The statistical analysis plan for the unification of treatments and interventions for tinnitus patients randomized clinical trial (UNITI-RCT).

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.

Prediction meets time series with gaps: User clusters with specific usage behavior patterns.

With mHealth apps, data can be recorded in real life, which makes them useful, for example, as an accompanying tool in treatments. However, such datasets, especially those based on apps with usage on a voluntary basis, are often affected by fluctuating engagement and by high user dropout rates. This makes it difficult to exploit the data using machine learning techniques and raises the question of whether users have stopped using the app. In this extended paper, we present a method to identify phases with varying dropout rates in a dataset and predict for each. We also present an approach to predict what period of inactivity can be expected for a user in the current state. We use change point detection to identify the phases, show how to deal with uneven misaligned time series and predict the user's phase using time series classification. In addition, we examine how the evolution of adherence develops in individual clusters of individuals. We evaluated our method on the data of an mHealth app for tinnitus, and show that our approach is appropriate for the study of adherence in datasets with uneven, unaligned time series of different lengths and with missing values.

Juxtaposing Medical Centers Using Different Questionnaires Through Score Predictors.

Background: Chronic tinnitus is a clinically multidimensional phenomenon that entails audiological, psychological and somatosensory components. Previous research has demonstrated age and female gender as potential risk factors, although studies to this regard are heterogeneous. Moreover, whilst recent research has begun to identify clinical "phenotypes," little is known about differences in patient population profiles at geographically separated and specialized treatment centers. Identifying such differences might prevent potential biases in joint randomized controlled trials (RCTs) and allow for population-specific treatment adaptations. Method: Two German tinnitus treatment centers were compared regarding pre-treatment data distributions of their patient population bases. To identify overlapping as well as center-specific factors, juxtaposition-, similarity-, and meta-data-based methods were applied. Results: Between centers, significant differences emerged. One center demonstrated some predictive power of the patients of the other center with regard to questionnaire score after treatment, indicating similarities in treatment response across center populations. Furthermore, adherence to the completion of the questionnaires was found to be an important factor in predicting post-treatment data. Discussion: Differential age and gender distributions per center should be considered as regards RCT design and individualized treatment planning.

Using Big Data to Develop a Clinical Decision Support System for Tinnitus Treatment.

Tinnitus is a common symptom of a phantom sound perception with a considerable socioeconomic impact. Tinnitus pathophysiology is enigmatic and its significant heterogeneity reflects a wide spectrum of clinical manifestations, severity and annoyance among tinnitus sufferers. Although several interventions have been suggested, currently there is no universally accepted treatment. Moreover, there is no well-established correlation between tinnitus features or patients' characteristics and projection of treatment response. At the clinical level, this practically means that selection of treatment is not based on expected outcomes for the particular patient.The complexity of tinnitus and lack of well-adapted prognostic factors for treatment selection highlight a potential role for a decision support system (DSS). A DSS is an informative system, based on big data that aims to facilitate decision-making based on: specific rules, retrospective data reflecting results, patient profiling and predictive models. Therefore, it can use algorithms evaluating numerous parameters and indicate the weight of their contribution to the final outcome. This means that DSS can provide additional information, exceeding the typical questions of superiority of one treatment versus another, commonly addressed in literature.The development of a DSS for tinnitus treatment selection will make use of an underlying database consisting of medical, epidemiological, audiological, electrophysiological, genetic and tinnitus subtyping data. Algorithms will be developed with the use of machine learning and data mining techniques. Based on the profile features identified as prognostic these algorithms will be able to suggest whether additional examinations are needed for a robust result as well as which treatment or combination of treatments is optimal for every patient in a personalized level.In this manuscript we carefully define the conceptual basis for a tinnitus treatment selection DSS. We describe the big data set and the knowledge base on which the DSS will be based and the algorithms that will be used for prognosis and treatment selection.

Towards a unification of treatments and interventions for tinnitus patients: The EU research and innovation action UNITI.

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.

The Effect of Non-Personalised Tips on the Continued Use of Self-Monitoring mHealth Applications.

Chronic tinnitus, the perception of a phantom sound in the absence of corresponding stimulus, is a condition known to affect patients' quality of life. Recent advances in mHealth have enabled patients to maintain a 'disease journal' of ecologically-valid momentary assessments, improving patients' own awareness of their disease while also providing clinicians valuable data for research. In this study, we investigate the effect of non-personalised tips on patients' perception of tinnitus, and on their continued use of the application. The data collected from the study involved three groups of patients that used the app for 16 weeks. Groups A & Y were exposed to feedback from the start of the study, while group B only received tips for the second half of the study. Groups A and Y were run by different supervisors and also differed in the number of hospital visits during the study. Users of Group A and B underwent assessment at baseline, mid-study, post-study and follow-up, while users of group Y were only assessed at baseline and post-study. It is seen that the users in group B use the app for longer, and also more often during the day. The answers of the users to the Ecological Momentary Assessments are seen to form clusters where the degree to which the tinnitus distress depends on tinnitus loudness varies. Additionally, cluster-level models were able to predict new unseen data with better accuracy than a single global model. This strengthens the argument that the discovered clusters really do reflect underlying patterns in disease expression.

Understanding adherence to the recording of ecological momentary assessments in the example of tinnitus monitoring.

The recording of Ecological Momentary Assessments (EMA) can assist people with chronic diseases in monitoring their health state. However, many users quickly lose interest in their respective EMA platforms. Therefore, we studied the adherence of users of the mHealth app TRACKYOURTINNITUS (TYT). The app is used to record EMA in people with tinnitus. 1292 users, who interacted with the app between April 2014 and February 2017, were analyzed in this work. We defined "adherence" based on the dimensions of interaction duration and interaction continuity. We propose methods that are able to predict the (dis)continuation of interaction with the app and identify user segments that are characterized by similar patterns of adherence. For the prediction task we used the data of the questionnaires MiniTF and TSCHQ, which are filled in when the users enter TYT for the first time. Additionally, time series of the eight items of the daily EMA questionnaire were used. The distribution of user activity pertaining to the adherence dimension of interaction duration revealed a very skewed distribution, with most users giving up after only 1 day of interaction. However, many users returned after interrupting for some time. Some of the MiniTF items indicated that the worries of users might have lead to an increased likelihood of returning back to the app. The MiniTF score itself was not predictive, though. The answers to the TSCHQ items, in turn, pointed to user strata (more than 65 years of age at registration), which tended towards higher interaction continuity. As the registration questionnaires predicted adherence only to a limited extent, it is promising to study the activities of the users in the very first days of interaction more deeply. It turned out in this context that the effects of interaction stimulants like personalized and non-personalized tips, pointers to information sources, and mechanisms used in online treatments for tinnitus (e.g., in iCBT) should be further investigated.