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The clinical heterogeneity of chronic tinnitus poses major challenges to patient management and prompts the identification of distinct patient subgroups (or phenotypes) that respond more predictable to a particular treatment. We model heterogeneity in treatment response among phenotypes of tinnitus patients concerning their change in self-reported health burden, psychological characteristics, and tinnitus characteristics. Before and after a 7-day multimodal treatment, 989 tinnitus patients completed 14 assessment questionnaires, from which 64 variables measured general tinnitus characteristics, quality of life, pain experiences, somatic expressions, affective symptoms, tinnitus-related distress, internal resources, and perceived stress. Our approach encompasses mechanisms for patient phenotyping, visualizations of the phenotypes and their change with treatment in a projected space, and the extraction of patient subgroups based on their change with treatment. On average, all four distinct phenotypes identified at the pre-intervention baseline showed improved values for nearly all the considered variables following the intervention. However, a considerable intra-phenotype heterogeneity was noted. Five clusters of change reflected variations in the observed improvements among individuals. These patterns of treatment effects were identified to be associated with baseline phenotypes. Our exploratory approach establishes a groundwork for future studies incorporating control groups to pinpoint patient subgroups that are more likely to benefit from specific treatments. This strategy not only has the potential to advance personalized medicine but can also be extended to a broader spectrum of patients with various chronic conditions., (© 2024. The Author(s).)

Background: Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potentially increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient., Methods: Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavioral therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in four treatment arms with single treatment and six treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT., Discussion: The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results., Trial Registration: ClinicalTrials.gov NCT04663828 . The trial is ongoing. Date of registration: December 11, 2020. All patients that finished their treatment before 19 December 2022 are included in the main RCT analysis., (© 2023. The Author(s).)

Tinnitus is the perception of a phantom sound and the patient's reaction to it. Although much progress has been made, tinnitus remains a scientific and clinical enigma of high prevalence and high economic burden, with an estimated prevalence of 10%-20% among the adult population. The EU is funding a new collaborative project entitled "Unification of Treatments and Interventions for Tinnitus Patients" (UNITI, grant no. 848261) under its Horizon 2020 framework. The main goal of the UNITI project is to set the ground for a predictive computational model based on existing and longitudinal data attempting to address the question of which treatment or combination of treatments is optimal for a specific patient group based on certain parameters. Clinical, epidemiological, genetic and audiological data, including signals reflecting ear-brain communication, as well as patients' medical history, will be analyzed making use of existing databases. Predictive factors for different patient groups will be extracted and their prognostic relevance validated through a Randomized Clinical Trial (RCT) in which different patient groups will undergo a combination of tinnitus therapies targeting both auditory and central nervous systems. From a scientific point of view, the UNITI project can be summarized into the following research goals: (1) Analysis of existing data: Results of existing clinical studies will be analyzed to identify subgroups of patients with specific treatment responses and to identify systematic differences between the patient groups at the participating clinical centers. (2) Genetic and blood biomarker analysis: High throughput Whole Exome Sequencing (WES) will be performed in well-characterized chronic tinnitus cases, together with Proximity Extension Assays (PEA) for the identification of blood biomarkers for tinnitus. (3) RCT: A total of 500 patients will be recruited at five clinical centers across Europe comparing single treatments against combinational treatments. The four main treatments are Cognitive Behavioral Therapy (CBT), hearing aids, sound stimulation, and structured counseling. The consortium will also make use of e/m-health applications for the treatment and assessment of tinnitus. (4) Decision Support System: An innovative Decision Support System will be implemented, integrating all available parameters (epidemiological, clinical, audiometry, genetics, socioeconomic and medical history) to suggest specific examinations and the optimal intervention strategy based on the collected data. (5) Financial estimation analysis: A cost-effectiveness analysis for the respective interventions will be calculated to investigate the economic effects of the interventions based on quality-adjusted life years. In this paper, we will present the UNITI project, the scientific questions that it aims to address, the research consortium, and the organizational structure., (© 2021 Elsevier B.V. All rights reserved.)

Chronic tinnitus is a complex, multi-factorial symptom that requires careful assessment and management. Evidence-based therapeutic approaches involve audiological and psychological treatment components. However, not everyone benefits from treatment. The identification and characterisation of patient subgroups (or "phenotypes") may provide clinically relevant information. Due to the large number of assessment tools, data-driven methods appear to be promising. The acceptance of these empirical results can be further strengthened by a comprehensive visualisation. In this study, we used cluster analysis to identify distinct tinnitus phenotypes based on self-report questionnaire data and implemented a visualisation tool to explore phenotype idiosyncrasies. 1228 patients with chronic tinnitus from the Charité Tinnitus Center in Berlin were included. At baseline, each participant completed 14 questionnaires measuring tinnitus distress, -loudness, frequency and location, depressivity, perceived stress, quality of life, physical and mental health, pain perception, somatic symptom expression and coping attitudes. Four distinct patient phenotypes emerged from clustering: avoidant group (56.8%), psychosomatic group (14.1%), somatic group (15.2%), and distress group (13.9%). Radial bar- and line charts allowed for visual inspection and juxtaposition of major phenotype characteristics. The phenotypes differed in terms of clinical information including psychological symptoms, quality of life, coping attitudes, stress, tinnitus-related distress and pain, as well as socio-demographics. Our findings suggest that identifiable patient subgroups and their visualisation may allow for stratified treatment strategies and research designs.

Tinnitus is a complex condition that is associated with major psychological and economic impairments - partly through various comorbidities such as depression. Understanding the interaction between tinnitus and depression may thus improve either symptom cluster's prevention, diagnosis and treatment. In this study, we developed and validated a machine learning model to predict depression severity after outpatient therapy (T1) based on variables obtained before therapy (T0). 1,490 patients with chronic tinnitus (comorbid major depressive disorder: 52.2%) who completed a 7-day multimodal treatment encompassing tinnitus-specific components, cognitive behavioural therapy, physiotherapy and informational counselling were included. 185 variables were extracted from self-report questionnaires and socio-demographic data acquired at T0. We used 11 classification methods to train models that reliably separate between subclinical and clinical depression at T1 as measured by the general depression questionnaire. To ensure highly predictive and robust classifiers, we tuned algorithm hyperparameters in a 10-fold cross-validation scheme. To reduce model complexity and improve interpretability, we wrapped model training around an incremental feature selection mechanism that retained features that contributed to model prediction. We identified a LASSO model that included all 185 features to yield highest predictive performance (AUC = 0.87 ± 0.04). Through our feature selection wrapper, we identified a LASSO model with good trade-off between predictive performance and interpretability that used only 6 features (AUC = 0.85 ± 0.05). Thus, predictive machine learning models can lead to a better understanding of depression in tinnitus patients, and contribute to the selection of suitable therapeutic strategies and concise and valid questionnaire design for patients with chronic tinnitus with or without comorbid major depressive disorder.

Background: Chronic tinnitus is a complex condition that can be associated with considerable distress. Whilst cognitive-behavioral treatment (CBT) approaches have been shown to be effective, not all patients benefit from psychological or psychologically anchored multimodal therapies. Determinants of tinnitus-related distress thus provide valuable information about tinnitus characterization and therapy planning., Objective: The study aimed to develop machine learning models that use variables (or "features") obtained before treatment to characterize patients' tinnitus-related distress status after treatment. Whilst initially all available variables were considered for model training, the final model was required to achieve highest predictive performance using only a small number of features., Methods: 1,416 tinnitus patients (decompensated tinnitus: 32%) who completed a 7-day multimodal treatment encompassing tinnitus-specific components, CBT, physiotherapy and informational counseling were included in the analysis. At baseline, patients were assessed using 205 features from 10 questionnaires comprising sociodemographic and clinical information. A data-driven workflow was developed consisting of (a) an initial exploratory correlation analysis, (b) supervised machine learning to predict tinnitus-related distress after treatment (T1) using baseline data only (T0), and (c) post-hoc analysis of the best model to facilitate model inspection and understanding. Classification methods were embedded in a feature elimination wrapper that iteratively learned on features found to be important for the model in the preceding iteration, in order to keep the performance stable while successively reducing the model complexity. 10-fold cross-validation with area under the curve (AUC) as performance measure was implemented for model generalization error estimation., Results: The best machine learning classifier (gradient boosted trees) can predict tinnitus-related distress in T1 with AUC = 0.890 using 26 features. Subjectively perceived tinnitus-related impairment, depressivity, sleep problems, physical health-related impairments in quality of life, time spent to complete questionnaires and educational level exhibited a high attribution towards model prediction., Conclusions: Machine learning can reliably identify baseline features recorded prior to treatment commencement that characterize tinnitus-related distress after treatment. The identification of key features can contribute to an improved understanding of multifactorial contributors to tinnitus-related distress and thereon based multimodal treatment strategies., Competing Interests: The authors have declared that no competing interests exist.