The study comprises a 2-arm randomized controlled clinical trial (NCT03945617). The study design and assessments are depicted in Figure 1.

Participants are randomly assigned to either a CBT group [18] following the UP or a waitlist control condition (WAIT) at a ratio of 3:1. In the CBT condition, participants receive an average of 16 weekly treatment sessions, and in the WAIT condition, participants undergo a waiting period of 16 weeks before receiving the same treatment. The WAIT condition is implemented to further test the specificity of predictive models.

In total, 3 main assessments are implemented at baseline, midtreatment (week 8), and posttreatment (week 16). For the CBT group, follow-up assessments at 6 and 12 months (follow-up 1 and 2) are conducted to index anxiety and depression symptom severity. The predictive features indexed at baseline are psychological, behavioral, and neurobiological features, as well as digital variables reflecting core transdiagnostic factors, such as emotion regulation, self-efficacy, learning abilities and biases, physical activity, and sleep.

Study participants are recruited via social media, mailing lists, newspaper articles, a study website, and through general practitioners’ offices and self-help groups located in Zurich. Participants are reimbursed for their time and expenses with 120 Swiss francs (US $134.62).

Participants with a primary anxiety diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, as assessed by the Mini International Neuropsychiatric Interview (MINI), German version 5.0 [19], are eligible to participate. Other inclusion criteria are as follows: (1) current diagnosis of an anxiety disorder as the primary diagnosis (eg, panic disorder with or without agoraphobia, social anxiety disorder, generalized anxiety disorder, anxiety disorder not otherwise specified, adjustment disorder with anxiety or adjustment disorder with mixed anxiety, and depressed mood); (2) aged between 18 and 65 years; (3) fluent in German; (4) currently not receiving psychotherapy; (5) provision of written informed consent; and (6) if on medication, stable dose(s) with no changes 3 months prior to treatment. Exclusion criteria are as follows: (1) medical contraindications and conditions that impede exposure (ie, cardiovascular diseases and autoimmune diseases); (2) current or past schizophrenia, psychosis, or bipolar disorder and current substance dependence or abuse (except for nicotine); (3) cluster A or B personality disorder; and (4) current suicidal ideation.

For the planned analyses using ML algorithms, no established methods are available to determine the required sample size. Although sensitivity is less of a concern in ML, overfitting represents a significant risk. In this study, this risk will be addressed by assessing the generalizability of the estimated models using k-fold cross-validation and by implementing a loss function to penalize complex models [20,21]. It is planned to include 112 participants in the CBT group and 38 participants in the WAIT group. Data from the CBT group will be split into a training data set and a test data set at a ratio of 3:2 [22].

We used a transdiagnostic protocol to treat anxiety [18], which comprised 16 weekly individual CBT sessions. The first 2 sessions were scheduled to last 60-90 minutes, while the following sessions were scheduled for around 60 minutes. To ensure protocol fidelity, psychotherapists received a UP training course as well as ongoing supervision by a clinical expert. The UP comprised 8 different modules, as follows: (1) introduction and motivation enhancement, (2) identifying and understanding emotions, (3) emotional awareness training, (4) cognitive flexibility training, (5) emotional avoidance and emotion-driven behaviors, (6) awareness and tolerance of bodily sensations, (7) interoceptive and situation-based exposures, and (8) relapse prevention. The UP is relatively standardized, and patients will work through their individual workbooks along with the modules. We also used an additional form to assess basic anamnestic information (eg, family of origin, marital status, and hobbies) using a standard protocol. An individualized case conceptualization is implemented according to a template after the first session. UP workbooks are handed to patients at the first session and primarily comprise psychoeducational content and instructions for exercises (eg, symptom monitoring protocols and exposure exercises), which are given as homework, and the content of each homework will be briefly discussed with the patients in the following session.

The study therapists (AS, MMB, DR, and CP) are trained clinical psychologists with several years of clinical experience who treat CBT and WAIT participants in approximately equal proportions. All therapists receive UP-specific training through workshops from the Center for Anxiety and Related Disorders at Boston University. Supervision is provided to study therapists by an experienced expert clinician (BS) to further enhance treatment fidelity and general quality. To estimate treatment fidelity, a random sample of 10% of all videotaped sessions will be rated for treatment fidelity based on standardized adherence ratings by an expert rater who is not involved in the study.

Multimedia Appendix 1 provides an overview of all measurements and their assessment time points.

Core clinical, behavioral, psychological, and neural characteristics are assessed as predictive features; an overview of these assessments is available in Multimedia Appendix 1. Variable selection is based on empirical and conceptual evidence.

Prior to participation, participants receive information on procedures and study goals and undergo a telephone screening for the presence of inclusion and exclusion criteria. Those eligible for the study are invited to a baseline assessment, which comprises several assessment days conducted at the outpatient center, where therapy sessions will also take place. After obtaining written informed consent, participants undergo a clinical interview and complete clinical questionnaires. Assessors are trained graduate-level clinical psychologists supervised by trained clinicians. On assessment days 2 and 3, biological specimens (eg, salvia and buccal swabs) are taken, and an additional questionnaire as well as task-based EEG recordings are administered. At the end of this baseline assessment, the smartphone-based study coach MAX is installed on the participants’ mobile devices to assess symptoms and emotions (using EMA and passive sensing), and the fitness trackers (activity tracking) are handed to the participants. Participants are instructed to use the MAX app consecutively on the following 14 days and to wear the fitness tracker day and night during the following 10 days.

All participants who meet the criteria are randomly assigned to an experimental group and cannot be excluded from then onward. Randomization is performed using DatInf Randlist (version 1.2) by an independent employee not associated in any further aspect of this study. Neither the study therapists nor the study team have access to the randomization list. Participants assigned to the CBT group receive treatment immediately after the baseline assessment, while WAIT group participants are required to undergo a waiting period of 16 weeks before treatment begins. The treatment comprises an average of 16 sessions of CBT according to the UP. After 8 weeks, participants complete a midassessment and a postassessment after treatment completion or after the waiting time.

To monitor adherence and therapy content, therapists complete standardized documentation forms for every session (eg, implemented modules, percent of time spent outside the UP due to current problems, and other notable events). Sessions are videotaped or alternatively audiotaped if participants do not agree to be videotaped. The WAIT group receives the same assessments as the CBT group, except for the weekly post-CBT session assessments. To ensure objective evaluation of diagnostic status, assessors are blind to condition assignment at mid- and postassessments, and participants are advised not to disclose information about their treatment assignment. The midassessment comprises clinical interviews and questionnaires. In addition, the smartphone app and the fitness tracker are applied in the 14 following consecutive days. The postassessment comprises the same instruments as the midassessment but includes additional measures that correspond with the measures taken at baseline (eg, EEG and biological specimens). Six and 12 months after treatment completion, the CBT group participants undergo follow-up assessments comprised of clinical and psychological questionnaires administered on the web.

Treatment is considered completed per the protocol when participants have attended 16 sessions and worked through each module or prior to that in case of a complete remission. Participants can withdraw from participation at any time. Data on all subjects randomized into the CBT or the WAIT group will be analyzed (intention-to-treat analysis), but we will also investigate potential differences in results based on completer analyses.

This study aims to develop a predictive ML model that forecasts primary therapy outcomes. Prior to ML modeling, data from different sources will be preprocessed, and relevant features will be extracted. With respect to EEG data (eg, event-related potentials related to emotion regulation and indices of bandwidth), spectral power will be extracted using software packages such as Brain Vision Analyzer II (Brain Products GmbH) and MATLAB, R2021b (The MathWorks, Inc). When the final set, including all predictive features, is established, the data will be forwarded as input to ML algorithms to build and test predictive models. Regarding ML, the data will be divided into a training data set and a test data set. The training data set will be used to derive the most promising model using parameter tuning and k-fold cross-validation, while the test data set will be used for an unbiased evaluation of the final model. Techniques to prevent overly complex models will be applied (eg, pruning of irrelevant features). Different algorithms will be used to optimize prediction accuracy and compare performance across algorithms. Applied algorithms include support vector machines, random forest, and gradient boosting [38-41], implemented using R (R Foundation for Statistical Computing). The final model tests will also include a test performed on the data from the WAIT group. This second test will serve as a test of the specificity of the final model (prediction accuracy for the WAIT group data is supposed to be lower than that of the CBT group).

We also aim to investigate prespecified and individually preregistered hypotheses regarding mechanistical associations between selected variables of interest and treatment outcomes to investigate active CBT mechanisms. Hierarchical models will be implemented as repeated measurements nested within the participants. For these analyses, we estimate both fixed and random intercepts and slopes. R will be used for the data analysis, and an intention-to-treat analysis will be used.

The study protocol and the documents for the informed consent were approved by the Cantonal Ethics Committee, Zurich (BASEC-No. 2017-01443). Written informed consent was obtained prior to participation. Participants have the option to opt out at any time. The study is carried out in accordance with the Good Clinical Practice and the Declaration of Helsinki.