Primary Objective: The primary aim of Transdiagnostic Microbiome is to build on MIND-Set by investigating associations between gut microbiota and transdiagnostic symptom profiles in stress-related and neurodevelopmental disorders. The…
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
- Cognitive and attention disorders and disturbances
- Depressed mood disorders and disturbances
Synonym
Research involving
Sponsors and support
Intervention
- Other intervention
N.a.
Outcome measures
Primary outcome
<p><strong>Microbial composition</strong></p><p>The gut microbiota contain many different types of bacteria with different abundance. Here, our main focus is on the abundance of each microbial genus (taxonomic composition). As the gut microbiome data is compositional and zero-dispersed, we will perform the analysis on genus level, transform the raw sequencing count data to central log ratio (clr) and apply 10% prevalence filtering. We will also perform the analysis on species level as we will also obtain higher resolution data from shotgun metagenomics sequencing. We will also look into the metabolic functions associated with the taxonomic profile. As measures of relevant global microbial dynamics, we will calculate alpha diversity (difference within group) and beta diversity (difference between group) from the raw sequence read count. Beta diversity will be computed using Aitchison distance.</p><p><strong>Clinical outcomes</strong></p><p>We derive the primary study parameters, clinical outcomes, from the MIND-Set 2 study. These are disorder-specific outcomes as measured with relevant questionnaires (for example IDS for depression) and mental health outcomes as assessed with general outcome questionnaires (OQ, WHODAS). The primary parameters will be symptom profile and functional domains. We will apply machine learning technique such as factor or hierarchical clustering analysis, supervised learning and exploratory factor analysis to establish and confirm the functional domains and symptom profile from the questionnaire data. </p><p><strong>Association analysis</strong></p><p>The clinical outcomes and microbial measures will be statistically associated using logistic regression and generalized linear mixed model. We will associate the clr-transform taxonomic abundance to the identified symptom and functional domains, as previously done in (11). In addition, we will also associate the metabolic functions of the bacterial taxa with the symptom and functional domains using generalized linear model. All the associations are subject to multiple hypothesis testing, hence all the p-values will be corrected by performing the Benjamini-Hochberg procedure.</p>
Secondary outcome
<p><strong>Fluctuations of gut microbiota</strong></p><p>To answer the secondary research questions, we will measure the changes of the gut microbiota over time as the secondary parameter. We will use volatility measure: the Euclidean distance of gut microbiota between each measured time point. We will also perform the same data transformation protocol on the follow up measurement and then compare them to the baseline measurement. In addition, we will also use generalized mixed linear model to identify significant changes in the gut microbiota composition.</p><p>We will also investigate the changes in metabolic functions over time. These will be linked to fluctuation in the composition. Considering the nature of gut microbiota data, generalized linear mixed-model is the optimal statistical test that we can use to assess these associations.</p><p><strong>Changes in symptom profile and functional domain</strong></p><p>The questionnaire data from the follow up measure will be the basis for determining the symptom profile and functional domain. We will contrast these measures between the two time points by performing t-tests and/or linear regression.</p><p><strong>Association analysis</strong></p><p>The gut microbiota composition and metabolic functions from both time points will be associated with symptom profiles and functional domains from both time points. To take into account the dependency within the data due to repeated measures, we will employ generalized linear mixed-models. All the association tests will be corrected for multiple comparisons with the Benjamini-Hochberg procedure.</p>
Background summary
An expanding body of research has explored biological markers that transcend traditional diagnostic boundaries, including those related to brain function, genetics, and inflammation. Gut microbiota alterations have also been observed across various psychiatric disorders, and attempts to identify disorder-specific microbial patterns have faced challenges with replication. A recent systematic review and meta-analysis of 59 studies found limited evidence for disorder-specific microbial signatures. Instead, it suggested that shared microbial changes across mood, anxiety, neurodevelopmental, and psychotic disorders may reflect common transdiagnostic mechanisms.
The MIND-Set (Measuring Integrated Novel Dimensions in Stress- and Neurodevelopmental Disorders) study was built upon the Research Domain Criteria (RDoC), a transdiagnostic perspective which transcends the traditional classification system of psychiatric disorders and focusing on the underlying functional systems of the disorders. The MIND-Set study has advanced its clinical application by utilizing in-depth phenotyping of a highly comorbid patient cohort to highlight transdiagnostic markers, clarify the relationships between symptom profiles and functional domains, and link them to underlying biological mechanisms and functional outcomes. Collectively, these results underscore the potential of transdiagnostic profiling to reveal meaningful interactions between symptoms and biology.
Adopting a transdiagnostic perspective, which recognizes shared clinical features and accommodates the high prevalence of comorbidities, could enhance our understanding of microbiota-behavior associations. In this study, we aim to integrate gut microbiota and detailed clinical phenotyping. By establishing an observational longitudinal cohort, we aim to identify transdiagnostic microbial markers of symptoms and disorder trajectories. This approach has the potential to elucidate the microbiota’s role in clinical outcomes across diagnoses.
Study objective
Primary Objective:
The primary aim of Transdiagnostic Microbiome is to build on MIND-Set by investigating associations between gut microbiota and transdiagnostic symptom profiles in stress-related and neurodevelopmental disorders. The primary research question is:
“What is the link between gut microbial community and transdiagnostic symptoms and symptom profiles in the clinical outcome of stress-and neurodevelopmental disorders?”
Secondary Objective(s):
The secondary objective is to elucidate the associations between gut microbiota fluctuations and changes in transdiagnostic symptom profiles in stress-related and neurodevelopmental disorders. The secondary research question is:
“What is the co-fluctuation pattern between gut microbial community and symptom profiles in the clinical outcome of stress-and neurodevelopmental disorders?
Study design
Transdiagnostic Microbiome is conducted within the framework of MIND-Set 2 (Protocol ID: 2022-1367). It is an observational, longitudinal study. While MIND-Set 2 collects extensive clinical data (questionnaires & blood), Transdiagnostic Microbiome will focus solely on stool sample collection and lifestyle questionnaires.
Procedures
1. Appointment at department of psychiatry
Upon the appointment day, patients come to the clinic and wait in the waiting room. We will put up recruitment posters on the waiting room of the clinic so that interested individuals may register their interest in donating stool sample. Upon scanning the barcode, individuals will see information about the study and provide a mean of contact, which will be registered in a secure digital platform (Castor). The list of questions we will ask in the registration form can be found in the appendix.
At the end of their appointment with the care provider, those who meet the inclusion criteria will receive information of the study from their care provided and will be invited to participate. Individuals will register by scanning the same barcode. In the context of the research, no further appointment will be made since the proceeding procedures are done from the convenience of participants’ home.
2. After the appointment
A research assistant will contact individuals who filled out the registration form via email. Participating patients will receive a study brochure and give consent (will be registered in Castor) to participate on Transdiagnostic Microbiome and to use their data for answering the research questions of this project and subsequent relevant questions. Then, they receive stool sample collection kits via Post. Individuals shall collect the first stool sample as soon as they receive the collection materials and note down the collection date, and then send back the collection kit by dropping it on any post box. On the same day, they will be asked to fill out a short lifestyle questionnaire and a short medication side effect questionnaire digitally.
3. Follow-up
16 weeks after first collection date, individuals collect the second stool sample, note down the collection date, then send the second collection kit with the same procedure as before, and fill out the lifestyle questionnaire digitally. Participants do not pay for any of the shipping cost.
Questionnaires
For the baseline and 16 weeks follow up clinical information, we will obtain it from questionnaires already collected within the standard care or practicefrom the MIND-Set 2 study (MIND-Set 2, Protocol ID: 2022-1367). This includes questionnaires that measure state-based symptoms, such as:
- CAARS (ADHD symtptoms),
- AQ-10 (ASD symptoms),
- IDS-SR and HDRS (depression symptoms),
- STAI-DY (anxiety symptoms),
- QQ-45 and WHODAS (state-based quality of life measurements).
The only additional questionnaire that we administer ourselves as part of this study is the lifestyle questionnaire. This contains questions about changes in lifestyle, living environment, nutrition, gastrointestinal complaints and any medication side effects in the past month.
Intervention
Not applicable
Study burden and risks
Participating patients are asked to provide two stool samples at home and fill out a short life-style, side effects and symptom questionnaire twice, six weeks apart. The risks and discomforts associated with participating in this study are negligible.
The procedure poses no safety concerns or extra burden to the patients, as the material is self-produced and the DNA investigated is bacterial and not human. As we receive the fecal material, the samples will be stored at -80°C in the clinical center the until sequenced. Sequencing of a discriminative region of the 16S rRNA gene and shotgun sequencing of the metagenome on an llumina platform will be outsourced.
A Arias Vasquez
Geert Grooteplein Zuid 10
Nijmegen 6525GA
Netherlands
+31 (0) 24 3613970
alejandro.ariasvasquez@radboudumc.nl
A Arias Vasquez
Geert Grooteplein Zuid 10
Nijmegen 6525GA
Netherlands
+31 (0) 24 3613970
alejandro.ariasvasquez@radboudumc.nl
Listed location countries
Age
Inclusion criteria
- Gave consent for utilization of their clinical data for research purposes (MIND-Set 2, Protocol ID: 2022-1367)
- Adult (≥ 18 years old) outpatients at the Department of Psychiatry, Radboudumc, referred for diagnostic or treatment questions related to:
- Stress-related disorders (e.g., mood, anxiety)
- Neurodevelopmental disorders (e.g., ASD, ADHD, personality disorders)
- Impulse-regulation disorders (substance abuse disorder, eating disorders)
Exclusion criteria
- Inadequate command of the Dutch language
- Mentally incompetent to provide informed consent
- Severe somatic comorbidities (i.e., terminal illnesses)
- Comorbidity with any psychotic disorder
Design
Recruitment
Medical products/devices used
IPD sharing statement
Plan description
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Research portal | NL-010181 |