To facilitate the organisation and management, the project is structured in “Work packages” which together comprise the project. EMTICS consists of 12 work packages (WPs). Each WP is carried out by a varying number of involved parties. The WP leader supervises and adjusts the process flow and works closely with the project office. The activity of the WP will be overseen by the chair of the working group.
WP01 Longitudinal Onset and Course Cohort Studies (Leader: UCL / A. Schrag): Objectives
- Establish clinical cohort studies ONSET and COURSE.
- Establish whether the childhood onset of tics and/or obsessive-compulsive symptoms in first-degree relatives of patients with TS or another chronic tic disorder is associated with pharyngeal GAS carriage or infection.
- Develop prediction models for the risk of onset of symptoms in first-degree relatives of patients with TS or another tic disorder, integrating information on demographic and clinical information, psychosocial stress, perinatal factors and environmental exposures.
- Examine the effects of exposure to GAS in the form of pharyngeal carriage or infection upon the risk of developing clinically relevant exacerbations of tics and/or obsessive-compulsive symptoms in children affected by TS or chronic tic disorder.
WP02 Microbiological Characterisation (Leader: ISS-RC / R. Creti): Objectives
- Assess GAS serotype distribution by performing emm sequence typing on the bacterial isolates received from both WP01 and WP07 studies as well as from controls.
- Determine the GAS bacterial population genetic structure both by a whole chromosomal DNA analysis method as Pulsed Field Gel Electrophoresis (PFGE) and by a sequence-based method as Multi Locus Sequence Typing (MLST).
- Evaluate the distribution of specific bacterial virulence genes, including their allelic variants, and their potential association with tic symptoms by Polymerase Chain Reaction (PCR) screening and DNA sequencing.
WP03 Anti-Streptococcal Immune Response (Leader: NVD / I. Margarit Y Ros): Objectives
- Investigate antibody response profiles to a large panel of GAS surface antigens in patients with a tic disorder and in healthy relatives recruited in the ONSET study (WP01), with particular attention to immune response variations in patients’ relatives experiencing first onsets of tics (ONSET study).
- Identify a subset of GAS antigens eliciting high antibody responses in patients with a tic disorder compared to healthy individuals (from WP01).
- Investigate the effect of antibiotic treatment in patient antibody response profiles, in relation to microbiological data (WP02) and clinical observations (WP07).
WP04 Immune Measurements (Leader: LMU / N. Müller): Objectives
- Identify non-streptococcal bacterial, viral and other microbial infections as potential environmental risk factors for TS/OCD.
- In depth analyse the cellular and humoral (antibodies, cytokines, CRP) immune response against the identified potentially causative microbes.
- Measure the effect of anti-neuronal glycolytic enzymes (NGE) antibodies on membrane excitability on neuronal cell lines.
- Investigate alteration of the kynurenine pathway, which has functional interconnections between the immune system and neurotransmitter systems.
WP05 Animal Model (Leader: ISS-GL / G. Laviola): Objectives
- Develop a mouse test battery aimed at mimicking behavioural (stereotypical, compulsive and perseverative patterns), immune and brain abnormalities isomorphic to clinical symptoms of TS, as a function of induced autoimmunities.
- Expose candidate mouse strains to passive transfer of streptococcus-induced antibodies, characterised by neuronal cross-reactivity (from both humans and animals) and validate its consequences on the test battery developed under objective 1.
- Identify the prototypical mouse strain that shows the highest isomorphism with TS clinical symptoms in response to streptococcus-induced antibodies.
- Active immunisation with GAS homogenates and/or pools of streptococcal antigens showing high antibody responses in patients with TS according to WP02 and WP03. The target mouse strain will thereof display appropriate antibody titres, T cell immunity, and brain lesions characteristic to autoimmunity.
- Evaluate whether the abnormalities identified under objective 4 are aggravated by psychosocial stress (in collaboration with WP08).
WP06 Genetics & Gene Expression (Leader: DUTH / P. Paschou): Objectives
- Identify genes and gene pathways that influence the pathogenesis of tics and obsessive-compulsive symptoms.
- Examine the gene pathways that influence the clinical course of tic disorders and that are activated upon symptom exacerbations.
- Explore the complex interaction between environment, autoimmunity and genetics related to the onset and clinical course of the disorder spectrum.
- Develop prediction models for the risk of onset of symptoms in first-degree relatives of patients with TS and other chronic tic disorders, integrating information on genetic background and environmental exposures.
- Develop prediction models describing the clinical course of TS and other chronic tic disorders and associated obsessive-compulsive symptoms, integrating individual genetic profiles with specific environmental exposures.
- Establish a European biobank of samples for the study of tic disorders and associated comorbidities.
- Develop novel data-mining and statistical methodology for the investigation of the aetiology of complex disorders, uncovering involved gene networks and gene-environment interactions.
WP07 Treatment (Leader: UniROMA / F. Cardona): Objectives
- Test the hypothesis that antibiotic treatment of GAS colonisation compared to placebo is associated with a larger reduction of tic and associated neuropsychiatric symptoms in the short term (1 month; primary objective). This will be determined by mean change from the baseline to endpoint (1 month) of the primary outcome measure, the Yale Global Tic Severity Scale (YGTSS); clinician based ratings of associated neuropsychiatric symptoms will be secondary outcome measures.
- Test the hypothesis that antibiotic treatment of GAS colonisation is superior to placebo in the long term (1 year) reduction of tic and associated neuropsychiatric symptoms in patients affected by TS or another chronic tic disorder (secondary objective). This will be determined by last observation carried forward (LOCF) mean change from baseline to endpoint (1 year) on the primary outcome measure, the YGTSS; clinician based ratings of associated neuropsychiatric symptoms will be secondary outcome measures.
- Investigate the effects of antibiotic treatment on patient’s immune responses to GAS antigens (in cooperation with WP03).
- Investigate the influence of possible moderators on treatment outcome; we will investigate the role of demographic and clinical variables; of chronic psychosocial stress (in cooperation with WP08); and of GAS colonisation characteristics (in cooperation with WP02).
WP08 Psychosocial Stress (Leader: TUD / V. Roessner): Objectives
- Establish whether chronic psychosocial stress assessed by rating scales as well as physiological parameters has an impact (A) on childhood onset of tics and/or obsessive-compulsive symptoms in at risk individuals as well as (B) on clinically relevant exacerbations of tics and/or obsessive-compulsive symptoms in children affected by TS or another chronic tic disorder (in collaboration with WP01). Evaluate the functioning of the hypothalamic-pituitary-adrenal axis stress system in children with TS or another chronic tic disorder by assessing the cortisol awaking response (CAR), a short diurnal profile as well as the stress reactivity to a standardised psychosocial stressor in a subsample of (A) and (B).
- Investigate the moderating impact of chronic psychosocial stress on the effectiveness of treatment of GAS colonisation with antibiotics on tics and/or obsessive-compulsive symptoms (in cooperation with WP07).
- Explore possible relationships between psychosocial stress and (A) the innate and adaptive immune system (in collaboration with WP04) and (B) occurrence and duration of new GAS colonisations in children with a tic disorder (COURSE study) and as yet unaffected high risk children (ONSET study; in collaboration with WP01).
- Evaluate the basal levels of corticosteroids (in plasma and hair samples) in the mouse model of TS and their variation in response to psychosocial stress, in collaboration with WP05.
WP09 Data Management (Leader: BHAM / A. Cavanna): Objectives
- Establish an effective electronic data capture system for the cohort studies described in WP01 and the treatment study of WP07.
- Enable coupling of measurements obtained in WPs 02, 04, 06 and 08 with the electronic data capture system.
- Establish a Europe-wide database for the longitudinal cohort studies described in WP01 and the associated measurements obtained in WPs 02, 04, 06 and 08.
WP10 Training and Dissemination (Leader: UNICT / R. Rizzo): Objectives
The specific training objectives will be:
- Assure an appropriate conduct of research in accordance with Good Clinical Practice (GCP).
- Provide EMTICS clinicians (including young female scientists and scientists from Eastern Europe) advanced training in Clinical Rating Files (CRF) and psychiatric assessment instruments developed by WP01 and WP08; and to check quality standards with respect to GCP.
- Provide EMTICS scientists advanced training in epidemiology and clinical aspects of Group A streptococcal (GAS) infections and non suppurative sequelae.
- Harmonise and improve, through ad hoc training courses and two external quality assessments (EQA), the microbiological methods used by different centres to isolate GAS from carriers with low bacterial density. This is essential to guarantee reliability of results. Particular attention will be devoted to the training of young female scientists and scientists from Eastern Europe in order to encourage their participation in research projects and improve their professional development.
The specific dissemination objectives will be:
Primary objective: Coordinate dissemination of project progress and results
- Coordinate the further development and regular updating of the dissemination and exploitation strategy.
- Generate information kits for investigators and participants.
- Identify relevant target group for dissemination of aims, methods and results of EMTICS project.
- Communicate with professionals, patient organisations and the general public.
WP11 Ethics (Leader: SCMCI / A. Apter): Objectives
- Set the highest standards for the ethical aspects of the proposed human studies complying with EU
- regulations and all participating countries.
- Allow appropriate Informed Consent (parent/ guardian) and assent (children/adolescents).
- Protect research participants’ confidentiality.
- Ensure care and protection of human research participants.
- Ensure adherence to the above determined ethical standards, thus insuring the EMTICS project will be carried out in compliance with fundamental ethical principles as stated by the European Union and all participating countries.
- Ensure animal use and experimentation (in association with WP05), according to the 3Rs principle.
WP12 Project Management (Leader: concentris / S. Stöber): Objectives
- Make EMTICS achieve its objectives and to deliver in time, budget and quality its milestones and deliverables.
- Help the consortium abide by the regulations and contractual obligations according to the grant agreement, its annexes and the consortium agreement.
- Look after the project`s finances and to report them properly to the European Commission.
- Establish a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run-time of the project.
- Preserve the rights of the partners regarding intellectual property and to act as a mediator in case of disputes.