Thesis

Patient Reported Outcome Measures in Otology and the development, validation and implementation of the Otology Questionnaire Amsterdam (OQUA) Jeroen T. Kraak

The research in this thesis was performed at the department of Otolaryngology and Head and Neck Surgery of the Amsterdam University Medical Center, location VUmc. Publication of this thesis was supported by Oticon Medical, DOS Medical and Schoonenberg HoorSupport Cover design: Marja Bergsma Layout: Douwe Oppewal Printing: Ipskamp Printing ISBN: 978-94-6473-864-3 Copyright © by Jeroen Kraak, Ouderkerk aan de Amstel, The Netherlands 2025. No parts of this thesis may be reproduced or transmitted in any form by any means, electronic or mechanical, including photocopying, recording or any information retrieval system, without permission in writing from the author VRIJE UNIVERSITEIT

VRIJE UNIVERSITEIT Patient Reported Outcome Measures in Otology and the Development, Validation, and Implementation of the Otology Questionnaire Amsterdam ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. J.J.G. Geurts, volgens besluit van de decaan van de Faculteit der Geneeskunde in het openbaar te verdedigen op dinsdag 7 oktober 2025 om 11.45 uur in de universiteit door Jeroen Timo Kraak geboren te Heemstede

promotoren: prof.dr. P. Merkus prof.dr. S.E. Kramer promotiecommissie: prof.dr. C.B. Terwee prof.dr. M.K.S. Hol prof.dr. R.R. van de Berg prof.dr.ir. J.C.M. Smits dr. R.J. Pauw

Table of Contents Part I: Patient Reported Outcome Measures in Otology Chapter 1 General Introduction 9 Chapter 2 Questionnaires in otology: a systematic mapping review 23 Syst Rev. 2021 Apr 20;10(1):119. Part II: The Otology Questionnaire Amsterdam Chapter 3 The Otology Questionnaire Amsterdam: a generic patient reported 47 outcome measure about the severity and impact of ear complaints. A cross-sectional study on the development of this questionnaire Clin Otolaryngol. 2018 Feb;43(1):240-248 Chapter 4 The Otology Questionnaire Amsterdam: a generic patient reported 63 outcome measure about the severity and impact of ear complaints. Validation, reliability and responsiveness Clin Otolaryngol. 2020 Jul;45(4):506-516. Chapter 5 Quality assessment of patient reported outcome measures for patients 87 with multiple ear complaints Clin Otolaryngol. 2024 Mar;49(2):235-242. Chapter 6 Ear complaints in the general population according to the Otology 107 Questionnaire Amsterdam (OQUA); the normative data. J Patient Rep Outcomes. Submitted Chapter 7 Barriers to and enablers of the use of the Otology Questionnaire 127 Amsterdam in clinical practice – A qualitative post-implementation study J Patient Rep Outcomes. 2024 Aug 14;8(1):96. Part III: General Discussion and Summary Chapter 8 General Discussion & Future Perspectives 157 Chapter 9 Summary 171 Chapter 10 Samenvatting 177 Appendix List of abbreviations 184 De Otology Questionnaire Amsterdam (Dutch version) 185 OQUA scoring manual 190 PhD portfolio 193 Dankwoord 196 Curriculum Vitae 199

PART I Patient Reported Outcome Measures in Otology

CHAPTER 1 General Introduction

10 Chapter 1 Dimensions of ear and hearing problems Ear and hearing problems are widespread across all age groups and regions globally. According to the World Health Organization (WHO), over 5% of the world’s population, or 430 million people, require rehabilitation to address their disabling hearing loss. This includes 34 million children. It is estimated that by 2050 over 700 million people will have disabling hearing loss.1 Similarly, conditions such as otitis media and dizziness are also well-known and commonly encountered. Worldwide Acute Otitis Media (AOM) affects about 11% of people yearly. That is about 325 to 710 million cases annually. Of those affected about 4.8% or 31 million develop chronic suppurative otitis media (CSOM). The total number of people with CSOM is estimated at 65–330 million people.2 Dizziness, including vertigo, affects about 15% to more than 20% of adults yearly in large populationbased studies. The overall incidence of dizziness, vertigo, and imbalance is 5–10%, and it reaches 40% in patients older than 40 years.3 These data indicate that the number of patients requiring attention from an ENT surgeon could be substantial. Fortunately, the actual number of patients who need to see an ENT specialist is much lower, because other healthcare professionals are also involved in the care for these patients. Examples are general practitioners, paediatricians, physiotherapists, audiologists, and hearing care professionals. Additionally, some of these ear conditions can be detected in early stage through nationwide screening programs of neonates to prevent more intensive treatment in the future. Moreover, ear and hearing problems typically extend beyond a single system; often involving multiple systems and accompanying other complaints. For example, patients with a hearing problem often experience concurrent dizziness or balance problems. Therefore, the health status of a patient with an ear or hearing issue should be considered comprehensively, beyond just the anatomical perspective. Finally, health is not just the absence of disease. The WHO formally defines health as ‘a state of complete physical, mental, and social well-being, not merely the absence of disease or infirmity’.1 There are many different diseases within the Ear, - Nose and Throat & Head and Neck Surgery domain that may underlie these complaints and potentially compromise the individuals’ health. Examples are cholesteatoma, hearing loss, chronic otitis media or Meniere’s disease and each of these conditions may have

11 General Introduction 1 different consequences for an individual’s mental wellbeing and quality of life. And so, we should not merely look at physical examination results and tests, laboratory tests and imaging techniques. Ear, - Nose- and Throat (ENT) surgeons should also listen very carefully to their patients. To facilitate this process, countless Patient Reported Outcomes Measures (PROMs) have been developed to evaluate treatment effects, monitor disease progression across various stages, evaluate symptom severity and measure health-related quality of life. Quality assessment To work towards a more value-based health care system in the Netherlands, constant analysis of registered parameters is needed. A value-based health care system is an approach to health care that focuses on providing the best possible health care for patients while controlling costs.4 In a value-based health care system, the focus is on the result that matter to the patient most. This approach emphasizes what is best for the patient, taking into consideration their individual needs, preferences, and health goals. By focusing on clinical-, patient-reported and process outcomes, value-based health care aims to reduce unnecessary or redundant investigations, surgeries, and hospital visits, thus controlling health care costs for both patients and the health care system. Providers (e.g. ENT surgeons) are held accountable for the quality of care they deliver, often through measurable metrics and outcomes. Next to clinical or process measures, patient reported outcome data comprise an important metric that can be used to evaluate value-based health care. Objective measures can also be used to assess outcome of treatment. For instance, adverse events or complications, recurrence of disease or hearing loss. All ENT surgeons in the Netherlands are expected to register their complications, incidents, and adverse effects of their treatment as part of quality control. Up until 2018, except for registration of active hearing-implants (e.g. cochlear implants), for patients with ear diseases, no quality indicators or audit was set up yet. In 2018 the Dutch ENT Society launched the Dutch Otologic Quality Registry (DOQ). The main goal of the DOQ is to gain insight into the quality of otological care in the Netherlands and further improve it through feedback to ENT specialists. Additionally, the DOQ serves purposes such as facilitating scientific research, providing patient information, and offering national steering information and accountability.

12 Chapter 1 There is a difference between success and quality when looking at ear surgery. Success is often presented as the number of patients in which the primary goal is achieved. Quality has a wider definition though and depends on the degree of achieving all goals with avoidance of side effects or complications. Success depends on the primary goal; it can be defined as absence of residual or recurrent disease in case of cholesteatoma or in case of conductive hearing loss it can be defined as hearing improvement. In case of chronic otorrhea (“running ear”) the quality / success is defined as reduction of otorrhea. These are all success measures and clinical objective outcomes. To assess quality of care it is necessary to redefine success and take not only objective measures into account but also incorporate the patient’s perspective. For example, improving a patient’s ability to hear can objectively be successful (audiometry), though it can be experienced as a failure subjectively at the same time, for example when other complaints like dizziness or tinnitus appear as a side effect of the treatment. Furthermore, improving a patient’s ability to hear will probably compensate for the small risks of complications of surgery. In general, risks of ear surgery include bleeding, infection, dizziness, (increase of) tinnitus, loss of- or diminished taste or severe hearing loss. But all these risks can be invalidating and require prolonged hospital admission, revision surgery or permanent disability. Although the complication rate of (often elective) ear surgery is low, careful decision making and setting the right indication for this patient is important. It is therefore necessary to have objective as well as subjective measures in the quality assessment of ear surgery. Data from PROMs can be very valuable and be added to the objective clinical data to assess quality of care. PROMs PROMs are increasingly being used for gathering patient data to support clinical decision making and to produce valuable data on the overall impact of an intervention or treatment. The SNOT-22 questionnaire is a good example of a PROM used in clinical decision making.5 The SNOT-22 is being used to evaluate nose-related complains with or without surgery. It is expected that the use of PROMs for clinical decision making will grow in the near future.6 However, at this moment, integration of PROMs into routine practice specifically in otology is limited. A PROM can be designed as a generic, domain-, complaint- or disease specific measurement. For example, a generic PROM might measure quality of life using tools like the EQ-5D, SF-367-9, or HUI-310. These generic PROMs allow comparisons across different diseases but may not be sensitive enough to detect changes within a single

13 General Introduction 1 condition or complaint. For instance, the widely used EQ-5D includes questions about mobility, self-care, daily activities, pain, and mood, but it does not include any questions related to hearing ability. To measure severity of complaints related to a particular condition, diseasespecific-questionnaires for specific ear diseases were developed. Examples are the chronic otitis media questionnaire (COMQ-12)11, the Eustachian Tube Dysfunction Questionnaire (ETDQ-7)12 or the Nijmegen Cochlear Implant Questionnaire13. These disease-specific PROMs are used to assess complaints, burden, or impact in patients with that certain disease. PROMs can also be complaint-specific questionnaires, like the Tinnitus Handicap Index (THI).14 A complaint specific PROM focusses on one complaint and not a spectrum of complaints in a disease. A complaint specific PROM is often more sensitive to changes and shorter, focusing only the one most prominent patient’s complaint related to that disease. When following a patient over time, with or without treatment the focus of complaints can shift. When a complaint is part of a disease, new complaints can Figure 1: applicability versus specificity of different PROM types in otology COMQ-12: Chronic Otitis Media Questionnaire; EDTQ-7: Eustachian Tube Dysfunction Questionnaire; ZCMEI-21: Zurich Chronic Middle Ear Inventory; COMOT-15: Chronic Otitis Media Outcome Test; PAN-QOL: Penn Acoustic Neuroma Quality-of-Life Scale; CES: Chronic Ear Survey; MD-POSI: Meniere’s Disease PatientOriented Severity Index; VSQOL Index; Vestibular Schwannoma Quality Of Life Index; DHI: Dizziness Handicap Inventory; THI: Tinnitus Handicap Inventory ; AIADH: Amsterdam Inventory for Auditory Disability and Handicap; OQUA: Otology Questionnaire Amsterdam; COQOL: Cambridge Otology Quality of Life; EOS-16: Ear Outcome Survey; PROMIS-10: Patient-Reported Outcomes Measurement Information System; HUI3: Health Utilities Index; SF-36: Short Form Health Survey; EQ-5D: the EuroQol 5 Dimm; WHO-5: The World Health Organisation - Five Well-Being Index.

14 Chapter 1 develop, for example after surgery or due to progression of the disease. When the patient has or develops multiple complaints, a complaint-specific questionnaire is inadequate or even falsely ‘proving’ success through a small focus. In general, it can be argued that the more specific a PROM is, the narrower its applicability (applicable to less patients, but more specific to a disease or complaint). And the less specific a PROM is, like the SF-36, the wider the applicability but the less specific the information on a certain disease or symptom (Figure 1). In otology, a domain-specific PROM could serve as a bridge between disease-specific and generic PROMs. It should cover ear-related complaints that are common across a wide range of ear diseases. If a variety of patients is seen in an ENT practice, using one ear-domain specific PROM could be a good solution, as using many different (disease- or complaint-specific) PROMs seems not very practical for the ENT surgeon. Practical steps for development of a PROM When starting this project there was no domain-specific questionnaire available, covering all ear complaints and the impact of these complaints. It was decided to develop the Otology Questionnaire Amsterdam (OQUA), and the developmental process is described in this thesis (chapter 3). A quality guideline, COSMIN, was used to develop the OQUA.15,16 According to the COSMIN guidelines, there are six to seven practical steps involved in the development of a questionnaire. Step one is to conduct a systematic literature review of the existing PROMs which is necessary to provide a comprehensive overview of the full spectrum of a particular symptom, disease or domain. This review can also result in the identification of an existing suitable PROM or inspire ideas for a new instrument. Using, translating, or adapting an existing PROM can save considerable time and effort. Additionally, the review can provide insights into how the PROM should be structured, offering guidance on what to include or avoid in its design. The second step is to define and elaborate the construct that one intends to measure. Then, the underlying relationship between the items and the construct to be measured (conceptual framework) needs to be established. This involves clearly identifying what you want to measure, in what population for what purpose, in what setting and ensuring that it is specific and well-understood. Next, in the third step, you need to decide on the measurement method. This step involves choosing the most suitable approach for measuring the construct. It could be a questionnaire, a rating scale or a physical test. The fourth step involves selecting and formulating the items. Experts play a crucial role in this process. Clinicians with extensive experience treating large

15 General Introduction 1 numbers of patients with the target condition offer valuable insights. At the symptom, functioning, and perceived health levels, patients themselves are the primary experts. The most effective way to gather information from clinicians or patients about relevant items is through focus groups or in-depth interviews. The items should be clear, relevant, and easy for respondents to understand. In practice, steps three and four are intertwined, it is a continuous process of evaluation and adaptation. In step five, scoring issues need to be addressed. Here, it is determined how the responses will be scored and whether any scoring rules or scales need to be established. Step six is about pilot testing the instrument. This involves testing the instrument on a small group of people to identify any potential issues, such as ambiguous questions or scoring inconsistencies. The feedback from this step helps refine the instrument. The final step is field-testing, where the instrument is tested in a larger group to ensure it works as intended in real-world settings. This step also helps evaluate the instrument’s validity and reliability on a broader scale, providing insights into how it performs with a diverse population. Measurement properties of a PROM The different properties of a PROM need to be investigated to ensure its quality. The COSMIN classified and defined the terminology and definitions of measurement properties.17 Figure 2 shows this COSMIN taxonomy, with terms for various measurement properties and their interrelationships. In short Reliability is defined as ‘the degree to which the measurement is free from measurement error’. Validity is defined as ‘the degree to which an instrument truly measures the construct(s) it purports to measure’. And Responsiveness is defined as ‘the ability of an instrument to detect change over time in the construct to be measured’. Implementation of a PROM Acknowledging the importance of individuals’ perspectives on their ear complaints and the impact on the quality of life, it is important to get the PROM implemented into routine care. The implementation of PROMs into routine care is known as a challenging process, as it requires a shift in the clinical practice and changes in the individual behaviour of both healthcare providers and patients.18 The registration of PROMs and other outcome values brings in an administrative burden and if not managed well, this can encroach on the valuable time healthcare

16 Chapter 1 workers have for their patients. Additionally, it imposes on patients who are required to complete time-consuming questionnaires. During development and implementation, it is therefore important to make appropriate decisions on the timing and the frequency of administration when implementing the PROM. The field of Implementation Science emerges as a critical player in understanding and addressing these challenges, employing theories and frameworks to emphasize the factors influencing the success or failure of innovations in healthcare practices.19 Implementation is a continuously ongoing process. By gathering more data, not only on individual level, but on group level as well, greater insights can be achieved. PROMs get more valuable and more accurate. This increased insight could lead to adjusted use of the PROM in daily practice and potentially even shift their role from being merely informative to guiding treatment. Ideally a PROM could help in the decision making, especially when certain PROM criteria prior intervention can guide the professional and patient in the possible outcomes. Figure 2. COSMIN taxonomy of relationships of measurement properties17 Abbreviations: COSMIN; COnsensus-based Standards for the selection of health Measurement Instruments; HR-PRO; health-related patient reported outcome.

17 General Introduction 1 Thesis outline Developing Patient Reported Outcomes Measures (PROMs) for ear and hearing problems presents several key challenges. Firstly, the diverse nature of ear and hearing issues, which range from acute infections to chronic conditions, might necessitates a wide range of PROMs or an ear domain specific PROM that can accurately capture the specific impacts of each condition. Secondly it can be difficult to ensure good reliability and validity of these measures across different populations and age groups. Thirdly, implementing PROMs in routine clinical care can be challenging due to the administrative burden on healthcare providers and patients. Best practices for implementation include simplifying the process of PROM administration, such as using digital platforms that integrate with existing electronic health records (EHR) systems and automating data collection and analysis. Educating both providers and patients on the benefits of PROMs can also increase acceptance and adherence. Additionally, involving patients in the development and selection of PROMs ensures that the measures are relevant and user-friendly. Insights gained from the implementation of PROMs can be used to continuously improve clinical practices and patient outcomes. Regularly reviewing PROM data allows healthcare providers to identify areas for improvement, adapt treatment protocols, and enhance patient education and support. Furthermore, aggregating and analysing PROM data at the population level can inform public health strategies and policy decisions, leading to better resource allocation and more effective healthcare interventions. By making PROMs a central component of clinical practice, the healthcare system can become more patient-centred and outcome-focused. This thesis highlights the abundance of available PROMs in otology and assesses its quality. It also navigates through the development, validation, implementation of the OQUA aiming to answer some of the issues addressed above. In chapter 2 a systematic mapping review of questionnaires in otology is presented. It is a comprehensive overview of all validated closed-ended otology questionnaires for adults found in the literature and of their basic characteristics. In chapter 3 a quality assessment of PROMs in otology for patients with multiple ear complaints is described. When conducting the studies in this dissertation, we used the COSMIN checklist and terminology as described earlier in this chapter. Chapter 4 reports on the multicentre development of the Otology Questionnaire Amsterdam, abbreviated as ‘OQUA’. We initiated this process by asking ourselves the most essential questions

18 Chapter 1 for that purpose: ‘What do we want to measure?’, ‘In which target population?’, and ‘For which purpose?’ Answers to these questions describe the construct and the framework for the OQUA. This was a cross-sectional study divided in two phases. In phase 1 in-depth interviews were done to identify relevant types of ear complaints and to formulate items. A pilot study of the first and second draft of the OQUA were part of phase 1 as well. In phase 2 the OQUA was field-tested, and item reduction was performed. The result is the OQUA consisting of 34 items. It covers eight types of ear complaints and consists of two constructs: complaints and impact. The development of the OQUA was based on the guidelines provided in Measurement in medicine20 and the COSMIN checklist15. In chapter 5 the construct validity, reliability and responsiveness of the Otology Questionnaire Amsterdam were examined. A new cohort of 194 patients visiting the ENT surgeons were recruited for the assessment of the responsiveness. A second prospective cohort of 50 consecutive patients undergoing ear surgery was recruited surgery for test-retest reliability of the OQUA. Additionally, a scoring system was developed to calculate subscale scores for all 8 ear complaints and impact of these complaints on Quality of Life. Chapter 6 describes the process of gathering insights in ear complaints in the general population in the Netherlands. OQUA data of 500 healthy adults, stratified on categorized age groups and gender were used to calculate normative data. These data can be valuable in a shared decision-making consultation, providing better understanding of the patient’s ear complaints as compared to the general population. In chapter 7 a prospective and qualitative analysis using focus groups and interviews with ENT professionals (n=15) and patients (n=25) with ear complaints of one tertiary referral hospital and two regional hospitals was performed. The barriers and enablers of using the OQUA as perceived by ENT surgeons and patients are presented and form the fundamentals for recommendations of an implementation strategy.

19 General Introduction 1 References 1. Organization WH. WHO global estimates on prevalence of hearing loss 2018 [Available from: https://www.who.int/pbd/deafness/estimates/en/. 2. Monasta L, Ronfani L, Marchetti F, Montico M, Vecchi Brumatti L, Bavcar A, et al. Burden of disease caused by otitis media: systematic review and global estimates. PLoS One. 2012;7(4):e36226. 3. Neuhauser HK. The epidemiology of dizziness and vertigo. Handb Clin Neurol. 2016;137:6782. 4. Porter ME, Teisberg EO. Redefining health care: creating value-based competition on results: Harvard business press; 2006. 5. Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 2009;34(5):447-54. 6. Cella D, Nolla K, Peipert JD. The challenge of using patient reported outcome measures in clinical practice: how do we get there? Journal of patient-reported outcomes. 2024;8(1):35. 7. Group E. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199-208. 8. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation. 2011;20(10):1727-36. 9. McHorney CA, Ware JE, Jr., Raczek AE. The MOS 36-Item Short-Form Health Survey (SF36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Medical care. 1993;31(3):247-63. 10. Feeny D, Furlong W, Torrance GW, Goldsmith CH, Zhu Z, DePauw S, et al. Multiattribute and single-attribute utility functions for the health utilities index mark 3 system. Medical care. 2002;40(2):113-28. 11. Phillips JS, Haggard M, Yung M. A new health-related quality of life measure for active chronic otitis media (COMQ-12): development and initial validation. Otol Neurotol. 2014;35(3):454-8. 12. McCoul ED, Anand VK, Christos PJ. Validating the clinical assessment of eustachian tube dysfunction: The Eustachian Tube Dysfunction Questionnaire (ETDQ-7). Laryngoscope. 2012;122(5):1137-41. 13. Hinderink JB, Krabbe PF, Van Den Broek P. Development and application of a health-related quality-of-life instrument for adults with cochlear implants: the Nijmegen cochlear implant questionnaire. Otolaryngol Head Neck Surg. 2000;123(6):756-65. 14. Newman CW, Jacobson GP, Spitzer JB. Development of the Tinnitus Handicap Inventory. Arch Otolaryngol Head Neck Surg. 1996;122(2):143-8. 15. Mokkink LB, Terwee CB, Patrick DL, Alonso J, Stratford PW, Knol DL, et al. COSMIN checklist manual2012. 16. Mokkink LB, Terwee CB, Patrick DL, Alonso J, Stratford PW, Knol DL, et al. The COSMIN checklist for assessing the methodological quality of studies on measurement properties of health status measurement instruments: an international Delphi study. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation. 2010;19(4):539-49.

20 Chapter 1 17. Mokkink LB, Terwee CB, Patrick DL, Alonso J, Stratford PW, Knol DL, et al. The COSMIN study reached international consensus on taxonomy, terminology, and definitions of measurement properties for health-related patient-reported outcomes. J Clin Epidemiol. 2010;63(7):737-45. 18. Michie S, van Stralen MM, West R. The behaviour change wheel: a new method for characterising and designing behaviour change interventions. Implement Sci. 2011;6:42. 19. Nilsen P. Making sense of implementation theories, models and frameworks. Implement Sci. 2015;10:53. 20. Vet HCWd, Terwee CB, Mokkink LB, Knol DL. Measurements in Medicine - A practical guide: Cambridge University Press; 2011.

24 Chapter 2 Abstract Background: Patient-reported outcome measures (PROMs) are valuable tools in assessing the quality of health care from a patient perspective and are increasingly used by otologists. However, selecting the right questionnaire has proven to be a difficult and time-consuming task. To facilitate this process, we will provide a comprehensive overview of existing questionnaires. Methods & Materials: A systematic literature search has been conducted on August 26, 2019, using the EMBASE and PubMed medical databases. 13,345 unique records were extracted. Questionnaires addressing any otologic complaint (tinnitus, hearing loss, earache, otorrhoea, and ear-related pressure sensation, vertigo, itch, or dysgeusia) were identified. All questionnaires were evaluated for eligibility by two independent researchers. Inclusion criteria were adult population, closed-ended questions, English language of the questionnaire, and the availability of the original article describing the development of the instrument or a validation paper describing the validation process written in English. Objective: Create a comprehensive overview of all validated closed-ended otology questionnaires for adults and demonstrate their basic characteristics. Main outcome measure: The number of questionnaires in English literature for the adult population, subdivided per symptom and target population. Results: A total of 155 unique questionnaires were selected: 33 tinnitus questionnaires, 23 vertigo questionnaires, 84 hearing loss questionnaires, and 15 multiple complaint questionnaires. A protocol for further questionnaire comparison is presented. Discussion: Two separate sequential searches were needed to identify unique questionnaires and to identify their development/validation paper. Although many ear diseases create multiple symptoms, the majority of the questionnaires were symptom specific. Conclusion: Many questionnaires concerning ear-related symptoms exist and predominantly concern hearing loss, vertigo, or tinnitus. Only a few questionnaires cover the multiple complaints that ear diseases can create. The presented overview is the most comprehensive overview of otology questionnaires in literature to date. It will serve as a basis for questionnaire selection by professionals and could serve as a protocol for questionnaire selection in other fields. Systematic review registration: PROSPERO CRD42017058155

25 Questionnaires in otology: a systematic mapping review 2 Background A patient-reported outcome measure (PROM) gathers information obtained directly from patients without any interference from others. The terms PROM and questionnaire are often being used interchangeably although not every questionnaire is a PROM.1 Questionnaires have great value in the collection of subjective outcome measures (e.g., perceived disability) as it is a fast and cost-effective method compared to the only alternative, a patient interview. The need for subjective outcome measures has been demonstrated in studies showing that outcomes of objective measurements do not necessarily correlate with the patients’ subjective experience (e.g., audiometric results vs. perceived hearing disability).2,3 Furthermore, the burden of disease is not only the direct result of symptoms, as it can be heavily affected by accompanying cognitive and emotional factors (e.g., the fear of a vertigo attack in between two episodes), as well as environmental factors. This may cause two persons with identical disease activity to suffer from different degrees of disability. Besides quantifying subjective symptoms, questionnaires give insight into what aspects of life a patient has complaints about, or within which disability is experienced (e.g., social interactions, work). This allows caregivers to customize therapy according to the specific needs of the patients. The shift towards patient centred care in modern health care is followed by an increasing demand for validated questionnaires. The need for otology questionnaires is further demonstrated by otological conditions, like otitis media and hearing loss, being world-wide among the most common short-term and chronic diseases, respectively. Age-related hearing loss is measured to have a greater impact on global health than asthma or lung carcinoma, with future incidence expecting to rise.4 Many new questionnaires have been developed in the last decades resulting in a substantial amount of literature. A thorough review of this literature is a time-consuming process. Systematic reviews on questionnaires used in tinnitus, vertigo, or hearing loss do exist, although recently performed comprehensive studies are rare. Furthermore, many of these studies provide an overview of existing questionnaires without any additional information about the questionnaire itself. This is demonstrated by the available literature in the field of Audiology. Both Granberg et al.5 and Akeroyd et al. 6 have conducted a (systematic) search for PROMs in hearing loss and present a list of often used questionnaire titles. However, no information about the questionnaire itself is presented.

26 Chapter 2 We believe the questionnaire is a vital tool for the assessment of complaints in ENT patients. However, questionnaire selection is often guided by prior experiences or by copying from the work of peers. The most suitable questionnaire is not always selected.7 A comprehensive overview of all published otology questionnaires demonstrating basic questionnaire and study characteristics will be a valuable addition to the current literature. It will facilitate the selection of questionnaires by caregivers. In the presented article, we will describe the systematic search of all closed-ended questionnaires, validated in adults, regarding at least one of the eight most prominent ear complaints like tinnitus, hearing loss, earache, otorrhoea, and ear-related vertigo, pressure sensation, prurigo, or dysgeusia.8 A distinct overview of questionnaires will be presented with their general characteristics, divided into several subgroups. More in depth assessment of the reliability/validity of every questionnaire in each group will follow in future studies. Objectives 1. To identify all validated closed-ended questionnaires covering one or multiple ear complaints (i.e., tinnitus, hearing loss, otalgia, otorrhoea, and ear related pressure sensation, vertigo, prurigo, or dysgeusia) for adults, in the literature published in the English language. 2. Create a comprehensive overview of identified questionnaires and their basic characteristics. Material and Methods Protocol and registration The methods for this systematic mapping review have been developed according to the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.9 A 27-item PRISMA checklist is available as an additional file to this protocol (Appendix 2.1 p.32-34). Our protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017058155. Search strategy The search strategy is illustrated using a flow diagram (Figure 1). Our search goal was to identify all otology questionnaires and subsequently to identify any original article concerning the development (“development paper”) and/or an article describing the evaluation of the measurement properties (“validation paper”) for every unique questionnaire. Therefore, the search consisted of two separate searches. The goal of

27 Questionnaires in otology: a systematic mapping review 2 the first search (Search 1) was questionnaire identification. Study input for Search 1 originated from 2 sources. The first source is “records identified through database searching.” A systematic literature search was performed in two bibliographic database sources, PubMed and Embase.com. The queries included indexed terms and free-text words and synonyms, for example “questionnaire,” “earache,” “hearing loss,” or “tinnitus.” The queries excluded “children” and “animal studies” (the complete search queries can be seen in Appendix 2.2 (p.35-36) The second source “records identified through other sources” was added. This could be any other source, e.g., journals not included in PubMed or Embase.com. This also included questionnaires suggested by experts in the field of otology and audiology at Amsterdam UMC location Vrije Universiteit Amsterdam who were asked to submit additional questionnaires, when this questionnaire was not found via the systematic search. Search 1 produced a set of records (i.e., study articles) that were screened in order to identify every otology questionnaire. At the end of this stage, the screening of the 2 sources created a list of potentially eligible otology questionnaire names. The identification of corresponding development/ validation articles was not part of this stage of the search. The goal of the second search (Search 2) was to identify a development and/or validation article for all the questionnaires identified in Search 1. Thus, for every questionnaire identified in Search 1, a separate search (Search 2) was performed in the PubMed and/or Embase. com databases. Search 2 started with examining the references corresponding to the questionnaires identified in our primary search. The study title, questionnaire name, questionnaire abbreviations or acronyms, or author name(s) were entered between double quotation marks as search term. This often resulted in iterative reference searching. At the end of Search 2, a development and/or validation article was identified for every included questionnaire. The first systematic search (Search 1) was performed in PubMed and Embase.com on January 1, 2016, by KV and JCFK. Search 2 was performed during the following months of eligibility assessment. The database search was repeated on August 26, 2019. We did not apply any restriction regarding the original publication date, language of publication, or study type of the papers in both searches. In both searches, additional study input could originate from the reference lists of assessed articles, “records identified from references” (Fig. 1). However, reference list checking was not routinely performed on all records. Exclusion of records could take place at every step in the

28 Chapter 2 study selection process. Search results were entered into reference management software (End-Note version X9, Clarivate Analytics, Philadelphia, PA). Eligible studies All PROMs regarding tinnitus, hearing loss, otalgia, otorrhoea, and/or ear-related pressure sensation, vertigo, prurigo, or dysgeusia, or all synonyms, in adults, presented in a full-text paper that concerns the development (“development paper”) and/or evaluation of the measurement properties (“validation paper”) were eligible for inclusion. These symptoms were defined in earlier research.8 Adult age is defined as 18 years or older. Questionnaires that were validated for an adult population including a small proportion of teenagers were also included, as we do not believe this immediately invalidates the questionnaire. All items in the questionnaire had to be closed-ended. Proxy-reported questionnaires or questionnaires assessing complaints in proxies (e.g., spouses) caused by patients’ disease were not considered eligible. Although generic questionnaires (e.g., generic QoL questionnaires) are applicable to the otology population, they were not considered eligible, as they do not specifically address the issues important for otology patients.10 However, questionnaires addressing the effect of otologic symptoms/diseases on a patient’s quality of life, disease-specific health-related quality of life (HR-QoL) questionnaires, were eligible for inclusion. Questionnaire language had to be English. Otherwise, questionnaires were eligible for inclusion provided that they have been validated, with full-text availability of the development and/or validation paper in the English language. All exclusion criteria were applied to Search 1, together with the inclusion criteria “questionnaire addressing otology complaint.” All inclusion and exclusion criteria (Table 1) were applied to Search 2. Article selection All search records from Search 1 were screened by two independent reviewers (KV and EB) for eligibility. This process was aimed at identifying questionnaires through screening of the title and abstract. Full text was examined in case of doubt over eligibility. Questionnaire identification was followed by identification of the corresponding development paper and/or validation paper (Search 2). Eligibility was assessed according to the criteria depicted in Table 1. This was performed by one reviewer. Full-text copies of potentially relevant original articles and/or validation papers were purchased. Any disagreement between the reviewers over the eligibility of particular articles was resolved through discussion between the reviewers. When needed, our expert team discussed selection difficulties.

29 Questionnaires in otology: a systematic mapping review 2 Figure 1: PRISMA flowchart illustrating the study selection process. Search 1 encompasses the identification of questionnaires through screening of the records originating from the database searches and by expert recommendation. Search 2 encompasses the eligibility assessment of the potentially relevant questionnaires by identifying and assessing their development and/or validation paper. This resulted in the inclusion of validated questionnaires. Records could be excluded at every step of the process, after screening of the title and abstract of the database record [1], full-text assessment of the database record [2], failure to identify a development or validation paper [3], and during eligibility assessment of development or validation paper [4]

30 Chapter 2 Data extraction Data extraction was conducted by one reviewer using a standardized extraction form and was checked by a second reviewer. This standardized extraction form is based on the patient-reported outcome (PRO)-specific checklist derived from the European Regulatory Issues on Quality of Life Assessment Working Group (ERIQA).11 Data extraction pertained to the secondary outcome measures: measurement properties and questionnaire characteristics of the identified questionnaires. The full Table 1: Inclusion and exclusion criteria used for the assessment of questionnaire eligibility as used in Search 2 INCLUSION CRITERIA EXCLUSION CRITERIA Exclusively closed-ended questions Presence of open-ended questions Adult population (≥ 18yrs) Paediatric population (< 18yrs) Copy of questionnaire available No copy of questionnaire available Availability of a development-, or validation paper in English No availability of a development-, or validation paper in English Questionnaire addressing otology complaints Proxy-reported questionnaires Table 2: Numbers of studies excluded per diagnostic group and reasons for exclusion. Each column represents a different symptom category. Q = questionnaire, OA = original article. See also Fig. 1, Search 2, exclusions [3] and [4] TINNITUS VERTIGO HEARING LOSS MULTIPLE COMPLAINT DYSGEUSIA ITCH No development/validation paper 13 15 34 3 - - Open-ended question(s) 7 2 25 - - - Q not self-administered 1 3 3 1 - - No description of development/ validation in OA 4 6 19 3 3 1 No definitive Q presented 1 - - - - - Off-topic 1 11 15 2 - - No English translation 3 2 3 - - - No Q availability 1 6 12 1 - - Paediatric Q - - 8 5 - - Not a Q 1 3 8 - - - 1-item Q 3 3 1 - - - Double Q 9 10 11 - - - Semi-structured Q - - 2 - - - Total 44 61 141 15 3 1

31 Questionnaires in otology: a systematic mapping review 2 extraction form is available as Appendix 2.3 (p.37) Outcomes used in this article were first author, year of publication, country of development, institution of development, number of items, means of item generation, demographics of the study population, and available validated translations. An overview of the other questionnaire characteristics that were extracted from the development and/or validation papers is shown in Appendix 2.3 (p.37) and is related to the measurement properties and psychometric characteristics of these questionnaires (e.g., questionnaire (sub) domains and test-retest reliability). The psychometric data will be separately assessed per symptom category in future work. Results The majority of identified questionnaires were found through our database search. The PubMed and Embase. - com searches resulted in a total of 16,370 records. After removal of duplicates, 13,345 unique records remained. In 10,670 cases, screening of the title and abstract was sufficient for record exclusion. However, the screening phase was primarily aimed at identifying potentially relevant questionnaires. Two records were added through expert recommendation. Full-text examination was performed if the use of a questionnaire could not be excluded on the basis of title and abstract. A total of 2715 articles were fully assessed. At this stage, exclusion of records (Fig. 1 “records excluded [1] and[ 2]”) was primarily because both the abstract and full-text publication of the article were not accessible, full-text language was not English, the study was off-topic (e.g., not in the field of otology, paediatric population), or because of the absence of a questionnaire. Full-text examination resulted in the exclusion of many “anonymous” questionnaires. These concerned questionnaires without a name, without a graphic representation, and without any information on the development and/or validation or reference to a corresponding article. Only records without a potentially eligible questionnaire were excluded. Two thousand three hundred forty-three records were excluded based on full-text examination out of the 2715 records. In total, 420 questionnaires were identified as potentially eligible. In the following phase, all 420 questionnaires were assessed for eligibility. From this point, data on all questionnaires were saved in a separate digital database including the reasons for questionnaire exclusion (Fig. 1: “records excluded [3] and [4]”). Eligibility was assessed by examination of the development and/or validation article. A total of 265 questionnaires were excluded for various reasons (Table 2), and the most common reason being that full

32 Chapter 2 text of the development and/or validation article could not be retrieved (N = 65). Excluded questionnaires were categorized according to symptoms. The remaining 155 questionnaires were included. One hundred forty-nine studies were included in our analyses, because several studies presented more than one questionnaire. The questionnaires were categorized based on the primary symptom of interest. This resulted in the following classification: 33 tinnitus questionnaires, 23 vertigo questionnaires, 84 hearing loss questionnaires, and 15 multiple complaint questionnaires (i.e., ≥3 symptoms of interest). Within these symptom categories, a subdivision was made based on the target population of the different questionnaires (Table 3). The majority of identified hearing loss questionnaires were designed for patients with sensorineural hearing loss using hearing aids or cochlear implants. Questionnaires for patients with autophony, hyperacusis, and patulous Eustachian tube completed this category. Thirty-three questionnaires have been designed for tinnitus sufferers. Unlike hearing loss questionnaires, tinnitus questionnaires do not pertain to specific patient groups, e.g., vestibular schwannoma or Meniere’s disease patients. Questionnaires specific for vestibular schwannoma or Meniere’s disease patients do exist. However, these questionnaires, together with symptom-specific questionnaires on otitis media, Eustachian tube dysfunction, and superior canal dehiscence, were categorized as multiple complaint questionnaires. Other multiple complaint questionnaires focused on dizziness, patients with a cochlear implant, or were designed as generic otology questionnaires. Most vertigo questionnaires did not relate to a specific condition. However, disease-specific questionnaires for benign paroxysmal positional vertigo, visual vertigo, persistent postural positional vertigo, motion sickness, and simulator sickness were also identified. An overview of all included questionnaires is presented together with the first author name, year of publication, institution and country of development, a description of the construct assessed by the questionnaire, demographics of the study population of the development/ validation study, methods of item generation, and the existing validated translations (Additional online files 4, 5, 6 and 7, link at the end of the chapter). However, the following conclusions can be drawn from the data as reported in the additional online files 4, 5, 6 and 7. First, in every symptom category, more questionnaires have been developed in the last 20 years than prior to this period: tinnitus (23 out of 33 were developed between 2000 and 2020), vertigo (13 out of 23), hearing loss (50 out of 84), and multiple complaints (13 out of 14). Long questionnaires (<60 items) are no longer conventional. In general, newly developed questionnaires are shorter (<40 items) and many existing questionnaires have been shortened. Furthermore, existing questionnaires are often used in the development of new questionnaires. Some questionnaires are composed out of items from various existing questionnaires, and sometimes a new questionnaire is generated by replacing a single word (i.e., the construct of interest) in every item of an existing questionnaire.

33 Questionnaires in otology: a systematic mapping review 2 Table 3: The selected 155 questionnaires subdivided per symptom category. TINNITUS (n=33) VERTIGO (n=23) HEARING LOSS (n=84) MULTIPLE COMPLAINT (n=15) Nonspecified tinnitus (n=33) Non-specified vertigo (n=14) Hyperacusis (n=4) Meniere’s disease (n=3) Simulator sickness (n=2) Hearing impaired (n=32) Otitis media (n=3) Motion sickness (n=2) Hearing aid users (n=16) Vestibular schwannoma (n=1) Benign Paroxismal Positional Vertigo (n=3) Cochlear implant users (n=11) Eustachian tube dysfunction (n=1) Persistent PosturalPositional Vertigo (n=1) Geriatric population / older adults (n=2) General otology population (n=2) Visual vertigo (n=1) Autophony (n=2) Superior canal dehiscence (n=1) Hearing aid candidates (n=4) Dizziness sufferers (n=1) General population (n=12) General population (n=2) Otology patient, not further defined (n=1) Cochlear Implant users (n=1) Patulous Eustachian tube (n=1) Discussion Questionnaires are essential for the assessment of subjective complaints and disability in the otology population. To date, no comprehensive overview of all, in English available, structured otology questionnaires for adults exist. As presented in this article, 155 unique validated questionnaires were identified, classified into four categories. These categories are tinnitus questionnaires, vertigo questionnaires, hearing loss questionnaires, and multiple complaint questionnaires (i.e., ≥3 symptoms of interest), containing 33, 23, 84, and 15 unique questionnaires, respectively. Questionnaires were categorized according to symptom and target population (Table 3) demonstrating a great variety between and within symptom categories. There is no subdivision within the tinnitus category. Thus, all 33 questionnaires are eligible for every tinnitus patient. The other 3 symptom categories do contain subcategories. In contrast to “tinnitus,” the “hearing loss” category has 10 subgroups with varying numbers of questionnaires. Table 3 gives a clear overview of the number of questionnaires available and shows how many questionnaires can be subdivided into different (sub)categories. We have not identified a similar overview in the literature on questionnaires in otology. Supported with the questionnaire characteristics presented in the additional online files 4, 5, 6, and 7, clinicians are facilitated in the selection of an appropriate questionnaire, being able to select a questionnaire based on its construct, number of items, or the availability of a validated translation.

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