Novel approaches for tinnitus subphenotyping: evidence synthesis, standardised assessment, and supervised and unsupervised machine learning applications

Clinical management of tinnitus is rather challenging and there is yet no cure for most tinnitus cases. It is speculated that tinnitus heterogeneity is hindering progress in scientific understanding and development of treatments. Phenotyping (i.e., assessment of observable characteristics) and subphenotyping (i.e., subgrouping based on differences in observable characteristics) are important for studying heterogeneous conditions like tinnitus. Identifying and defining clinically relevant tinnitus subphenotypes could help achieve transformational advances in the field. This dissertation reports the application of several advanced methodological approaches and has two main aims. The first aim is to contribute to an international standardisation of tinnitus assessment relevant for tinnitus phenotypic profiling and subphenotyping. The second aim is to further our understanding of tinnitus heterogeneity by investigating the presence of robust subphenotypes, consistent across multiple independent datasets. Two chapters focus on the first aim. Chapter 2 reviews the literature, summarises current knowledge on tinnitus subphenotypes and identifies research gaps. It also summarises methods used so far and presents a novel framework of variable concepts that have been used for tinnitus subphenotyping. Chapter 3 describes the development of a self-report questionnaire intended to be used as a standard for tinnitus phenotyping. This questionnaire was developed through an international collaboration with tinnitus researchers from many centres. The questionnaire is already translated into 9 languages (Albanian, Dutch, French, German, Greek, Italian, Polish, Spanish, and Swedish) and is being used by multiple research teams as a tool for standardised tinnitus assessment. The second aim is addressed in Chapters 4 and 5. Chapter 4 provides a detailed description of three tinnitus-specific datasets that were subsequently analysed in Chapter 5, and highlights commonalities and differences in the studied populations and the collected variables. Chapter 5 describes a novel data-driven approach for discovering tinnitus subphenotypes. This Chapter reports on a comprehensive unsupervised machine learning methodology applied to the three datasets. Findings indicate that this method was able to identify robust tinnitus subphenotypic patterns. Finally, Chapter 6 relates the overall findings to the wider context of the published literature and presents suggestions and recommendations for future research. Age, sex, hearing ability, problems with sounds, symptoms of depression, and mandible problems were highlighted as important variables for tinnitus subphenotyping and should be considered for assessment in future tinnitus studies. Overall, this work provides a basis for standardised tinnitus assessment in future studies and gives novel insights into the characteristics of tinnitus subphenotypes

Novel approaches for tinnitus subphenotyping: evidence synthesis, standardised assessment, and supervised and unsupervised machine learning applications

Clinical management of tinnitus is rather challenging and there is yet no cure for most tinnitus cases. It is speculated that tinnitus heterogeneity is hindering progress in scientific understanding and development of treatments. Phenotyping (i.e., assessment of observable characteristics) and subphenotyping (i.e., subgrouping based on differences in observable characteristics) are important for studying heterogeneous conditions like tinnitus. Identifying and defining clinically relevant tinnitus subphenotypes could help achieve transformational advances in the field. This dissertation reports the application of several advanced methodological approaches and has two main aims. The first aim is to contribute to an international standardisation of tinnitus assessment relevant for tinnitus phenotypic profiling and subphenotyping. The second aim is to further our understanding of tinnitus heterogeneity by investigating the presence of robust subphenotypes, consistent across multiple independent datasets. Two chapters focus on the first aim. Chapter 2 reviews the literature, summarises current knowledge on tinnitus subphenotypes and identifies research gaps. It also summarises methods used so far and presents a novel framework of variable concepts that have been used for tinnitus subphenotyping. Chapter 3 describes the development of a self-report questionnaire intended to be used as a standard for tinnitus phenotyping. This questionnaire was developed through an international collaboration with tinnitus researchers from many centres. The questionnaire is already translated into 9 languages (Albanian, Dutch, French, German, Greek, Italian, Polish, Spanish, and Swedish) and is being used by multiple research teams as a tool for standardised tinnitus assessment. The second aim is addressed in Chapters 4 and 5. Chapter 4 provides a detailed description of three tinnitus-specific datasets that were subsequently analysed in Chapter 5, and highlights commonalities and differences in the studied populations and the collected variables. Chapter 5 describes a novel data-driven approach for discovering tinnitus subphenotypes. This Chapter reports on a comprehensive unsupervised machine learning methodology applied to the three datasets. Findings indicate that this method was able to identify robust tinnitus subphenotypic patterns. Finally, Chapter 6 relates the overall findings to the wider context of the published literature and presents suggestions and recommendations for future research. Age, sex, hearing ability, problems with sounds, symptoms of depression, and mandible problems were highlighted as important variables for tinnitus subphenotyping and should be considered for assessment in future tinnitus studies. Overall, this work provides a basis for standardised tinnitus assessment in future studies and gives novel insights into the characteristics of tinnitus subphenotypes

The spatial percept of tinnitus is associated with hearing asymmetry: subgroup comparisons

The spatial percept of tinnitus is hypothesized as an important variable for tinnitus subtyping. Hearing asymmetry often associates with tinnitus laterality, but not always. One of the methodological limitations for cross-study comparisons is how the variables for hearing asymmetry and tinnitus spatial perception are defined. In this study, data from two independent datasets were combined (n= 833 adults, age ranging from 20 to 91 years, 404 males, 429 females) to investigate characteristics of subgroups with different tinnitus spatial perception focusing on hearing asymmetry. Three principle findings emerged. First, a hearing asymmetry variable emphasizing the maximum interaural difference most strongly discriminated unilateral from bilateral tinnitus. Merging lateralized bilateral tinnitus (perceived in both ears but worse in one side) with unilateral tinnitus weakened this relationship. Second, there was an association between unilateral tinnitus and ipsilateral asymmetric hearing. Third, unilateral and bilateral tinnitus were phenotypically distinct, with unilateral tinnitus being characterized by older age, asymmetric hearing, more often wearing one hearing aid, older age at tinnitus onset, shorter tinnitus duration, and higher percentage of time being annoyed by tinnitus. We recommend that careful consideration is given to the definitions of hearing asymmetry and tinnitus spatial perception in order to improve the comparability of findings across studies

Doctoral Studies as part of an Innovative Training Network (ITN): Early Stage Researcher (ESR) experiences [version 2; peer review: 2 approved]

Background: The Marie-Skłodowska-Curie Actions’ (MSCA) Innovative Training Network (ITN) is a doctoral training programme jointly implemented by academic institutions and industries from countries across Europe and beyond. To our knowledge no study has examined the experience of students participating in MSCA-ITNs. This study aims to evaluate and report MSCA-ITN Early Stage Researcher (ESR) experiences. Methods: The Innovative Training Network - Evaluation Questionnaire (ITN-EQ) was developed to assess supervision, training, collaborations and experiences of ESRs and forwarded to two tinnitus-related ITNs and seven ITNs of other disciplines. Results: Key advantages identified included better career prospects, multidisciplinary research opportunities/collaborations, international exposure, personal/professional development, plus generous salaries and research budgets. However, lack of a common EU framework resulted in the experience being largely dependent on the host institution, country and supervisor. Moreover, managing the dual requirements of ITNs and host institutions while completing a three-year PhD seemed challenging for most ESRs. ESR involvement in workshop and training school planning was desirable. More than 80% of ESRs rated the overall ITN experience favourably and 98.3% would recommend the same to prospective PhD students. Conclusions: This report could provide valuable insights in planning and management of future ITNs and could assist prospective students in their decision of joining an ITN for their PhD

Doctoral Studies as part of an Innovative Training Network (ITN):Early Stage Researcher (ESR) experiences [version 2; peer review: 2 approved]

Background: The Marie-Skłodowska-Curie Actions’ (MSCA) Innovative Training Network (ITN) is a doctoral training programme jointly implemented by academic institutions and industries from countries across Europe and beyond. To our knowledge no study has examined the experience of students participating in MSCA-ITNs. This study aims to evaluate and report MSCA-ITN Early Stage Researcher (ESR) experiences. Methods: The Innovative Training Network - Evaluation Questionnaire (ITN-EQ) was developed to assess supervision, training, collaborations and experiences of ESRs and forwarded to two tinnitus-related ITNs and seven ITNs of other disciplines. Results: Key advantages identified included better career prospects, multidisciplinary research opportunities/collaborations, international exposure, personal/professional development, plus generous salaries and research budgets. However, lack of a common EU framework resulted in the experience being largely dependent on the host institution, country and supervisor. Moreover, managing the dual requirements of ITNs and host institutions while completing a three-year PhD seemed challenging for most ESRs. ESR involvement in workshop and training school planning was desirable. More than 80% of ESRs rated the overall ITN experience favourably and 98.3% would recommend the same to prospective PhD students. Conclusions: This report could provide valuable insights in planning and management of future ITNs and could assist prospective students in their decision of joining an ITN for their PhD

Corrigendum:Multidisciplinary Tinnitus Research: Challenges and Future Directions From the Perspective of Early Stage Researchers (Front. Aging Neurosci., (2021), 13, (647285), 10.3389/fnagi.2021.647285)

In the original article, there was an error. For the sentence “NMDA receptor antagonists (AM-101) have been discontinued in phase III for not meeting endpoints (van de Heyning et al., 2014)” there was a typographical error (phase III should have been phase II). In addition, it was brought to our attention that clinical trials for AM-101 are ongoing. A correction has been made to section 6. Treatment Development, Subsection 6.4. Pharmacology-Based Interventions, paragraph 1. The corrected paragraph is below. A wide variety of therapeutic drugs have been used to relieve tinnitus (Elgoyhen and Langguth, 2010). For acute tinnitus, a dose-dependent reduction in tinnitus intensity was observed with intravenous lidocaine (Trellakis et al., 2006). However, its use is controversial due to its short-lasting response, its potentially life threatening arrhythmogenic side effects, and the low bioavailability of its oral form (Israel et al., 1982; Trellakis et al., 2007; Gil-Gouveia and Goadsby, 2009). A potential goal of pharmacologic tinnitus research could be to identify the mechanism by which lidocaine interferes with tinnitus and mimic this effect using a drug with better tolerance that can be orally administered. For chronic tinnitus, the off-label use of medicines like betahistine (Hall et al., 2018d), anticonvulsants (Hoekstra et al., 2011), and glutamate receptor antagonists have shown little or no effect in clinical trials. Prescription of antidepressants and benzodiazepines is limited to tinnitusassociated comorbidities such as depression, insomnia and anxiety (Langguth et al., 2019). Moreover, three clinical research programs, in the last few years, were discontinued in phase II and III. AMPA antagonist selurampanel (BGG492) has not resulted in a new compound (Cederroth et al., 2018). NMDA receptor antagonists (AM-101) did not meet the primary endpoint of improving minimum masking level in acute tinnitus in a phase II clinical trial but showed improvement for tinnitus loudness, annoyance, sleep difficulties, and tinnitus impact in patients with tinnitus after noise trauma or otitis media (van de Heyning et al., 2014). Many other treatments decreasing tinnitus percept or targeting central auditory processing pathways are at a preclinical phase (Schilder et al., 2019). The modulator of voltage-gated potassium channels (Kv3.1) (AUT00063) was not effective in alleviating tinnitus symptoms (Hall et al., 2019b). The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated

Standardised profiling for tinnitus research: The European School for Interdisciplinary Tinnitus Research Screening Questionnaire (ESIT-SQ)

Background: The heterogeneity of tinnitus is substantial. Its numerous pathophysiological mechanisms and clinical manifestations have hampered fundamental and treatment research significantly. A decade ago, the Tinnitus Research Initiative introduced the Tinnitus Sample Case History Questionnaire, a case history instrument for standardised collection of information about the characteristics of the tinnitus patient. Since then, a number of studies have been published which characterise individuals and groups using data collected with this questionnaire. However, its use has been restricted to a clinical setting and to the evaluation of people with tinnitus only. In addition, it is limited in the ability to capture relevant comorbidities and evaluate their temporal relationship with tinnitus. Method: Here we present a new case history instrument which is comprehensive in scope and can be answered by people with and without tinnitus alike. This ‘European School for Interdisciplinary Tinnitus Research Screening Questionnaire’ (ESIT-SQ) was developed with specific attention to questions about potential risk factors for tinnitus (including demographics, lifestyle, general medical and otological histories), and tinnitus characteristics (including perceptual characteristics, modulating factors, and associations with co-existing conditions). It was first developed in English, then translated into Dutch, German, Italian, Polish, Spanish, and Swedish, thus having broad applicability and supporting international collaboration. Conclusions: With respect to better understanding tinnitus profiles, we anticipate the ESIT-SQ to be a starting point for comprehensive multi-variate analyses of tinnitus. Data collected with the ESIT-SQ can allow establishment of patterns that distinguish tinnitus from non-tinnitus, and definition of common sets of tinnitus characteristics which might be indicated by the presence of otological or comorbid systemic diseases for which tinnitus is a known symptom

Multidisciplinary Tinnitus Research: Challenges and Future Directions from the Perspective of Early Stage Researchers

Tinnitus can be a burdensome condition on both individual and societal levels. Many aspects of this condition remain elusive, including its underlying mechanisms, ultimately hindering the development of a cure. Interdisciplinary approaches are required to overcome long-established research challenges. This review summarizes current knowledge in various tinnitus-relevant research fields including tinnitus generating mechanisms, heterogeneity, epidemiology, assessment, and treatment development, in an effort to highlight the main challenges and provide suggestions for future research to overcome them. Four common themes across different areas were identified as future research direction: (1) Further establishment of multicenter and multidisciplinary collaborations; (2) Systematic reviews and syntheses of existing knowledge; (3) Standardization of research methods including tinnitus assessment, data acquisition, and data analysis protocols; (4) The design of studies with large sample sizes and the creation of large tinnitus-specific databases that would allow in-depth exploration of tinnitus heterogeneity

A Review and a Framework of Variables for Defining and Characterizing Tinnitus Subphenotypes

Tinnitus patients can present with various characteristics, such as those related to the tinnitus perception, symptom severity, and pattern of comorbidities. It is speculated that this phenotypic heterogeneity is associated with differences in the underlying pathophysiology and personal reaction to the condition. However, there is as yet no established protocol for tinnitus profiling or subtyping, hindering progress in treatment development. This review summarizes data on variables that have been used in studies investigating phenotypic differences in subgroups of tinnitus, including variables used to both define and compare subgroups. A PubMed search led to the identification of 64 eligible articles. In most studies, variables for subgrouping were chosen by the researchers (hypothesis-driven approach). Other approaches included application of unsupervised machine-learning techniques for the definition of subgroups (data-driven), and subgroup definition based on the response to a tinnitus treatment (treatment response). A framework of 94 variable concepts was created to summarize variables used across all studies. Frequency statistics for the use of each variable concept are presented, demonstrating those most and least commonly assessed. This review highlights the high dimensionality of tinnitus heterogeneity. The framework of variables can contribute to the design of future studies, helping to decide on tinnitus assessment and subgrouping