Outcomes measurement is an important component of routine hemophilia care, clinical trials and economic evaluations. Assessing outcomes in patients living with hemophilia is challenging due to a lack of validated outcome measures. Conventional clinical outcomes, for instance, bleeding rate, structural changes of joints or functional joint scores may be less relevant for the decision-making process. Patient reported outcomes measures has been increasingly interested in routine medical care and clinical research. However, the available validated patients reported outcome measures for patients with hemophilia are not generally implemented in routine care or clinical trials. The Patent Reported Outcomes, Burdens, and Experiences (PROBE) study aims to develop a validated patient reported outcome measure for patients living with hemophilia. The PROBE questionnaire is organized in 4 sections, comprising 29 questions. Section I contains questions pertaining to demographic data. Section II contains questions pertaining to patient reported outcomes. Section III contains questions pertaining to hemophilia specific problems and treatments. Section IV contains the EuroQol five dimension 5-level instrument (EQ-5D-5L). The psychometric analysis of revealed that the PROBE questionnaire has a good internal consistency (Cronbach’s alpha coefficient=0.84). PROBE items showed moderate to strong correlations with corresponding EQ-5D-5L domains. The PROBE Score has a known group validity among known groups. The psychometric properties of the PROBE questionnaire demonstrated the validity of the instrument in both patients living with hemophilia and control population (participants without bleeding disorder). The test-retest reliability analysis demonstrated that the PROBE questionnaire has a substantial agreement when the questionnaire was repeatedly administrated. There were acceptable reliability properties between the paper-based and web-based questionnaires. The reliability properties of the PROBE questionnaire were established in both patients living with hemophilia and control population. The PROBE questionnaire was cross-cultural implemented in 21 countries. The results showed that the regions of participant contributed a trivial variability of the PROBE score, indicating that the PROBE questionnaire is valid for assessing the health status among hemophilia patients and participants without bleeding disorder across regions. Sexual health of patients living with hemophilia was evaluated using the PROBE questionnaire. The results showed that sexual difficulty was more prevalent in patients with hemophilia and associated with markers of disease severity. This finding warrants the sexual health assessment in routine hemophilia care. / Thesis / Doctor of Philosophy (PhD)

Patient-reported outcome measures (PROMs) are becoming an integral part of healthcare decision making. Clinical trials, systematic reviews, and clinical practice guidelines incorporate them to learn about the effect of medical interventions in patients’ health status, without interference or mediation from clinicians or proxies. The use of these types of measures, however, is not without challenges. In particular, the complexity of the PROMs makes it difficult for patients, clinicians, and researchers to fully grasp the extent to which a treatment effect is negligible or trivial, small but important, moderate, or large. One of the most documented ways to address this issue is the use of the minimal important difference (MID), the smallest change in a PROM, either beneficial or harmful, that patients would perceive as important. A patient-oriented way to determine this threshold is the estimation of an anchor-based MID, where PROM results are compared against an external independent criterion the anchor that is in itself understandable and relevant for patients. This dissertation is an effort to facilitate the identification, evaluation, and utilization of MID estimates for PROMs. First, this thesis describes the development and reliability assessment of a new instrument to determine the credibility of primary studies ascertaining MID estimates, Second, it describes the conduct of a systematic survey to inform the creation of an inventory of all available anchor-based MIDs in the medical literature until 2015. Third, it reports an analysis of the state of the art of current MID estimates from a reporting and credibility perspective. Finally, this work concludes with a summary of the main results, presentation of strengths and limitations, and insights related to the implications for future research. / Dissertation / Doctor of Philosophy (PhD)

Background: Commonly used response scales in patient-reported outcome (PRO) measures include the visual analogue scale, 11-point numeric rating scale, 5-point numeric rating scale, 5-point verbal rating scale, and 5-point verbal-numeric rating scale. Although prior studies have explored the interpretation of response scale labels and compared scores resulting from the response scale, many questions remain. Purpose: To identify sets of verbal descriptors interpreted with the least variation and to explore whether the response scales provide interval level data and whether the scales are interchangeable. Methods: Subject recruitment and screening was through an online drug-drug interaction service (MediGuard.org). Via an online survey platform, subjects used a scale (0 = lowest possible and 10=highest possible) to assign interpretation scores to verbal descriptors. Repeated measures analysis of variance informed the test interval data between scores. Subjects also completed repeated administrations of four symptom-specific item stems with different response scales. Ordinal regression informed the analysis of scores assigned to verbal descriptors, comparison of probabilities of responding in given categories across scales, and prediction of response category on one scale conditional on observed response on another scale. Cut-points informed tests for interval level data. Results: The sample (n=350) comprised 223 females and 127 males with a mean (SD) age of 56.9 (12.1) years. Number of health conditions per subject ranged from 1 to 12 (median = 5). Age, sex, level of education, and number of health conditions were associated with the interpretation of verbal descriptors. Scores assigned to "poor," "fair," "good," "very good," "excellent," "somewhat," "sometimes," and "quite a bit," had the largest variation. The probability of responding in the same categories on the different response scales was significantly different across scales before and after collapsing categories. No scale yielded interval level data. The 11-NRS data tended more towards interval level than the data from other scales. Conclusions: Using different response scales with verbal descriptors in non-randomized studies may introduce bias. Differential item functioning and subgroup analyses should be investigated in the development and use of these response scales. The scales are not interchangeable. Compared with other scales the 11-NRS produced data approaching interval level. Collapsing categories entails significant probabilities of misclassification.

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.

Severe perineal trauma with injury to the anal sphincter at childbirth can have a profound effect on the physical and psychological wellbeing of women. This thesis describes literature examining resulting outcomes including effects on body image. It describes patient-based outcome measures used to capture this information, and evaluation of their psychometric properties. Body Image can be defined as an individual's perceptions and feelings about their own body. There is a growing interest in how this concept can influence quality of life and psychosocial dysfunction in medical disorders. This thesis aimed to examine relationships between severity of perineal trauma, general and genital specific body image and potentially influences such as symptoms of pelvic floor dysfunction. No patient-reported outcome measure validated for use in women after anal sphincter injury exists and this thesis also aimed to psychometrically evaluate an existing electronic questionnaire, ePAQ (electronic personal assessment questionnaire), for this application. In the thesis, a retrospective review of body image and physical outcomes attending a perineal clinic shows over half of women report perceived changes in body image after anal sphincter injury, with negative effects on self-esteem. A prospective observational cohort study explored genital and general body image in primiparous women grouped according to degree of perineal trauma or caesarean delivery. Women completed the Female Genital Self Image Score, the modified Body Image Score, ePAQ and the Edinburgh Postnatal Depression Scale a mean of 15.5 weeks (standard deviation 1.6) after delivery. There were significant differences in genital body image scores between the groups, but not in general body image, with regression analysis showing the greatest influence on genital body image to be the anatomical extent of the trauma. Embedded into this study was the evaluation of reliability (internal consistency and test-retest) and validity (face, content and construct) of ePAQ in the group of women with anal sphincter tears. This thesis presents the first research to quantify issues surrounding severe perineal trauma and body image and demonstrates that more severe trauma leads to a poorer genital body image. It also reports psychometric evaluation of ePAQ in women after anal sphincter injury providing the first single instrument with validity and reliability for use in this context.

Introduction The use of Patient Reported Outcome Measures (PROMs) to measure the effects of care is being advocated increasingly in clinical settings. Current patient data capture involves completion of paper questionnaires which is costly and environmentally perplexing. New innovations are required to balance the challenges of introducing data capture directly from patients while considering budgets, access to Information Technology, and the capability to use technological devices. Methods Two qualitative studies were undertaken to identify the views of patients and clinicians concerning electronic PROM data capture in osteopathic practice. One qualitative study involved patient interviews to identify their views on a selection of specific PROMs. Clinician focus groups and interviews (osteopaths, chiropractors, and physiotherapists) were undertaken concerning their views and experiences of using PROMs. Scoping of PROMs in musculoskeletal practice was undertaken followed by a systematic review of one identified PROM. The review and qualitative work informed the development of content for a mobile and web app for capturing PROM data. The app was piloted to evaluate feasibility, and the clinimetric performance of the included PROMs. Feedback from the pilot informed revisions to the app prior to implementation into osteopathic practice. Results Clinicians (n=46) identified a range of barriers and facilitators to PROM use. Patients (n=22) while generally more enthusiastic than clinicians welcomed the opportunity to provide feedback and although undaunted by the use of technology highlighted the need for assurances concerning confidentiality of data, and limits on data sharing. The systematic review identified good measurement properties for the Bournemouth (BQ). Piloting of the app involved 257 participants contributing 404 data returns: it performed well requiring minimal revision prior to implementation. Conclusions The app performed well demonstrating great potential for further development to collect outcome data in a musculoskeletal clinical setting.

Efficient allocation of public resources requires identification, measurement and quantification of costs and benefits of alternative programs. Patient reported outcomes (PROs) are routinely incorporated into economic evaluations of health technologies, but patient experience is often overlooked. This thesis aims to develop a descriptive system for patient experience that can be valued and used to inform economic evaluation. The generation and selection of items is key in the development of any PRO measure. The thesis provides a contemporary overview of recommended methods and those actually used by instrument developers. Frequently a staged approach is used to establish dimensions first, using exploratory factor analysis, followed by item selection using item response theory (IRT), Rasch or structural equation modelling (SEM). I demonstrate the use of different methods for item selection and its underlying mechanics, followed by comparison of the methods. An existing patient dataset, the Inpatient survey (2014) that collected information on nearly 70 aspects of healthcare delivery from NHS users was used. Logistic regression analyses were applied with respondents' rating of overall patient experience specified as dependent variable. Advanced statistical analyses focussed mostly on patients who had an operation or procedure. Latent construct or dimensions were derived and measurement model was confirmed using confirmatory factor analysis. IRT and factor analysis were employed in each one-factor model for item selection. Regression analyses identified many significant variables but most overlapped conceptually. An 11 and 8 factor model for patients with A&E and planned admissions respectively was determined. A generalised partial credit model and a factor analysis model identified different items to include in each dimension. Broadly the items identified by different methods related to respect, comfort and clear communication to patients. This thesis presents descriptive systems for patient experience that is amenable to valuation. It also demonstrates that different patient experience instruments are generated based on patient population used and item selection technique adopted.

Velofarynxinsufficiens (VPI) innebär en otillräcklig förmåga att stänga passagen mellan mun- och näshåla. En ofullständig slutning får konsekvenser framför allt för talet, då luft passerar genom näsan även vid orala språkljud och leder till en avvikande talklang och artikulation. Dessa avvikelser kan vara mer eller mindre framträdande i talet och innebära allt ifrån en lätt förvrängning av talklangen till att talet blir oförståeligt för omgivningen, vilket får allvarliga konsekvenser för möjligheten att kommunicera verbalt.   VPI kan behandlas på flera sätt, dels protetiskt, dels med kirurgi. Deltagarna i denna studie har alla genomgått operation med uppåtbaserad farynxlambå, som är en väldokumenterad och effektiv metod för att behandla VPI. En vanligt förekommande biverkning till operationen är luftvägshinder, exempelvis nästäppa, snarkning och sömnapné.    Syftet med studien var att undersöka deltagarnas egen uppfattning om operationsresultatet gällande tal och biverkningar, med hjälp av en enkät för självskattning. 61 patienter opererade med uppåtbaserad svalglambå under perioden 2000-2011 vid Akademiska Sjukhuset i Uppsala deltog i studien. Deltagarna delades in i tre undergrupper utifrån etiologi: deltagare med spalt (n  =  35), deltagare med spalt och syndrom (n  =  13), samt deltagare utan spalt (n  =  13).   Resultat: 55 av 61 deltagare (90  %) ansåg att operationen förbättrade deras tal. 49 av 61 deltagare (80  %) skulle dessutom rekommendera operationen till någon annan med samma besvär. 42 av 61 deltagare (68,8  %) uppgav att de är nöjda med sitt tal. Kvarstående biverkningar som rapporterades var nästäppa, snarkning, dagtrötthet och muntorrhet. Deltagarna upplevde dock dessa biverkningar i liten grad. Ingen tydlig skillnad sågs mellan de olika patientgrupperna. / Velopharyngeal insufficiency (VPI) is the inability to completely close the velopharyngeal port. Velopharyngeal closure is an important part of speech. VPI leads to a leakage of air into the nasal cavity during speech, which can cause hypernasal resonance and misarticulations. The effect of VPI on speech differs depending on the nature of the insufficiency. It can affect speech intelligibility severely.   VPI can be treated prosthetically or surgically. The patients in this study have all undergone pharyngeal flap surgery; a well established surgical method with documented effect in correcting VPI and reducing hypernasality in speech. Pharyngeal flap surgery can have negative consequences, such as airway obstruction, sleep apnea and snoring.   The aim of this study was to investigate the patients experiences of speech, complications and side-effects after pharyngeal flap surgery, through self-reports. 61 patients who underwent superior pharyngeal flap surgery during the period 2000 to 2011 at Uppsala University Hospital participated in the study. They were divided into three sub-groups: patients with cleft (n  =  35), patients with cleft and syndrome (n  =  13), patients without cleft (n  =  13).   Result: 55 of 61 participants (90 %) were of the opinion that the pharyngeal flap surgery had improved their speech. 49 of 61 participants (80 %) said they would recommend someone else with the same problem to undergo the operation. 42 of 61 participants (68,8 %) were content with their speech. Reported residual side effects, though experienced in low degree, were nasal congestion, snoring, weariness during daytime and dry mouth. No evident difference was seen between the sub-groups.