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)

Background: Standardized outcome measures used in assessment of chronic disease need to be relevant to the client if interventions based on the results are to be meaningful. The Modified Health Assessment Questionnaire (MHAQ) (Pincus et al., 1983) is an eight-item questionnaire used commonly with individuals with Rheumatoid Arthritis (RA) to assess self-reported function. This scale has been translated and validated in multiple languages and cultures but has never been evaluated for its relevance with a Canadian Indigenous population despite its frequent application in clinical and health research settings. Purpose: The primary objective of the following study was to determine whether or not the MHAQ is an appropriate measurement tool to adequately document the lived experiences of activity and participation in First Nations individuals diagnosed with RA. Methodology: A mixed methods sequential explanatory approach was utilized. The quantitative component consisted of secondary analysis of an existing clinical database developed at the University of Manitoba Health Sciences Arthritis Centre (UMHSAC). MHAQ scores and other indicators of disease activity of First Nations (n=252) and Caucasian (n=633) individuals with RA were examined for significant differences. The results informed a qualitative phase using interpretive description methodology whereby semi-structured interviews were held with 25 First Nations individuals with RA. Results: A significant relationship was observed between ethnicity and MHAQ score (p<0.001) where the First Nations cohort demonstrated significantly higher scores in pain and MHAQ scores (p<0.001), as well as physician global assessment and morning stiffness (p<0.05). Pain was the single greatest predictor of MHAQ score (p<0.001). In contrast, a convergence coding matrix comparing MHAQ scores to first-hand narratives found only 65% agreement in responses. The thematic analysis of the qualitative component resulted in three key themes: Ka-wachi-wa-pinaywin (“Coldness in the bones”), Adaptive Resilience, and Family Relations. Conclusion: Concurrent validity of the MHAQ in a First Nations population was supported through statistical analyses but convergent validity was not supported by subsequent qualitative and mixed methods approaches. The assessment of disability requires an integrated approach that takes into consideration an individual’s personal context. Both barriers and facilitators in the environment, as well as personal factors, must be addressed. / February 2016

In our society, American citizens expect public policies to result in programs that address social problems in ways that are both efficient and effective. In order to judge if these two values are being achieved, public programs are often scrutinized through program monitoring and evaluation. Evaluation of public programs often is a responsibility delegated to local-level managers. The resulting discretion has to be balanced with the need for accountability that is also inherent in public programs. Evaluation is often difficult because outcomes are not readily measurable due to the complexity of the problems faced in the public setting. The Upward Bound program provides an example of this. Upward Bound provides services to students from low-income families and those in which neither parent holds a bachelor’s degree in order to increase the rate at which participants complete secondary education and enroll in and graduate from postsecondary institutions. Upward Bound is implemented and evaluated based upon specifications decided upon at the local level. This discretion granted to local level managers has resulted in wide variations in the way the program is being evaluated. This presents a problem for evaluation and has resulted in inconclusive results as to the success of the program. One way to correct this problem is to try and gain a clear understanding of how the evaluation outcome measures are being chosen for Upward Bound. My study accomplished this task.

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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)

Introduction: Digital ulcers (DUs) are responsible for much of the pain and disability associated with systemic sclerosis (SSc), and are a biomarker of internal organ involvement and poor prognosis. DUs are often used as the primary end-point in SSc clinical trials, although the reliability of rheumatologists in grading DUs is poor to moderate at best. Fingertip DUs are believed to be ischaemic in aetiology, whereas, extensor DUs are thought to occur due to mechanical factors and recurrent microtrauma. Treatments for DUs are often poorly tolerated due to systemic vasodilation. The overarching aim was to investigate the definition and objective measurement of SSc-related DUs, their pathophysiology, and a new light treatment. Method: Five studies were undertaken. (1) A web-based study in which photographs of digital lesions were graded, all either with or without clinical context. (2) A pilot study to assess the feasibility and tolerability of high-frequency ultrasound (HFUS) imaging to measure DUs. (3) A retrospective study examining whether thermographic abnormalities are associated with DUs. (4) A double-blind, randomised, crossover, controlled study of glyceryl trinitrate (GTN) to explore the pathophysiology of DUs in SSc. (5). A feasibility study of a novel light (red, infrared and blue) device to treat SSc-related DUs. Results: (1) 51 rheumatologists graded ≥ 4500 images. The clinical context (without vs with, weighted kappa statistic) did not significantly improve the intra- (0.32,0.36) or inter-rater (0.64,0.71) reliability. (2) HFUS was performed on 15 DUs and was well tolerated and feasible in the majority. DU measurement was possible in most (n=13) DUs, the mean DU depth and width were 0.99mm and 5.74mm, respectively. (3) Patients (n=138) with abnormal (compared to normal) thermography were more likely (adjusted odds ratio = 2.84) to develop future DUs, including multiple episodes. (4) 16 DUs were studied; the microvessels of the DU centre were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. There was less of a clear signal in the DU periphery. (5) Light treatment was safe, feasible and well tolerated (46 light treatments administered in 8 patients, one studied on three separate occasions). There was a significant improvement (change in visual analogue score per visit) in DUs as assessed by both patient (-7.1, P = < 0.001) and clinician opinion (-5.2, P = < 0.001). DU perfusion (measured by LDI) significantly increased post-treatment. Conclusion: The reliability of DU grading did not improve with clinical context. HFUS was feasible and well tolerated, and measurement was possible in most DUs. Our data suggests that many DUs might have an ischaemic drive, including extensor DUs. A novel light treatment was safe, feasible and well tolerated, with a tentative suggestion of treatment efficacy.

BACKGROUND: In a 2006 WHO report, diarrheal diseases ranked second among conditions afflicting children. Pediatric acute diarrhea, although most often the result of a gastrointestinal infection, can also occur as a result of antibiotic exposure. This is often referred to as antibiotic-associated diarrhea (AAD). Previous research suggests that probiotics may be effective in the treatment or prevention of various types of PAD. METHODS: The first study involved a systematic review and meta-analysis of RCTs involving probiotics as an adjunct to antibiotics for preventing AAD in children. The second study was a systematic review of definitions and primary outcome measures employed in RCTs of PAD. The third study used a modified Delphi consensus procedure to develop a new instrument for evaluating the severity of PAD. The study involved steering committee discussions (phase 1) and two electronic surveys (phase 2 and 3) of leading experts in measurement and clinical gastroenterology. RESULTS: The per protocol meta-analysis of ten RCTs significantly favored probiotics to prevent the incidence of diarrhea (NNT = 10). However, this effect did not withstand ITT analysis and among included trials there was considerable inconsistency regarding definitions for the reviews primary outcome measure, the incidence of diarrhea. Study two identified 121 RCTs that reported 62 unique definitions of diarrhea, 64 unique definitions of diarrhea resolution and 62 unique primary outcome measures. Thirty-one trials used grading systems to support outcome evaluation. However, none of the trials (or their citations) reported evidence of their validation. In study three experts agreed on the inclusion of five attributes containing 13 items. Attributes proposed for the IPADDS include: Diarrhea Frequency and Duration, Vomiting Frequency and Duration, Fever, Restrictions in Normal Daily Activities and Dehydration. CONCLUSION: It is premature to draw a valid conclusion about the efficacy of probiotics for pediatric AAD. Definitions of diarrhea and primary outcome measures in RCTs of PAD are heterogeneous and lack evidence of validity. The third study represents content validity evidence for IPADDS. A numerical scoring system needs to be added and further empirical evidence of reliability and validity are required. / Experimental Medicine

Upper limb function is important for individuals with tetraplegia because upper limb function supports global function for these individuals. As a result, a great deal of time and effort has been devoted to the restoration of upper limb function. Appropriate outcome measures that can be used to characterize the neurological status of the upper limb have been one of the current barriers in substantiating the efficacy of interventions. Techniques and protocols to evaluate changes in upper limb neurological status have not been applied to the SCI population adequately. The objectives of this thesis were to develop a measure; which is called the Graded Redefined Assessment of Strength Sensibility and Prehension (GRASSP). Development of the scoring approach, testing for reliability and construct validity, and determining impairment and function relationships specific to the upper limb neurological were established. The GRASSP is a clinical measure of upper limb impairment which incorporates the construct of “sensorimotor upper limb function”; comprised of three domains which include five subtests. The GRASSP was designed to capture information on upper limb neurological impairment for individuals with tetraplegia. The GRASSP defines neurological status with numerical values, which represent the deficits in a predictive pattern, is reliable and valid as an assessment technique, and the scores can be used to determine relationships between impairment and functional capability of the upper limb. The GRASSP is recommended for use in the very early acute phases after injury to approximately one year post injury. Use of the GRASSP is recommended when a change in neurological status is being assessed.

Upper limb function is important for individuals with tetraplegia because upper limb function supports global function for these individuals. As a result, a great deal of time and effort has been devoted to the restoration of upper limb function. Appropriate outcome measures that can be used to characterize the neurological status of the upper limb have been one of the current barriers in substantiating the efficacy of interventions. Techniques and protocols to evaluate changes in upper limb neurological status have not been applied to the SCI population adequately. The objectives of this thesis were to develop a measure; which is called the Graded Redefined Assessment of Strength Sensibility and Prehension (GRASSP). Development of the scoring approach, testing for reliability and construct validity, and determining impairment and function relationships specific to the upper limb neurological were established. The GRASSP is a clinical measure of upper limb impairment which incorporates the construct of “sensorimotor upper limb function”; comprised of three domains which include five subtests. The GRASSP was designed to capture information on upper limb neurological impairment for individuals with tetraplegia. The GRASSP defines neurological status with numerical values, which represent the deficits in a predictive pattern, is reliable and valid as an assessment technique, and the scores can be used to determine relationships between impairment and functional capability of the upper limb. The GRASSP is recommended for use in the very early acute phases after injury to approximately one year post injury. Use of the GRASSP is recommended when a change in neurological status is being assessed.