthritis that has previously not been considered in this population. Furthermore, while the effects of these autoimmune arthropathies on functionality is well-documented, it is not known whether there is a significant effect on functionality in patients that experience immune checkpoint inhibitor-induced arthritis. Given that patient reported outcomes are a validated and routinely utilized measure of functionality and quality of life, the Health Assessment Questionnaire, pain visual analogue scale and Patient Global Assessment were used to measure these outcomes following diagnosis. Our aim here is to explore the subtypes of inflammatory arthritis that result from this type of treatment and its overall effect on functionality and quality of life. METHODS: This study was a retrospective review of patients at one academic center who experienced an inflammatory arthritis resulting from immune checkpoint inhibition and required a referral to a rheumatologist for further work-up. Patients were evaluated in clinic at which time they also completed a Health Assessment Questionnaire as part of standard of care. Once patients were evaluated, their inflammatory arthritis was classified based on which clinical arthritis that it matched most closely, including polymyalgia rheumatica, rheumatoid arthritis, seronegative spondyloarthritis, or an exacerbation or osteoarthritis. Other demographic information such as gender, age, and race were also collected. Patient questionnaires were scored and compared to the type of inflammatory arthritis to assess for any correlations. RESULTS: We found 30 patients that had an inflammatory arthritis resulting from immune checkpoint inhibition, with 12 having a polyarthritis similar to rheumatoid arthritis, 11 patients having osteoarthritis exacerbation, 4 patients with a polymyalgia rheumatica arthritis phenotype and 3 patients with a spondyloarthopathy. In terms of the patient reported outcomes, the overall score was 0.57 ± 0.47, indicating that there was little effect of these arthropathies on overall functionality. The pain visual analogue scale had an average score of 41.8 ± 31.4 mm and the Patient Global Assessment had an overall score of 25.6 ± 26.7 mm. DISCUSSION: The overall results suggest that the inflammatory arthritis phenotypes do not significantly impact the functionality or quality of life of most patients who experience this side effect. Given that the use of immune checkpoint inhibitors will continue to grow, the overall need to better understand the resulting arthritis presentations is key. This is perhaps most true for those with pre-existing osteoarthritis, given the widespread nature of the disease in the general population and the prominence of the exacerbation as seen in our cohort.

Objectives: Patient-reported outcomes (PROs; self-report assessments) are increasingly important in evaluating medical care and treatment efficacy. Electronic administration of PROs via computer is becoming widespread. This article reviews the literature addressing whether computer-administered tests are equivalent to their paper-and-pencil forms. Methods: Meta-analysis was used to synthesize 65 studies that directly assessed the equivalence of computer versus paper versions of PROs used in clinical trials. A total of 46 unique studies, evaluating 278 scales, provided sufficient detail to allow quantitative analysis. Results: Among 233 direct comparisons, the average mean difference between modes averaged 0.2% of the scale range (e.g., 0.02 points on a 10-point scale), and 93% were within ±5% of the scale range. Among 207 correlation coefficients between paper and computer instruments (typically intraclass correlation coefficients), the average weighted correlation was 0.90; 94% of correlations were at least 0.75. Because the cross-mode correlation (paper vs. computer) is also a test-retest correlation, with potential variation because of retest, we compared it to the within-mode (paper vs. paper) test-retest correlation. In four comparisons that evaluated both, the average cross-mode paper-to-computer correlation was almost identical to the within-mode correlation for readministration of a paper measure (0.88 vs. 0.91). Conclusions: Extensive evidence indicates that paper- and computer-administered PROs are equivalent.

Patient-reported outcomes (PROs) produce meaningful information about patient-perceived health status reported directly by patients. Routine collection of PROs data is particularly important in chronic conditions, such as heart failure (HF). Major cardiovascular societies and regulatory agencies encouraged PRO inclusion in randomized controlled trials (RCTs), but PROs remain underutilized as a key outcome in these studies. In this systematic review, we aimed to evaluate temporal trends and explore trial characteristics associated with PRO inclusion in HF RCTs published in high-impact medical journals. We also assessed the quality of PRO reporting against the Consolidated Standards of Reporting Trials PRO extension. We found that over half of HF RCTs included a PRO. The proportion of RCTs with PROs increased significantly since 2000. A number of RCT characteristics such as multicentre; medium-sized (n = 51-250 participants); trials coordinated in Central and South America; and that tested health services, devices or surgery, exercise and rehabilitation interventions were independently associated with higher odds of PRO inclusion. The quality of PRO reporting was modest, with better reporting in RCTs with PROs a primary or co-primary endpoint. Consistent PRO inclusion and high-quality reporting are necessary to increase the utility of these findings by patients, clinicians, and health care policy makers. / Thesis / Master of Science (MSc)

No description available.

Background: The management of cleft lip and/or palate (CL/P) includes multidisciplinary care beginning in infancy and continuing through to adulthood. Outcomes of cleft care have been difficult to measure because of the subjective nature of evaluating concepts such as appearance and speech. Including the patient perspective in outcome evaluation through the use of a patient-reported outcome (PRO) measure would provide a more accurate reflection of a patient’s status. The overall objective of this thesis is to show that through adherence to rigorous methods of development, a PRO measure can provide clinically meaningful outcome evaluation in cleft care. Methods: The first paper uses the qualitative method of interpretive description to define a conceptual framework to guide the development of a PRO measure for patients with CL/P, the CLEFT-Q. The second paper describes the protocol for the entire development of the CLEFT-Q. The third paper analyzes the results of the cross-sectional field-test of the CLEFT-Q scales to determine whether or not the CLEFT-Q is able to detect differences between specific cleft types. Results: The qualitative study included 138 patients with CL/P from six countries. The final conceptual framework contained thirteen concepts within the domains of appearance, facial function, and health-related quality of life. The second paper details the process of designing the CLEFT-Q scales. The field-test included 2,434 patients from thirty sites in twelve countries, and CLEFT-Q scores were found to vary with cleft type for all scales. Conclusions: PRO measures need to be rigorously designed in order to provide scientifically sound, clinically meaningful measurement. The CLEFT-Q is able to detect differences between patients with various cleft types, and will be a useful tool to provide the patient perspective in future outcome evaluation in cleft care. / Thesis / Doctor of Philosophy (PhD) / Measuring outcomes of treatment for cleft lip and/or palate (CL/P) should include the patient perspective. The objective of this thesis is to show that through rigorous methods of development, a patient-reported outcome (PRO) measure, the CLEFT-Q, can provide clinically meaningful evaluation of outcomes. First, 136 patients with CL/P from six countries were interviewed to learn what concepts related to having a cleft or its treatment are important to them. A conceptual framework was developed that informed the CLEFT-Q scales. Describing the methodology behind developing the CLEFT-Q then served to inform and engage members of the community. A field-test of the CLEFT-Q scales showed that in a sample of 2,434 patients with CL/P from twelve countries, CLEFT-Q outcomes varied in patients with different types of CL/P. The CLEFT-Q can be used to provide rigorous measurement of PROs in patients with CL/P in the future.

Background Stroke is a major cause of disability worldwide. After treatment in a specialized stroke unit, early supported discharge (ESD) followed by home rehabilitation has shown to be an effective way to improve patient outcome and quality of care for persons with mild to moderate stroke. ESD service is recommended in the national and international guidelines for stroke care, but has only partially been implemented in Sweden. Following stroke, fatigue is a common consequence that often becomes more evident when the patient comes home. Currently, there is insufficient evidence about how to measure, treat and handle post-stroke fatigue. The overall aim of this thesis was to evaluate and implement early supported discharge (ESD) based on stroke patients experience after discharge from the stroke unit and local conditions. The aim was also to evaluate post-stroke fatigue with a potentially valid and reliable scale and finally to prepare for a study to evaluate cardiorespiratory training as a part of ESD service for patients with post-stroke fatigue. Methods In paper I, nine strategically chosen patients were interviewed of their experience of falling ill, the hospital stay, discharge, contact with health care after discharge and their request of support. Papers II-III describe and evaluate the development, content, implementation and effects of a locally adopted method for early supported discharge (Umeå Stroke Center ESD) in modern stroke care. Paper II included 153 consecutive patients and paper III, 30 232 patients with first-ever stroke registered in the Riksstroke registry in Sweden. Paper II evaluated number of patients/year, clinical and functional health status, satisfaction in relation to needs, accidental falls/other injuries and resources with the result summarized in a value compass. The implementation process was evaluated retrospectively by means of Consolidated Framework for Implementation (CFIR). Paper III evaluated patient reported outcome measurements (PROMs) at 3 months. The primary outcome in paper III was satisfaction with the rehabilitation after discharge. Secondary outcomes were information about stroke provided, tiredness/fatigue, pain, dysthymia/depression, general health status and dependence in activities of daily living (mobility, toilet hygiene and dressing). Multivariable logistic regression models for each PROM was used to analyze associations between PROMs and ESD/no ESD. In Paper IV, the Fatigue Assessment scale (FAS) was translated into Swedish and evaluated regarding psychometric properties when self-administered by persons with mild to moderate stroke. 72 consecutively patients selected from the stroke unit admission register received a letter including three questionnaires: the FAS, the Short Form Health Survey (SF-36) subscale for vitality and the Geriatric Depression Scale GDS-15. A second letter with FAS was sent within 2 weeks, for re-test evaluation. Paper V is a study protocol for a planned randomized controlled trial (RCT) of 50 consecutive stroke patients will who receive stroke unit care followed by ESD-service at Umeå Stroke Center, University Hospital, Umeå, Sweden. Paper V will investigate if a structured cardiorespiratory interval training program (CITP) added to the ESD-service may result in relieved post-stroke fatigue and increased oxygen uptake. Results The interviews in Paper I revealed three main categories with subcategories: “Responsible and implicated”, “Depersonalized object for caring measures” and “The striving for repersonalization and autonomy”. The findings indicate that coming home gave the informants’ important insights and understanding of the stroke, its consequences and was also an important factor for the recovery. Paper II-III showed that it is possible to develop and implement an adapted ESD service for stroke patients based on the patients’ experiences and requests, evidence-based recommendations and local conditions. The ESD service reduced dependence of activity, increased mobility with seemingly no increased risk of accidental falls or other injuries. The patient satisfaction in relation to needs regarding the ESD was high. Paper III showed that patients that received ESD were more satisfied with rehabilitation after discharge, had less need for assistance with ADL and less dysthymia/depression compared to patients that did not receive ESD. Study IV showed that the Swedish FAS used at home as a selfadministered questionnaire is a reliable and valid questionnaire for measuring fatigue in persons with mild to moderate stroke. The internal consistency was good, the agreement between the test and retest reliability for individual items (weighted kappa) was for the majority of items good or moderate. The relative reliability for total scores was good and the absolute reliability was 9 points. The Swedish FAS had no floor nor ceiling effects and correlated both with the SF-36, subscale for vitality and the GDS-15 indicating convergent construct validity, but not divergent construct validity. Conclusion It is possible to develop and implement ESD care for stroke patients based on patients’ experience and needs, evidence-based principles and local conditions. Early supported discharge (ESD) in the setting of modern stroke unit care appears to have positive effects on rehabilitation in the subacute phase. The Swedish FAS used at home as a self-administered questionnaire is reliable and valid for measuring fatigue in persons with mild to moderate stroke.

Bone bruise lesions (BBL) are documented on MRIs diagnosing acute knee ligament injury (AKLI). Recent evidence has indicated that a majority of patients that sustain an AKLI, especially anterior cruciate ligament (ACL) knee injury, will develop post-traumatic osteoarthritis (PTOA) 10-20 years following injury. It has been proposed that the initial damage sustained to the articular cartilage overlying BBL causes a cascade of events that may result in PTOA. Researchers have proposed a modification to treatment protocols for more severe BBL, or have stressed the need for the development of protective therapies to protect the articular cartilage. However, there are limited tools available to evaluate the clinical outcome of articular cartilage overlying BBL. Furthermore, damage to the cartilage overlying BBL may be different according to differing BBL severities. Therefore, the use of a cartilage degradation biomarker, serum cartilage oligomeric matrix protein (sCOMP) and the use of a BBL severity classification system may be useful to determine if differences exist between patients with and without BBL, and with differing BBL severities. The purpose of this dissertation was to investigate the utility of sCOMP as a biomarker for acute articular cartilage damage. The purposes of these studies were to determine the inter and intraday reliability of this marker, to document sCOMP longitudinally in collegiate athletes and following AKLI, and to determine if differences in sCOMP and self-reported pain and function exist for patients with and without BBL, and differing BBL following AKLI. The results of these studies indicated sCOMP measures had strong inter and intraday reliability. Additionally, exercise does seem to influence sCOMP levels; however, these elevations may not be clinically meaningful. Furthermore, sCOMP levels were not different between patients with BBL and without, and between differing BBL severities. The results of these studies support the use of a BBL severity classification for future research studies in order to further elucidate the outcomes of these lesions.

Unicompartmental knee replacement (UKR) is the principal alternative to total knee replacement (TKR) in the treatment of end-stage knee osteoarthritis. It involves less tissue resection, resulting in lower rates of morbidity and faster recoveries compared to TKR. However, UKR has a significantly higher revision rate compared to TKR. As a result, whilst over a third of patients are eligible for UKR, only around 8% receive it. A comprehensive comparison of matched patients undergoing TKR and UKR was undertaken using a large dataset from the National Joint Registry for England and Wales (NJR). Failure rates (revision, reoperation, complications and mortality), length of stay and patient-reported outcomes (PROMs) were studied. Whilst patients undergoing TKR had lower reoperation and revision rates, they had higher rates of morbidity and mortality, longer hospital stays, and inferior PROMs compared to UKR. The main reason for revision in UKR was loosening. In view of the high revision rate in UKR, NJR data was studied to identify modifiable risk factors for failure in UKR. Important patient factors were identified including age, gender and pre-operative function. Surgeons with a higher UKR caseload had significantly lower revision rates and superior patient-reported outcomes. Increasing usage (offering UKR to a greater proportion of knee replacement patients) appears to be a viable method of increasing caseload and therefore of improving results. Surgeons with optimal usage (around 50% of patients, using appropriate implants) achieved revision/reoperation rates similar to matched patients undergoing TKR. Two clinical studies were conducted to establish whether the use of cementless fixation would improve fixation and reduce the revision rate of UKR. Cementless UKR was demonstrated to be safe and reliable, with PROMs similar or superior to those demonstrated in cemented UKR. Patients with suboptimal cementless fixation were examined and pre-disposing technical factors were identified. Finally, using NJR data, the effect of the introduction of cementless UKR on overall outcomes was examined. The number of cementless cases was small, and no significant effect on implant survival was demonstrated. However, patients undergoing cementless UKR demonstrated superior PROMs. These studies demonstrate that UKR has numerous advantages over TKR in terms of morbidity, mortality and PROMs. If surgeons perform high volumes of UKR (achievable by increasing their UKR usage), these advantages can be attained without the large difference in revision rates previously demonstrated. Cementless UKR is safe and provides superior fixation and outcomes in the hands of high-volume surgeons. Further work is needed to quantify the revision rate of cementless UKR, and to assess its results in the hands of less experienced surgeons.