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

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Abstract

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.

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... The primary objective of the UNITI project is the development of a computational model to predict patients' responses to distinct treatments in order to facilitate personalized therapies in tinnitus. For a detailed overview of goals and procedures of the UNITI project, see Schlee et al. [38]. ...
... The blood samples are sent to the Center for Genomics and Oncological Research (GENyO), Universidad de Granada (Granada, Spain) and the plasma samples to the Karolinska Institutet (Stockholm, Sweden) for further analysis of genetic parameters and plasma proteins respectively. Both laboratories are part of the UNITI consortium [38]. Storage, shipping, and analysis of participants biological samples are done according to the EU GDPR (2016/679) as well as country-specific legislations. ...
... The UNITI-RCT aims at making a significant contribution to the personalization of tinnitus treatments by means of the validation of a specific DSS. The system will be developed during the UNITI project [38], in order to support clinicians in choosing the optimal treatment based on an individual patient's profile [39]. Such a system and its underlying computational model has not only the potential to significantly contribute to our understanding of the tinnitus pathology, but also improve clinical practice and the way we are trying to treat tinnitus. ...
Article
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Background Tinnitus represents a relatively common condition in the global population accompanied by various comorbidities and severe burden in many cases. Nevertheless, there is currently no general treatment or cure, presumable due to the heterogeneity of tinnitus with its wide variety of etiologies and tinnitus phenotypes. Hence, most treatment studies merely demonstrated improvement in a subgroup of tinnitus patients. The majority of studies are characterized by small sample sizes, unstandardized treatments and assessments, or applications of interventions targeting only a single organ level. Combinatory treatment approaches, potentially targeting multiple systems as well as treatment personalization, might provide remedy and enhance treatment responses. The aim of the present study is to systematically examine established tinnitus therapies both alone and in combination in a large sample of tinnitus patients. Further, it wants to provide the basis for personalized treatment approaches by evaluating a specific decision support system developed as part of an EU-funded collaborative project (Unification of treatments and interventions for tinnitus patients; UNITI project). Methods/study design This is a multi-center parallel-arm randomized clinical trial conducted at five different clinical sites over the EU. The effect of four different tinnitus therapy approaches (sound therapy, structured counseling, hearing aids, cognitive behavioral therapy) applied over a time period of 12 weeks as a single or rather a combinatory treatment in a total number of 500 chronic tinnitus patients will be investigated. Assessments and interventions are harmonized over the involved clinical sites. The primary outcome measure focuses on the domain tinnitus distress assessed via the Tinnitus Handicap Inventory. Discussion Results and conclusions from the current study might not only provide an essential contribution to combinatory and personalized treatment approaches in tinnitus but could also provide more profound insights in the heterogeneity of tinnitus, representing an important step towards a cure for tinnitus. Trial registration ClinicalTrials.gov NCT04663828 . Registered on 11 December 2020.
... The blood samples are sent to the Center for Genomics and Oncological Research (GENyO), Universidad de Granada (Granada, Spain) and the plasma samples to the Karolinska Institutet (Stockholm, Sweden) for further analysis of genetic parameters and plasma proteins respectively. Both laboratories are part of the UNITI consortium [38]. Storage, shipping and analysis of participants biological samples are done according to the EU GDPR (2016/679) as well as country speci c legislations. ...
... The UNITI-RCT aims at making a signi cant contribution to the personalization of tinnitus treatments by means of the validation of a speci c DSS. The system will be developed during the UNITI-project [38], in order to support clinicians in choosing the optimal treatment based on an individual patient`s pro le [39]. Such a system and its underlying computational model has not only the potential to signi cantly contribute to our understanding of the tinnitus pathology, but also improve clinical practice and the way we are trying to treat tinnitus. ...
... One employee of Sivantos Pte. Ltd/ WSAudiology is part of the External Advisory Board of the UNITI project[38], but has no in uence on the conduction of the RCT. The results of the study are only made available to companies or external authorities via peer-reviewed publications.Author contributions The authors BL, WS, MS, BM, JL, DK, RC and SS (Stefan Schoisswohl) are main responsible for the conceptualization of the study. ...
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Background Tinnitus represents a relatively common condition in the global population accompanied by various comorbidities and severe burden in many cases. Nevertheless, there is currently no general treatment or cure, presumable due to the heterogeneity of tinnitus with its wide variety of etiologies and tinnitus phenotypes. Hence, most treatment studies merely demonstrated improvement in a subgroup of tinnitus patients. The majority of studies are characterized by small sample sizes, unstandardized treatments and assessments or applications of intervention targeting only a single organ level. Combinatory treatment approaches, potentially targeting multiple systems as well as treatment personalization might provide remedy and enhance treatment responses. The aim of the present study is to systematically examine established tinnitus therapies both alone and in combination in a large sample of tinnitus patients. Further it wants to provide the basis for personalized treatment approaches by evaluating a specific decision support system developed as part of an EU-funded collaborative project (Unification of treatments and interventions for tinnitus patients; UNITI-project). Methods/ Study design This is a multi-center parallel-arm randomized clinical trial conducted at five different clinical sites over the EU. The effect of four different tinnitus therapy approaches (sound therapy, structured counselling, hearing aids, cognitive behavioral therapy) applied over a time period of 12 weeks as a single or rather a combinatory treatment in a total number of 500 chronic tinnitus patients will be investigated. Assessments and interventions are harmonized over the involved clinical sites. The primary outcome measure focuses on the domain tinnitus distress assessed via the Tinnitus Handicap Inventory. Discussion Results and conclusions from the current study might not only provide an essential contribution to combinatory and personalized treatment approaches in tinnitus but could also provide more profound insights in the heterogeneity of tinnitus, representing an important step towards a cure for tinnitus. Trial registration ClinicalTrials.gov: NCT04663828. Registered on 11. December 2020
... A systematic review of the tinnitus literature including Randomized Clinical Trial (RCTs) has been conducted aiming towards the identification of common methodological flaws and insufficiencies. Finally, a brief overview of a Decision Support System (DSS) which is the core outcome of EU-funded project Unification of Treatments and Interventions for Tinnitus Patients (UNITI) is presented [12]. The DSS takes into account epidemiological data, audiological measurements, genetic background and socioeconomic data in order to choose the optimal treatment out of the most widely used treatments (sound therapy, sound amplification, Cognitive Behavioral Therapy and Structured Counselling) at an individualized level [12]. ...
... Finally, a brief overview of a Decision Support System (DSS) which is the core outcome of EU-funded project Unification of Treatments and Interventions for Tinnitus Patients (UNITI) is presented [12]. The DSS takes into account epidemiological data, audiological measurements, genetic background and socioeconomic data in order to choose the optimal treatment out of the most widely used treatments (sound therapy, sound amplification, Cognitive Behavioral Therapy and Structured Counselling) at an individualized level [12]. ...
... A potential solution to this could be the use of ecological momentary assessment, which is commonly integrated through mobile applications and allows ongoing recording of fluctuations in tinnitus severity as well as the correlation with certain incidents and behaviors which are captured at the same time (e.g., environmental noise, road traffic, etc.) [12]. This approach, if not well designed or capable of adjustments, may contradict efforts of habituation, since it requires that patients be frequently occupied with their tinnitus and its characteristics. ...
Article
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Although a wide range of tinnitus management interventions is currently under research and a variety of therapeutic interventions have already been applied in clinical practice, no optimal and universal tinnitus treatment has been reached yet. This fact is to some extent a consequence of the high heterogeneity of the methodologies used in tinnitus related clinical studies. In this manuscript, we have identified, summarized, and critically appraised tinnitus-related randomized clinical trials since 2010, aiming at systematically mapping the research conducted in this area. The results of our analysis of the 73 included randomized clinical trials provide important insight on the identification of limitations of previous works, methodological pitfalls or gaps in current knowledge, a prerequisite for the adequate interpretation of current literature and execution of future studies.
... The tinnitus research field has benefited from multidisciplinary consortia such as the Tinnitus Research Initiative (TRI) , the TINnitus research NETwork (TINNET, 2014), the European School on Interdisciplinary Tinnitus Research (ESIT) , the Tinnitus Genetic and Environmental Risks (TIGER, 2019), the TINnitus -Assessment, Causes and Treatments (TIN-ACT, 2017), and the Unification of Treatments and Interventions for Tinnitus Patients (Schlee et al., 2021). Despite all the efforts by these welcomed initiatives, tinnitus still remains an under-researched field. ...
... In addition, different applications of simultaneous multimodal stimulation have shown promising results e.g., combination of sound and somatosensory stimulation (Marks et al., 2018;Conlon et al., 2020). Another example of combination of approaches is the ongoing UNITI clinical trial (Schlee et al., 2021), where different interventions, including CBT, structured counseling, sound therapy, and hearing aids will be investigated in a randomized controlled trial for their effects when delivered individually and in combination with one another. ...
Article
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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.
... Funding: This work was partly funded by the ESIT (European School for Interdisciplinary Tinnitus Research [49]) project, which is financed by European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement number 722046 and the UNITI (Unification of Treatments and Interventions for Tinnitus Patients) project financed by the European Union's Horizon 2020 Research and Innovation Programme, Grant Agreement Number 848261 [50]. This publication was supported by the Open Access Publication Fund of the University of Würzburg. ...
Article
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Tinnitus is an auditory phantom perception without external sound stimuli. This chronic perception can severely affect quality of life. Because tinnitus symptoms are highly heterogeneous, multimodal data analyses are increasingly used to gain new insights. MHealth data sources, with their particular focus on country- and season-specific differences, can provide a promising avenue for new insights. Therefore, we examined data from the TrackYourTinnitus (TYT) mHealth platform to create symptom profiles of TYT users. We used gradient boosting engines to classify momentary tinnitus and regress tinnitus loudness, using country of origin and season as features. At the daily assessment level, tinnitus loudness can be regressed with a mean absolute error rate of 7.9% points. In turn, momentary tinnitus can be classified with an F1 score of 93.79%. Both results indicate differences in the tinnitus of TYT users with respect to season and country of origin. The significance of the features was evaluated using statistical and explainable machine learning methods. It was further shown that tinnitus varies with temperature in certain countries. The results presented show that season and country of origin appear to be valuable features when combined with longitudinal mHealth data at the level of daily assessment.
... In addition, a smartphone application will offer the patients a daily exercise program, based upon the standard physiotherapy treatment for ST [14][15][16][17][18][19][20][21][22], and psychological tinnitus counselling. This tinnitus counselling program consists of two sessions a week and is developed by psychologists of the University of Regensburg [64,65]. Before the start of the program, the exercises will be tailored to the area, type and degree of the patient's dysfunctions. ...
Article
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Background Tinnitus is a highly prevalent symptom, affecting 10–15% of the adult population. Tinnitus influenced by alterations in somatosensory afference from the neck or jaw is referred to as somatic tinnitus (ST). ST is known to respond positively to physiotherapy treatment; however, it is challenging to motivate patients to systematically perform home exercises correctly, and the necessary tinnitus counselling is often lacking. The aim of this study is twofold, namely to investigate both the effectiveness and cost-effectiveness of a blended physiotherapy program for ST, including a smartphone application designed to increase exercise therapy compliance and provide tinnitus counselling. Methods This study is designed as a single-blind two-arm 1:1 randomised controlled trial (RCT). Adult patients diagnosed with ST, without psychiatric comorbidities and with experience in using a smartphone, will be recruited at the Ear Nose Throat (ENT) department of the Antwerp University Hospital (UZA). Patients will be randomised into two groups. The experimental group will receive the blended physiotherapy program comprising six in-clinic physiotherapy sessions over a period of 12 weeks (1x/2 weeks) and an exercise and counselling program provided by the smartphone application. The control group will receive the standard care program comprising twelve weekly in-clinic physiotherapy sessions. Each physiotherapy session has a duration of 30 min. The primary outcome measure is the change in Tinnitus Functional Index (TFI) score. Additionally, a cost-effectiveness analysis will be performed from a societal perspective considering both direct and indirect costs. There will be follow-up assessments at one and 3 months after the final treatment session. Discussion Our study is the first to combine both tinnitus counselling and neck/jaw treatment provided by a digital application in a blended physiotherapy program. This, in order to empower ST patients to improve and better manage their own health and, possibly, reduce economic costs by alleviating the tinnitus burden that ST patients experience. The strengths of the planned RCT are the high-quality methodological design, the large sample size and the expertise of the involved multidisciplinary research team. Trial registration Clinicaltrials.gov NCT05245318. Registered on 26 January 2022.
... The data were stored in a BrainVision data format [24]: One electroencephalography (.eeg) file, containing binary data from 62 EEG and 2 ECG channels (i.e., the voltage values), a text header file (.vhdr), containing meta data, and a text marker file (.vmrk), containing information about the events in the data. Note that project is carried out within the scope of the UNITI project, which aims to unify treatment and interventions for tinnitus patients in a pan-European setting [25]. ...
Conference Paper
Tinnitus is attributed by the perception of a sound without any physical source causing the symptom. Symptom profiles of tinnitus patients are characterized by a large heterogeneity, which is a major obstacle in developing general treatments for this chronic disorder. As tinnitus patients often report severe constraints in their daily life, the lack of general treatments constitutes such a challenge that patients crave for any kind of promising method to cope with their tinnitus, even if it is not based on evidence. Another drawback constitutes the lack of objective measurements to determine the individual symptoms of patients. Many data sources are therefore investigated to learn more about the heterogeneity of tinnitus patients in order to develop methods to measure the individual situation of patients more objectively. As research assumes that tinnitus is caused by processes in the brain, electroencephalography (EEG) data are heavily investigated by researchers. Following this, we address the question whether EEG data can be used to classify tinnitus using a deep neural network. For this purpose, we analyzed 16,780 raw EEG samples from 42 subjects (divided into tinnitus patients and control group), with a duration of one second per sample. Four different procedures (with or without noise reduction and down-sampling or up-sampling) for automated preprocessing were used and compared. Subsequently, a neural network was trained to classify whether a sample refers to a tinnitus patient or the control group. We obtain a maximum accuracy in the test set of 75.6% using noise reduction and down-sampling. Our findings highlight the potential of deep learning approaches to detect EEG patterns for tinnitus patients as they are difficult to be recognized by humans.
... Identifying the economic burden of tinnitus in various cost categories is crucial to better understand tinnitus healthcare organization and treatment implementation in current practice in various countries and consequently reduce unnecessary costly and ineffective treatment strategies for patients and healthcare systems. Funding: This research is part of the UNITI (Unification of Treatments and Interventions for Tinnitus Patients) project and has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement number 848261 [25]. The work of CRC, SG and AL is partially supported by the GENDER-Net Co-Plus Fund (GNP-182). ...
Article
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Tinnitus disability is a heterogeneous and complex condition, affecting more than 10% and compromising the quality of life of 2% of the population, with multiple contributors, often unknown, and enigmatic pathophysiology. The available treatment options are unsatisfactory, as they can, at best, reduce tinnitus severity, but not eliminate its perception. Given the spread of tinnitus and the lack of a standardized treatment, it is crucial to understand the economic burden of this condition. We conducted a systematic review of the literature on PubMed/MEDLINE, Embase, the Cochrane Database of Systematic Reviews (CDSR) and Google Scholar, in order to identify all the articles published on the economic burden of tinnitus before 1 April 2021 (PROSPERO—International prospective register of systematic reviews—No: CRD42020180438). Out of 273 articles identified through our search strategy, only five articles from studies conducted in the United States of America (USA), the Netherlands and the United Kingdom (UK) provided data on tinnitus’s economic costs. Three studies provided mean annual estimates per patient ranging between EUR 1544 and EUR 3429 for healthcare costs, between EUR 69 and EUR 115 for patient and family costs and between EUR 2565 and EUR 3702 for indirect costs, including productivity loss. The other two studies reported an annual mean cost of EUR 564 per patient for tinnitus-related clinical visits, and total costs of EUR 1388 and EUR 3725 for patients treated with a sound generator and Neuromonics Tinnitus Treatment, respectively. Our comprehensive review shows a gap in the knowledge about the economic burden of tinnitus on healthcare systems, patients and society. The few available studies show considerable expenses due to healthcare and indirect costs, while out-of-pocket costs appear to be less financially burdensome. Comprehensive health economic evaluations are needed to fill the gaps in current knowledge, using a unified method with reliable and standardized tools.
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Tinnitus is an auditory phantom perception in the ears or head in the absence of a corresponding external stimulus. There is currently no effective treatment available that reliably reduces tinnitus. Educational counseling is a treatment approach that aims to educate patients and inform them about possible coping strategies. For this feasibility study, we implemented educational material and self-help advice in a smartphone app. Participants used the educational smartphone app unsupervised during their daily routine over a period of four months. Comparing the tinnitus outcome measures before and after smartphone-guided treatment, we measured changes in tinnitus-related distress, but not in tinnitus loudness. Improvements on the Tinnitus Severity numeric rating scale reached an effect size of 0.408, while the improvements on the Tinnitus Handicap Inventory (THI) were much smaller with an effect size of 0.168. An analysis of user behavior showed that frequent and intensive use of the app is a crucial factor for treatment success: participants that used the app more often and interacted with the app intensively reported a stronger improvement in the tinnitus. Between study allocation and final assessment, 26 of 52 participants dropped out of the study. Reasons for the dropouts and lessons for future studies are discussed in this paper.
Article
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Background: The heterogeneity of tinnitus is thought to underlie the lack of objective diagnostic measures. Methods: Longitudinal data from 20,349 participants of the Swedish Longitudinal Occupational Survey of Health (SLOSH) cohort from 2008 to 2018 was used to understand the dynamics of transition between occasional and constant tinnitus. The second part of the study included electrophysiological data from 405 participants of the Swedish Tinnitus Outreach Project (STOP) cohort. Results: We determined that with increasing frequency of the occasional perception of self-reported tinnitus, the odds of reporting constant tinnitus after 2 years increases from 5 for previous tinnitus (sometimes) to 30 for previous tinnitus (often). When previous tinnitus was reported to be constant, the odds of reporting it as constant after 2 years rose to 603, suggesting that once transitioned to constant tinnitus, the likelihood of tinnitus to persist was much greater. Auditory brainstem responses (ABRs) from subjects reporting non-tinnitus (controls), occasional tinnitus, and constant tinnitus show that wave V latency increased in constant tinnitus when compared to occasional tinnitus or non-tinnitus. The ABR from occasional tinnitus was indistinguishable from that of the non-tinnitus controls. Conclusions: Our results support the hypothesis that the transition from occasional to constant tinnitus is accompanied by neuronal changes in the midbrain leading to a persisting tinnitus, which is then less likely to remit. Trial registration: Not applicableFUNDING. This study was supported by the GENDER-Net Co-Plus Fund (GNP-182), the European Union's Horizon 2020 Grant No. 848261 (UNITI) and No. 722046 (ESIT).
Conference Paper
More and more observational studies exploit the achievements of mobile technology to ease the overall implementation procedure. Many strategies like digital phenotyping, ecological momentary assessments or mobile crowdsensing are used in this context. Recently, an increasing number of intervention studies makes use of mobile technology as well. For the chronic disorder tinnitus, only few long-running intervention studies exist, which use mobile technology in a larger setting. Tinnitus is characterized by its heterogeneous patient's symptom profiles, which complicates the development of general treatments. In the UNITI project, researchers from different European countries try to unify existing treatments and interventions to cope with this heterogeneity. One study arm (UNITI Mobile) exploits mobile technology to investigate newly implemented interventions types, especially within the pan-European setting. The goals are to learn more about the validity and usefulness of mobile technology in this context. Furthermore, differences among the countries shall be investigated. Practically, two native intervention apps have been developed for UNITI and the mobile study arm, which pose features not presented so far in other apps of the authors. Along the implementation procedure, it is discussed whether these features might leverage similar types of studies in future. Since instruments like the mHealth evidence reporting and assessment checklist (mERA), developed by the WHO mHealth technical evidence review group, indicate that aspects shown for UNITI Mobile are important in the context of health interventions using mobile phones, our findings may be of a more general interest and are therefore being discussed in the work at hand.
Conference Paper
Tinnitus is the perception of a phantom sound and the individual's reaction to it. Although much progress has been made, tinnitus remains an unresolved scientific and clinical issue, affecting more than 10% of the general population and having a high prevalence and socioeconomic burden. Clinical decision support systems (CDSS) are used to assist clinicians in their complex decision-making processes, having been proved that they improve healthcare delivery. In this paper, we present a CDSS for tinnitus, attempting to address the question which treatment approach is optimal for a particular patient based on specific parameters. The CDSS will be developed in the context of the EU-funded "UNITI" project and, after the project completion, it will be able to determine the suitability and expected attachment of a particular patient to a list of available clinical interventions, utilizing predictive and classification machine learning models.Clinical Relevance - The proposed clinically utilizable CDSS will be able to suggest the optimal treatment strategy for the tinnitus patient based on a set of heterogeneous data.
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Conference Paper
Electronic health records (EHR) often include multiple perspectives on a patient's current state of well-being (e.g. vital signs and subjective indicators measured by questionnaires). In this study, we use these perspectives to build phenotypes of chronic tinnitus patients and investigate how these phenotypes are associated with response to treatment. Therefore, we model patients as nodes in a network, where those perspectives are interpreted as layers of a multi-layer network. To identify phenotypes of patients in the network, we implement a community detection algorithm. Some of these communities can be considered as phenotypes if they represent subgroups of patients that are similar according to the investigated perspectives. Furthermore, we analyze the influence of the layers on the final community structure of patients. We then propose a method to add layers given their community structure similarity. Finally, we fit a model, per community, to predict the treatment outcome. In some communities, this prediction outperformed the baseline scenario where the predictor was fitted to all patients.
Chapter
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.
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Towards an Understanding of Tinnitus Heterogeneity Despite being a common condition that affects nearly 15% of the population, and despite much research progress made in the recent years, tinnitus remains a scientific and clinical enigma. Subjective tinnitus is defined as a phantom perception of a tone or noise in the absence of any physical source. It is known to be a heterogeneous condition, both in the way of manifestation and of generation. In general, “heterogeneity” describes the fact that there is a non-uniform appearance of a substance, organism, or disease. Whenever there is a non-uniformity in at least one quality, we can call it “heterogeneous.” Tinnitus patients differ on at least four dimensions: First, tinnitus patients may present diverse clinical profiles with respect to the perception of tinnitus (e.g., laterality of tinnitus, tinnitus pitch, ringing, buzzing, hissing, or cricket sounds). Additionally, tinnitus can be occasional or permanent, acute or chronic, pulsatile, or constant. Second, while there are multiple ways of perceiving tinnitus, it is also associated with multiple causal risk factors—hearing loss, temporomandibular joint disorder, and aging being among the most common ones. There are also numerous related comorbidities that add to the complex clinical picture of tinnitus (e.g., hyperacusis, depression, sleep disorders, headache, concentration problems). A third dimension is the associated tinnitus distress, the psychological reaction to the ongoing tinnitus perception; it can differ largely among patients. Fourth, there is a large variation of treatment responses of the tinnitus patients. With the heterogeneity in these four dimensions, we describe a diversity of observable qualities that can be investigated with the currently available research. The current interpretation of this observed heterogeneity is that several different tinnitus subtypes may exist and that these different subtypes may have different etiologies, different clinical profiles and different treatment responses. So far, the number of the potentially existing tinnitus subtypes is not known, nor the diagnostic criteria to identify them. The situation gets even more complex when we consider patients with a combination of several subtypes. This heterogeneity culminates in the challenge for tinnitus treatment: A uniformly effective treatment for all tinnitus patients is unlikely. For each individual patient, a personalized treatment plan has to be developed, considering the tinnitus profile, the comorbidities, the psychological distress and the previous treatment experiences of the patient. To solve this clinical enigma, conceptual models of tinnitus are needed to develop innovative solutions for personalized medicine. The aim of this research topic is to investigate the challenge of tinnitus heterogeneity by involving multiple disciplines ranging from neuroscience, neurology, genetics, audiology, otolaryngology, psychology, psychiatry, pharmacology, epidemiology, medical informatics, data mining, and statistics. The main idea is to move away from an abstract view of tinnitus toward an detailed understanding of what could constitute tinnitus subtypes in view of improving fundamental knowledge and ultimately lead to optimized therapeutic interventions. Within this topic, current knowledge is reviewed and new theories of tinnitus generation are proposed, animal models are used to understand the neural correlates better, audiological, and psychological aspects are explored, neuroimaging techniques investigate the involved brain networks, new questionnaire instruments are developed and others adapted to new languages, genome-wide associations are pioneered, mobile applications are used to explore tinnitus on new time-scales, and, finally, multiple therapeutic approaches are tested. Statistics on this research topic: The research topic was open between February 18, 2016 and October 29, 2017. It received 96 submissions by 335 authors. 79 submissions were finally accepted after a rigorous and constructive reviewing process. During the phase in which the topic was active, it received over two million views.
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Tinnitus is a common medical condition which interfaces many different disciplines, yet it is not a priority for any individual discipline. A change in its scientific understanding and clinical management requires a shift toward multidisciplinary cooperation, not only in research but also in training. The European School for Interdisciplinary Tinnitus research (ESIT) brings together a unique multidisciplinary consortium of clinical practitioners, academic researchers, commercial partners, patient organizations, and public health experts to conduct innovative research and train the next generation of tinnitus researchers. ESIT supports fundamental science and clinical research projects in order to: (1) advancing new treatment solutions for tinnitus, (2) improving existing treatment paradigms, (3) developing innovative research methods, (4) performing genetic studies on, (5) collecting epidemiological data to create new knowledge about prevalence and risk factors, (6) establishing a pan-European data resource. All research projects involve inter-sectoral partnerships through practical training, quite unlike anything that can be offered by any single university alone. Likewise, the postgraduate training curriculum fosters a deep knowledge about tinnitus whilst nurturing transferable competencies in personal qualities and approaches needed to be an effective researcher, knowledge of the standards, requirements and professionalism to do research, and skills to work with others and to ensure the wider impact of research. ESIT is the seed for future generations of creative, entrepreneurial, and innovative researchers, trained to master the upcoming challenges in the tinnitus field, to implement sustained changes in prevention and clinical management of tinnitus, and to shape doctoral education in tinnitus for the future.
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For understanding the heterogeneity of tinnitus, large samples are required. However, investigations on how samples recruited by different methods differ from each other are lacking. In the present study, three large samples each recruited by different means were compared: N = 5017 individuals registered at a self-help web platform for tinnitus (crowdsourcing platform Tinnitus Talk), N = 867 users of a smart mobile application for tinnitus (crowdsensing platform TrackYourTinnitus), and N = 3786 patients contacting an outpatient tinnitus clinic (Tinnitus Center of the University Hospital Regensburg). The three samples were compared regarding age, gender, and duration of tinnitus (month or years perceiving tinnitus; subjective report) using chi-squared tests. The three samples significantly differed from each other in age, gender and tinnitus duration (p < 0.05). Users of the TrackYourTinnitus crowdsensing platform were younger, users of the Tinnitus Talk crowdsourcing platform had more often female gender, and users of both newer technologies (crowdsourcing and crowdsensing) had more frequently acute/subacute tinnitus (<3 months and 4–6 months) as well as a very long tinnitus duration (>20 years). The implications of these findings for clinical research are that newer technologies such as crowdsourcing and crowdsensing platforms offer the possibility to reach individuals hard to get in contact with at an outpatient tinnitus clinic. Depending on the aims and the inclusion/exclusion criteria of a given study, different recruiting strategies (clinic and/or newer technologies) offer different advantages and disadvantages. In general, the representativeness of study results might be increased when tinnitus study samples are recruited in the clinic as well as via crowdsourcing and crowdsensing.
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Purpose: Genetic contributions to tinnitus have been difficult to determine due to the heterogeneity of the condition and its broad etiology. Here, we evaluated the genetic and nongenetic influences on self-reported tinnitus from the Swedish Twin Registry (STR). Methods: Cross-sectional data from the STR was obtained. Casewise concordance rates (the risk of one twin being affected given that his/her twin partner has tinnitus) were compared for monozygotic (MZ) and dizygotic (DZ) twin pairs (N = 10,464 concordant and discordant twin pairs) and heritability coefficients (the proportion of the total variance attributable to genetic factors) were calculated using biometrical model fitting procedures. Results: Stratification of tinnitus cases into subtypes according to laterality (unilateral versus bilateral) revealed that heritability of bilateral tinnitus was 0.56; however, it was 0.27 for unilateral tinnitus. Heritability was greater in men (0.68) than in women (0.41). However, when female pairs younger than 40 years of age were selected, heritability of 0.62 was achieved with negligible effects of shared environment. Conclusion: Unlike unilateral tinnitus, bilateral tinnitus is influenced by genetic factors and might constitute a genetic subtype. Overall, our study provides the initial evidence for a tinnitus phenotype with a genetic influence.Genet Med advance online publication 23 March 2017Genetics in Medicine (2017); doi:10.1038/gim.2017.4.
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A nearly endless number of procedures has been tried and in particular sold for the treatment of tinnitus, unfortunately they have not been evaluated appropriately in an evidence-based way. A causal therapy, omitting the tinnitus still does not exist, actually it cannot exist because of the various mechanisms of its origin. However or perhaps because of that, medical interventions appear and reappear like fashion trends that can never be proven by stable and reliable treatment success. This contribution will discuss and acknowledge all current therapeutic procedures and the existing or non-existing evidence will be assessed. Beside external evidence, the term of evidence also encompasses the internal evidence, i.e. the experience of the treating physician and the patient’s needs shall be included. While there is no evidence for nearly all direct procedures that intend modulating or stimulating either the cochlea or specific cervical regions such as the auditory cortex, there are therapeutic procedures that are acknowledged in clinical practice and have achieved at least a certain degree of evidence and generate measurable effect sizes. Those are in particular habituation therapy and psychotherapeutic measures, especially if they are combined with concrete measures for improved audio perception (hearing aids, CI, hearing therapies).
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Tinnitus is the perception of phantom sound in the absence of a corresponding external source. It is a highly prevalent disorder, and most cases are caused by cochlear injury that leads to peripheral deafferentation, which results in adaptive changes in the CNS. In this article we critically assess the recent neuroimaging studies in individuals with tinnitus that suggest that the disorder is accompanied by functional and structural brain abnormalities in distributed auditory and non-auditory brain regions. Moreover, we consider how the identification of the neuronal mechanisms underlying the different forms of tinnitus would benefit from larger studies, replication and comprehensive clinical assessment of patients.
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Tinnitus is the perception of sound in the absence of an external source. Genetic studies on families, twins, and adoptees cohorts have been conducted supporting tinnitus heritability, with higher heritability in men with bilateral tinnitus at any age, and young women with bilateral tinnitus, but not in unilateral tinnitus. The condition is associated with several comorbidities such as hearing loss, Meniere disease, sleep disorders, depression, and migraine and may lead toward suicidal attempts in extreme cases. Several studies have reported few regulatory allelic variants in candidate genes and pathways associated with tinnitus development, but replication studies are needed to validate them.
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Objectives: The aim of this study was to examine the costs of tinnitus in The Netherlands from a health care and a societal perspective. Furthermore, the impact of disease characteristics and demographic characteristics on these costs were examined. Methods: A bottom-up cost of illness study was performed, using the baseline data on a cost questionnaire of a randomized controlled trial investigating the (cost) effectiveness of an integral multidisciplinary treatment for tinnitus versus care as usual. Mean yearly costs were multiplied by the prevalence figure of tinnitus for the adult general population to estimate the total cost of illness of tinnitus to society. Because cost data usually are not normally distributed, a nonparametric bootstrap resampling procedure with 1000 simulations was performed to determine statistical uncertainty of the cost estimates per category. Several questionnaires measuring disease and demographic characteristics were administered. The impact of disease characteristics and demographics on costs was investigated using a multivariate regression analysis. Results: Total mean societal cost of illness was €6.8 billion (95% confidence interval: €3.9 billion-€10.8 billion). The larger part of total cost of illness was not related to health care. Total mean health care costs were €1.9 billion (95% confidence interval: €1.4 billion-€2.5 billion). Significant predictors of both health care costs and societal costs were tinnitus severity, age, shorter duration of tinnitus, and more severe depression. Conclusion: The economical burden of tinnitus to society is substantial, and severity of tinnitus is an important predictor of the costs made by patients.
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Recent research suggests that hearing impairment is declining among older adults compared with earlier generations of the same age. Tinnitus is often associated with hearing impairment, so one might hypothesize that the prevalence of tinnitus is declining in a similar manner. The purpose of this study was to use multigenerational data with repeated measures to determine whether the prevalence of tinnitus is declining among more recent generations. Using data from the Epidemiology of Hearing Loss Study (1993-1995, 1998-2000, 2003-2005, and 2009-2010) and the Beaver Dam Offspring Study (2005-2008), the authors examined birth cohort patterns in the report of tinnitus for adults aged 45 years and older (n =12,689 observations from 5764 participants). Participants were classified as having tinnitus if they reported tinnitus in the past year of at least moderate severity or that caused difficulty falling asleep. A low-frequency (500, 1000, and 2000 Hz) and high-frequency (3000, 4000, 6000, and 8000 Hz) pure tone average from the worse ear was used to summarize hearing status. Other potential risk factors for tinnitus were also explored to determine if changes in the prevalence of these factors over time could explain any observed birth cohort differences in the prevalence of tinnitus. These included the following: education, history of head injury, history of doctor-diagnosed ear infections, history of cardiovascular disease (myocardial infarction, stroke, or angina), current noisy job, longest-held job, target shooting in the past year, number of concerts ever attended, alcohol use in the past year, doctor diagnosis of arthritis, current aspirin use, regular exercise, and consulting with a physician in the past year about any hearing/ear problem. Birth cohort effects were modeled with alternating logistic regression models which use generalized estimating equations to adjust for correlation among repeated measurements over time that are nested within families. The report of tinnitus tended to increase with more recent birth cohorts compared with earlier birth cohorts. For example, at ages 55 to 59 years, 7.6% of participants born between 1935 and 1939 reported tinnitus, compared with 11.0% of those born in 1940 to 1944, 13.6% of those born between 1945 and 1949, and 17.5% of those born between 1950 and 1954. Similarly, at ages 65 to 69 years, 7.9% of participants born between 1925 and 1929 reported tinnitus, compared with 10.0% of those born between 1930 and 1934, 11.9% of those born between 1935 and 1939, and 13.7% of those born between 1940 and 1944. Final alternating logistic regression model results indicated that, on average, after adjusting for age and other factors, participants in a given generation were significantly more likely to report tinnitus than participants from a generation 20 years earlier (odds ratio = 1.78, 95% confidence interval = 1.44, 2.21). Increased reports of tinnitus may reflect increased prevalence of symptoms, increased awareness of symptoms, or higher health expectations among more recent generations of adults. Regardless of the reasons, the increasing prevalence of tinnitus suggests that health care providers may see an increased number of patients bothered by this common but little understood symptom.
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Hearing problems are among the top 10 most common burdens of disease and are projected to be become even more common by the year 2030. The aim of the present study was to give a current assessment of the prevalence of communication difficulties because of hearing loss and tinnitus, in the general Swedish working and non-working populations in relation to sex, age, socioeconomic status (SES) and noise exposure. How prevalence is affected by SES has not been previously established. A total of 18 734 individuals were invited to participate in the study, of which 11 441 (61%) enrolled. Of the participants, 9756 answered the questionnaire for those who work and 1685 answered the version for non-workers. The most important findings are that 31% in the working population and 36% in the non-working population report either hearing loss or tinnitus or both. The prevalence of hearing problems increases with age, is higher among men and persons with low self-rated SES, and covaries with exposure to noise at work. Severe hearing problems are already present in men and women under 40 years of age who are exposed to work-related noise. Prevalence of hearing problems is far more common than previously estimated and is associated with SES and noise exposure history. Hearing problems have a gradual onset that can take years to become recognised. In order to proactively intervene and prevent this deleterious, yet avoidable handicap, statistics need to be regularly updated.