Background: The International Classification of Function, Disability and Health (ICF) describes health using 1424 categories from 4 components: body functions (BF), body structures (BS), activities and participation (AP) and contextual factors (environmental (EF) and personal (PF)). In this study the ICF was used to describe and compare aspects of ANCA-Associated Vasculitis (AAV) measured in clinical trials and those important to clinicians and patients. Methods: Individual interviews and focus groups were used to capture the perspective of AAV patients. Clinicians’ perspective was obtained with an email-based questionnaire. Outcomes used in AAV randomized trials were extracted from results of a systematic review of literature. Identified concepts were mapped to the ICF according to previously published ICF linking rules, and the resulting lists of relevant AAV outcomes were compared descriptively. Results: Twelve individual interviews and 2 focus groups represented the patient perspective while responses from 27 clinicians yielded the clinicians’ perspective. Systematic literature review identified 67 clinical trials and 28 abstracts from which measured outcomes were extracted. All three perspectives demonstrated detailed coverage of ICF components BF and BS. In the component AP patients and clinicians identified similar ICF categories, a number of which were under-sampled by AAV trials. Contextual factors appear to be significantly more relevant to patients than clinicians and researchers. Conclusion: Patients and clinicians have different views of the relevance of various AAV outcomes, and these views differ from what is measured in clinical trials of AAV. This highlights the need for a broad and standardized approach to developing and selecting outcomes for complex medical conditions such as AAV.

Objective: To explore quality of life in patients with multiple sclerosis. Concept Analysis: A concept analysis of quality of life in multiple sclerosis was conducted using Rodgers’ evolutionary concept analysis method. Eighty-three studies were reviewed. Study Proposal for Secondary Analysis: The proposal was for a secondary analysis using a quantitative, longitudinal, repeated measures design to determine if stem cell transplant has an impact on the quality of life of multiple sclerosis patients with aggressive disease. Summary of Findings: A concept analysis provided valuable insight into the use and understanding of the concept of quality of life in the multiple sclerosis literature. The subjective and multidimensional attributes of quality of life in multiple sclerosis were similar to findings in previous concept analyses of quality of life in general and in other diseases. The other attributes of the concept being measureable, modifiable and predictable revealed the uniqueness of quality of life in multiple sclerosis and provided a foundation for the development of future research. The results of the secondary analysis will provide new knowledge of a novel treatment for multiple sclerosis and its impact on quality of life. This advancement of knowledge in nursing and across health care disciplines will aid in the delivery of collaborative and comprehensive patient-centred care to ultimately improve the lives of multiple sclerosis patients.

Lateral ankle sprains are the most common musculoskeletal injury among the general population and U.S. military personnel. Despite the common perception of being a minor injury, at least 1 out of 3 individuals with a previous ankle sprain will develop chronic ankle instability (CAI). This clinical phenomenon creates a significant barrier for patients to return to their prior level of physical function. Specifically, CAI is associated with reductions in physical activity level, leading to decreases in lower health-related quality of life and increase risk of developing of post-traumatic ankle osteoarthritis. Current evidence has largely focused on characterizing the mechanical and sensorimotor insufficiencies associated with CAI in adolescent and young-adult populations, with little attention on middle- and older-aged adults. This restricts our understanding of how these insufficiencies associated with CAI that develop in early adulthood progress over time and contribute to other chronic diseases such as post-traumatic osteoarthritis. Therefore, the overall objective of this study was to compare self-reported and physical function between three age groups: 1) young, 2) middle-aged, and 3) older-aged adults with and without CAI. We hypothesized participants with CAI would have age-related changes in self-reported and physical function compared to non-injured individuals across the lifespan. The objective of this dissertation was to compare regional and global health- related quality of life (HRQoL), static and dynamic balance, spinal reflex excitability of the soleus muscle, open- and closed-kinetic chain dorsiflexion range of motion and spatiotemporal gait parameters between those with and without CAI across the lifespan. Her callIt was hypothesized that all self-reported and physical characteristics would be decrease with age, but significantly more in those with CAI compare to non-injured individuals. Results from the first study demonstrated participants with CAI had worse regional HRQoL compared to healthy-controls as evidenced by the lower Foot and Ankle Disability Index scores. Likewise, participants with CAI reported having worse overall physical function and pain interference during activity compared to healthy-controls. There was no significant interaction for Injury (CAI and healthy-control) and Age group (young, middle, and old) for any dependent variable. In the second, it was determined that static and dynamic balance, spinal reflex excitability, ankle (dorsiflexion and plantarflexion) and hip extension torque were all lower in the older-aged participants compared to the younger-aged adults. In addition, it was determined that participants with CAI had decreased dorsiflexion range of motion, ankle (dorsiflexion and plantar flexion) and hip extension peak isometric torque compared to the healthy-control group. However, no significant interaction was found for Injury (CAI & healthy-control) and Age (young, middle, old) for any dependent variable. In the third study, there were no differences in spatiotemporal gait parameters between groups (CAI vs. healthy-controls) or age categories. It can be concluded from this dissertation that regardless of the age, individuals with CAI have worse region-specific HRQoL, lower overall physical function, greater pain interference, limited dorsiflexion range of motion, and decreased ankle and hip peak isometric torque compared to healthy-controls. Several age-related observations were found including decreased static and dynamic balance, ankle and hip strength, and spinal reflex excitability. Though no relationship was found between CAI and age, several interactions were found to be trending towards significance. Therefore, future work is needed to better understand the consequences of CAI on middle- and older-aged adults.

Throughout the last decades, evolving treatment-opportunities provide a better chance of cure and thereby a higher percentage of patients is being treated for chronic disease (Robert Koch Institut, 2016). As treatment-toxicity, side effects and disease-derived symptoms remain high, it has become crucial to assesses parameters reflecting patients’ perspective, instead of solely focusing on illness-centered outcomes such as survival or treatment response. During the last decades, Patient-reported outcomes (PROs) are on the rise throughout research and cancer care as a key component to capture a patient’s perspective. This work illustrates the broad framework that PROs can be conducted in. We gathered experience and pioneered a systematic PRO-assessment in routine outpatient care, which continues to be updated. We identified a suitable PRO-based geriatric screening tool to avoid a time and resource consuming comprehensive geriatric assessment. Furthermore, we explored the beneficial effects of a PRO-based tailored intervention on HRQoL and provided effect-size estimations. Assessing PROs yields many benefits throughout the care pathway (Andreassen et al., 2006; Basch et al., 2016; Kofoed et al., 2012; Velikova et al., 2004; Yang et al., 2018) and was shown to be feasible in different entities and treatment setting (Bennett et al., 2016; M. K. Schuler et al., 2016; Strasser et al., 2016; Warrington et al., 2019). As a strikingly large discordance between patients’ and clinicians’ perception of symptoms exists (Atkinson et al., 2016), PROs can increase the accuracy of detection of adverse events and even predict survival (Efficace et al., 2021). Based on these advantages, the EMA and the FDA advocate the use of PROs as endpoints in cancer research (European Medicines Agency, 2016; U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research et al., 2006). Throughout previous years, methodological progress has been made resulting in elaborated measurement technics such as computerized adaptive testing being applied to PRO-instruments (Petersen et al., 2018, 2020). Clinical usability was increased with development of summary scores, cut-off values and emerging normative data (Giesinger et al., 2016, 2020). Interventions based on PROs are promising (Ishaque et al., 2019; Kotronoulas et al., 2014). Despite this ever increasing body of literature on PRO, a significant number of questions remain unanswered. Firstly, there was scarce knowledge about the benefits of a PRO-based intervention in sarcoma patients as there was limited PRO-data available in this entity. Sarcomas are rare diseases, still accounting for slightly less than 1% of all malignant neoplasia worldwide. The age adjusted incidence ranged from 7.4 per 100.000 men and 6.6 per women in Germany (Ressing et al., 2018). As sarcoma-treatment is improving, side-effects and toxicity remain to occur frequently (Gough et al., 2011; McDonough et al., 2019; Reichardt et al., 2012; Storey et al., 2019; Winnette et al., 2017). Until recently, there was quite limited knowledge about the patient-reported burden in terms of HRQoL, symptoms and psychological distress in patients with STS (Tang et al., 2012). PRO-based interventions yield beneficial effects in different cancer entities. Nevertheless, the effects of a PRO-based intervention in STS-patients was scarcely explored. The YonLife-Study (Publication B, Hentschel et al., 2020) contributes new evidence that a PRO-based intervention yields beneficial effects on HRQoL and suggests a positive, yet non-significant effect on survival. Concerning symptoms, the results of the YonLife-intervention remain far from being encouraging. As effects sizes are available now, RCTs which are powered to a confirmatory purpose could be performed in this population. Secondly, the importance of PROs are emphasized by authorities such as EMA or FDA that emphasize the need to incorporate PRO in scientific studies. Yet during the early 2010s, the actual incorporation of PROs in clinical routine was limited in Germany. We therefore designed and established a routine assessment of PROs (Publication C, (Trautmann, Hentschel et al., 2016) incorporating the automatized calculation, comparison with normative or threshold data and implemented it to our hospital information system. As until recently, feasibility data such for such an intervention is scarce, we collect measures of adherence, required time and barriers reported by staff. For the clinical benefit, the established PRO-assessment is being developed further and expanded to other departments and clinics of our institution. Thirdly, as numbers of geriatric cancer patients rise (Le Saux et al., 2019), older patients continue to be underrepresented in clinical trials (Singh et al., 2017), therefore an immense lack of knowledge on treatment-toxicities and side effects in this population exists. Treatment needs to be adapted to older patients frailty-level, which can be conducted applying a time- and resource consuming Comprehensive Geriatric Assessment (Le Saux et al., 2019). Still, there is no consensus on which domains to include and how to measure them (Hamaker, Jonker, et al., 2012). A geriatric screening can alleviate burden of conducting a whole CGA. Several screening instruments exists, yet there is inconsistent data (Kotzerke et al., 2019; Mohile et al., 2018; Soubeyran et al., 2014) which tool yields the best predictive performance. Our project aimed to compare three of the available screening tools (VES-13, G8, POT/CARG). Being far from having a perfect predictive performance, the POT/CARG occurs to be the screening instrument with a high sensitivity and sufficient negative predictive value. Furthermore, our research supports the increasing evidence that ultra-short-screeners such as ECOG state or age bear only insufficient predictive performance.:1. Introduction 1.1 What are Patient-reported outcomes (PROs)? 1.2 Assessment of PROs 1.2.1 Feasible in clinical routine, improving relevant outcomes 1.2.2 Improving diagnostic accuracy 1.2.3 Supporting drug development 1.2.4 Evolving measurement techniques and standardization 1.3 PRO-based feedback interventions 1.4 PRO-based geriatric screening 1.5 Research needs 1.5.1 Identifying a suitable geriatric screener 1.5.2 Limited PRO-data on Soft-Tissue Sarcoma (STS) patients 1.5.3 Feasibility-research in routine care 1.6 study aims 2. Methods 2.1 Design and Sample of Publication A 2.2 Design and Sample of Publication B 2.3 Design and Sample of Publication C 2.4 Instruments 2.5 Non-PRO-Outcomes 2.5.1 Predictive performance 2.5.2 Survival analysis 2.5.3 Feasibility analysis 2.6 Statistical Analysis 2.6.1 Sample Size Estimation 2.6.2 Non-participation and drop-out analysis 2.6.3 Regression Analyses 2.6.4 Statistical software 2.6.5 Statistical analysis plans 3. Outline of Publications Publication A Publication B Publication C 4. Discussion 4.1 Main findings, integration in existing research and research implications 4.1.1 Geriatric screening tools 4.1.2 PROs in soft tissue sarcoma (STS) 4.1.3 Implementation of PROs into routine care 4.2 Strengths and Limitations 4.2.1 Strengths 4.2.2 Limitations 5. Conclusions 6. Summary 7. References 8. Appendix 8.1 Darstellung des eigenen Beitrags 8.1.1 Darstellung des eigenen Beitrags zur Publikation A 8.1.2 Darstellung des eigenen Beitrags zur Publikation B 8.1.3 Darstellung des eigenen Beitrags zur Publikation C 8.2 Erklärung über die eigenständige Abfassung der Arbeit 8.3 Curriculum Vitae 8.4 Publikationsverzeichnis 8.5 Danksagung

In deciding whether to use a particular treatment for conditions such as depression, arthritis, or heart disease, clinicians and patients must balance the benefits against the side effects and burden. To make this trade-off, they must understand the likely degree of benefit in patients’ symptoms and perceived wellbeing, best undertaken using patient-reported outcomes (PROs). PROs are measures of any aspect of a patients’ health status that are obtained from direct patient inquiry without interpretation by a clinician or anyone else. PRO measures (PROMs) are increasingly used in clinical trials and systematic reviews to evaluate health care interventions, and information obtained from PROMs can guide clinical decisions and inform shared-decision making. The use of PROMs, however, involves challenges, the most important of which is deciding if a particular treatment effect is trivial, small but important, moderate or large. One way to make this judgment is to consider the minimal important difference (MID), the smallest change in a PROM score that is important enough that patients would consider a change in treatment to achieve that benefit. The number of published studies providing anchor-based MIDs for PROMs has grown rapidly over the last three decades, and researchers have proposed several anchor-based methods to derive MID estimates, each with its own merits and limitations. This thesis begins with the development of a framework to determine the extent to which the design and conduct of studies measuring anchor-based MIDs are likely to have protected against misleading estimates. Subsequently, this thesis presents a comprehensive inventory of empirically estimated anchor-based MIDs and their associated credibility for all PROMs published in the medical literature. Further, this thesis highlights critical issues that key stakeholders should consider, and demonstrates how the use of credible MIDs may inform the development of a clinical practice guideline in which PROs were identified as critically important. Finally, this thesis concludes with insights to improve the methodological quality and transparency for researchers in the PRO and MID field. / Thesis / Doctor of Philosophy (PhD)

BACKGROUND:Patients receiving complementary and alternative medicine (CAM) therapies often report shifts in well-being that go beyond resolution of the original presenting symptoms. We undertook a research program to develop and evaluate a patient-centered outcome measure to assess the multidimensional impacts of CAM therapies, utilizing a novel mixed methods approach that relied upon techniques from the fields of anthropology and psychometrics. This tool would have broad applicability, both for CAM practitioners to measure shifts in patients' states following treatments, and conventional clinical trial researchers needing validated outcome measures. The US Food and Drug Administration has highlighted the importance of valid and reliable measurement of patient-reported outcomes in the evaluation of conventional medical products. Here we describe Phase I of our research program, the iterative process of content identification, item development and refinement, and response format selection. Cognitive interviews and psychometric evaluation are reported separately.METHODS:From a database of patient interviews (n = 177) from six diverse CAM studies, 150 interviews were identified for secondary analysis in which individuals spontaneously discussed unexpected changes associated with CAM. Using ATLAS.ti, we identified common themes and language to inform questionnaire item content and wording. Respondents' language was often richly textured, but item development required a stripping down of language to extract essential meaning and minimize potential comprehension barriers across populations. Through an evocative card sort interview process, we identified those items most widely applicable and covering standard psychometric domains. We developed, pilot-tested, and refined the format, yielding a questionnaire for cognitive interviews and psychometric evaluation.RESULTS:The resulting questionnaire contained 18 items, in visual analog scale format, in which each line was anchored by the positive and negative extremes relevant to the experiential domain. Because of frequent informant allusions to response set shifts from before to after CAM therapies, we chose a retrospective pretest format. Items cover physical, emotional, cognitive, social, spiritual, and whole person domains.CONCLUSIONS:This paper reports the success of a novel approach to the development of outcome instruments, in which items are extracted from patients' words instead of being distilled from pre-existing theory. The resulting instrument, focused on measuring shifts in patients' perceptions of health and well-being along pre-specified axes, is undergoing continued testing, and is available for use by cooperating investigators.

The effectiveness of treatments for degenerative spine conditions, where the primary symptom is back pain, is typically determined using patient-reported quality of life (QoL) measures. However, patients may adjust their internal standards when scoring QoL based on factors other than their health. This response shift phenomenon could confound the interpretation of study data and impact effectiveness conclusions. In the current study, response shift was examined using structural equation modeling (SEM) and previously collected clinical trial data comparing 2 minimally invasive medical devices in lumbar spinal stenosis patients through 1 year postintervention. In subject QoL results, reprioritization shift between 3 months and 12 months that could confound standard analysis was identified. Treatment group did not influence response shift identified at 12 months. SEM provided an effective and practical tool for clinical investigators to assess response shift in available clinical study data. As response shift could lead to invalid conclusions when QoL measures are analyzed, clinical investigators should include response shift assessment in the design of clinical trials. This research into how response shift phenomenon can impact clinical trial results improves the ability of clinical investigators to interpret clinical trial data, potentially preventing erroneous conclusions. This research may also assist researchers and government regulators in the identification and reimbursement of beneficial, cost-effective medical treatments for patients worldwide. For clinical research designers, this study demonstrates a practical application of response shift assessment.

Background: Urinary incontinence (UI) and urgency are common conditions and can have a profound influence on many aspects of life. Approximately one in four women has UI and one in ten has daily symptoms. Knowledge is lacking, however, on the impact of UI and urgency on the lives of affected women and their partners and on the situation of women with urinary leakage one year postoperatively. Aims: To study the consequences of female UI and urgency for patients and their partners on quality of life (QoL), the partner relationship, and their sexual lives. Also to evaluate the success rates of three operation methods: tension-free vaginal tape (TVT), tension-free vaginal tape-obturator (TVT-O), and transobturator tape (TOT) for stress urinary incontinence (SUI), with a particular focus on women who still have urinary leakage one year after surgery. Methods: Women seeking healthcare for UI and/or urgency and their partners were invited to answer questionnaires. The women completed disease-specific questionnaires and both the women (n = 206) and their partners (n = 109) answered questions about their psychosocial situation, partner relationship, and sexual life. Patient-reported outcomes one year after surgery with TVT, TVT-O, or TOT (n = 3334) were derived from the Swedish National Quality Register for Gynaecological Surgery. Results: Most of the women reported that their urinary problems negatively affected their physical activities, and almost half reported negative consequences for their social life. Women aged 25–49 years were less satisfied with their psychological health, sexual life, and leisure than women aged 50–74 years. One third of both the women and their partners (all the partners were men) experienced a negative impact on their relationship, and sexual life was negatively affected in almost half of the women and one in five of their men. Coital incontinence was reported in one third of the women. Most of their men did not consider this a problem, but the majority of the affected women did. Satisfaction with outcome of the operation did not differ between TVT, TVT-O, and TOT, but TVT showed a higher success rate for SUI than TOT did. Higher age, higher body mass index, a diagnosis of mixed urinary incontinence, and a history of urinary leakage in combination with urgency each constitute a risk for a lower operation success rate. After one year, 29% of the women still had some form of UI, but half of these were satisfied with the outcome and most reported fewer negative impacts on family, social, working, and sexual life than before the operation. Conclusions: Female UI and/or urgency impaired QoL, particularly in young women, and had negative effects on partner relationships and on some partners’ lives. Sexual life was also affected, more often in women with UI and/or urgency than in their partners. At one-year follow-up after surgery, about one third of the women still had some form of UI, but the negative impact on their lives was reduced. A challenge for health care professionals is to initiate a dialogue with women with urinary symptoms about sexual function and what surgery can realistically be expected to accomplish.

The aim of this study was to provide a short German self-report measurement, assessing subjective CRCI for a broad variety of cancer survivors. For this purpose, the AFI (Attentional Function Index) was translated into German and psychometric properties have been presented in the following publication among a sample of 1312 haematological cancer survivors. In the resulting article the factorial structure of the German translation of the AFI, the internal consistency among the total score and each subscale, construct validity and the associations of the AFI sum score with medical and socio-demographic variables are provided. Comparisons to the English version are additionally drawn. With the validated AFI, researchers and clinicians in German-speaking countries may now have new tool to assess, and thus improve an important component of QoL in cancer survivors [38].

Objective: To explore the measurement of subsyndromal mood symptoms in relation to studies of maintenance therapy for bipolar disorder. Methods: Literature review of the Medline database using the following selection criteria: (1) ‘bipolar disorder’ plus ‘inter-episode or interepisode or subsyndromal or subclinical or residual or subthreshold’ and (2) ‘bipolar disorder’ plus ‘maintenance or prophylaxis or longitudinal’. Studies of children or adolescents and non-English-language reports were excluded. Results: Of the studies published between 1987 and October 2007, 77 articles about subsyndromal mood symptoms and 257 studies of maintenance therapy agents were found. Only 11 of the 257 studies of maintenance therapy agents discussed subsyndromal mood symptoms. Of the 77 articles, two thirds were published after 2000. Inconsistent definitions of subsyndromal mood symptoms and different evaluation tools and methodologies were used in the studies. Conclusions: There is a need to standardize definitions and validate measuring approaches for subsyndromal mood symptoms. However, when measured in both naturalistic studies and clinical trials, subsyndromal mood symptoms were frequently reported by patients receiving maintenance therapy and were associated with poor functioning. As with other chronic illnesses, knowledge of the patient’s perspective of daily morbidity is important for improving the clinical outcome. Studies of maintenance therapy for bipolar disorder, regardless of the approach, should measure subsyndromal mood symptoms as an additional outcome. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.