DateTitlePlace 
30.11.-02.12.2016   6th General Assembly meeting       Lisbon, Portugal
19.05.-20.05.2016  10th Steering Committee meeting  Leiden, The Netherlands

 

December 2016

 

EMTICS cohort studies and database management

With the GA meeting held in Lisbon from the 30th of November to the 2nd of December, EMTICS has now completed its 5th year. Over the past 6 months, highly intensive, commendable and concerted work was brought forward by the Database team of the Istituto Superiore di Sanita’ (ISS) in Rome, Andrea Dietrich and Pieter Hoekstra in UMCG, Groningen, and Zachos Anastasiou, statistician working at the UCL site in order to structure the statistical file and data codebook, develop a data release in SPSS format, syntax storage and maintenance policy, and fix the pending data inconsistencies. Further work in these weeks is focusing on rectifying final inconsistencies or missing data from the database, finalizing the data codebook, and on incorporating biological results for the main analysis.

At the current stage of follow-up (mean duration 1.35 years), 260 participants have been recruited in ONSET, and 55 of these 260 (21%) manifested a new onset of tics. In the COURSE study, 716 patients were enrolled and have been followed up to date for a mean duration of 1.07 years; 181 (25%) underwent at least one clinically relevant exacerbation, for a total number of 213 exacerbations of tics from the whole cohort.

 

TREATMENT study

As intensely discussed over the past 2 years, our clinical antibiotic trial in which children with an already established chronic tic disorder and non-symptomatic throat carriage of group A Streptococcus were enrolled confirms to be the most problematic part of the EMTICS study. Only 13 out of the 46 planned patients were recruited by 4 different institutions (UNICT, UniRoma, SAS, UZH), and recruitment into the study has now closed. Major hurdles to its full accomplishment have been limited participation rates of families, limited rates of children with a positive throat swab, refusal of some clinical sites to take part, and lengthy ethical approval processes. Overall, the study appears to be underpowered, but it could still provide useful data on treatment that would expand information on “active surveillance” of GAS infections in patients with tics.

 

News on microbiological and proteomic studies

The Microbiology team of the Istituto Superiore di Sanità (ISS) in Rome continues its work in order to address one of the core hypotheses of the study: are the onset and/or exacerbation of tic and comorbid obsessive-compulsive disorders in children associated with increased preceding occurrence of Streptococcus pyogenes (group A streptococcus, GAS) exposure or with an infection caused by specific molecular subtypes of this germ? This team is working on the microbiological characterization of GAS strains isolated from the throat swabs of patients during the ONSET, COURSE and TREATMENT studies. The aim is to assess if specific clones and/or their repertoire of virulence factors can be associated to the insurgence or recrudescence of tic symptoms. GAS strains are isolated from the throat of children, swabbed both at the time of recruitment and according to a planned visit schedule by clinical partners. Throat swabs are processed by the microbiology laboratories following a common validated microbiological protocol.

GAS positivity at the time of recruitment was identified on throat swabs in 17.3% of ONSET participants and in 8.4% of COURSE patients; the percentages calculated at any visits were 21.9% for the ONSET study and 20.5% for the COURSE study, with a potential predictable impact of age on the frequency of GAS positivity. Interestingly, the GAS positivity of throat swabs was more frequent in family clusters where exacerbation and onset of tics occurred than in family clusters where those events were not detected. Out of 147 GAS-positive COURSE patients, 43 (29.2%) were repeatedly positive, and 29 of them for the same serotype. Microbiological data will need to be coupled to clinical and other laboratory data during the first semester of 2017.  

Our partners from NVD have completed the protein microarray layout to explore the relationship between anti-streptococcal immune response and clinical and other laboratory data. Analysis on more than 1500 serum samples has started in October.

 

Genomic and transcriptomic studies in EMTICS

The aim of the genetic workpackage of EMTICS is to unravel genes and pathways that may be implicated in the pathogenesis of tics and related comorbidities in TS patients, as well as to unveil gene-environment interactions that may influence disease onset or its clinical course and are activated upon symptom exacerbations. For this purpose, our partners at the Democritus University of Thrace, in Greece, have been building, since 2013, a biobank consisting of DNA and RNA samples from a large number of subjects from the COURSE and ONSET cohorts. In cooperation with the 16 EMTICS clinical sites, they have collected DNA samples which are being currently whole-genome genotyped on an Illumina microarray targeting more than 710,000 polymorphic markers (i.e. SNPs). The EMTICS genotyping data were merged with 1000genomes – European Outliers. Our genome-wide association study (GWAS) aims to explore the genetic basis as well as potential gene-gene interactions that may influence the pathogenesis of tics and related co-morbidities. A pipeline to analyze GWAS data and methods for population stratification correction, typically introduced in such type of analysis, has been established.

In parallel, RNA samples are being collected to perform genome-wide gene expression analyses, aiming to gain insight into the biological pathways that influence the onset of tic disorders and the clinical course of TS (i.e. exacerbation versus remission). To this end, samples from the majority of the target ONSET cohort at baseline and 116 complete pairs of tic exacerbation and remission for the COURSE study have been collected. RNA samples are being shipped to Biolytix SA, Switzerland, for analysis, with about 200 RNA samples already been sent.

 

Immunological studies in EMTICS

The analysis of immune markers from serum and whole blood of cohort participants is a key component of the EMTICS study, managed by our LMU partners. Serum sample testing is being completed this month with respect to streptococcal serology, whereas serological assays for different pathogens and tryptophan pathway intermediates will be conducted in the first trimester of 2017.

 

Exploring psychosocial stress

Workpackage 8 of EMTICS investigates the influence of stress on the tic fluctuations. Our colleagues at the University of Dresden are coordinating this work and completed their first experimental study, which explored the effects of the Trier Social Stress Test for children (TSST-C) on tic frequency in 31 children and adolescents with tic disorders. A relaxation and a concentration situation served as control conditions. Considering the suggestion that stress has an influence on the ability to suppress tics, patients received two different instructions for each situation: 1) to suppress their tics and 2) to “tic freely”. Physiological measures of stress were measured throughout the whole experiment. The TSST-C elicited a clear stress response with elevated levels of saliva cortisol, increased heart rate and higher number of skin conductance responses. With regard to tic frequency, our colleagues observed an interaction effect between situation and instruction: during relaxation and concentration the instruction to suppress tics reduced the number of tics, while during stress the number of tics was low regardless of the instruction. Their study suggests that stress might result in a situational decrease of tic frequency. Different from previous findings, stress did not reduce the ability to suppress tics. Discrepancies to previous self-report studies might be explained by the irritability of subjective tic ratings.

The analysis of the hair strains has made considerable progress with 2544 hair samples analysed so far. There was a high percentage (>80%) of suitable hair specimens collected. With these additional stress markers, we expect to obtain information about the association between stress and tics in a long-term perspective.

 

Animal model studies

These studies have been conducted at the Istituto Superiore di Sanita’ (ISS) in Rome. The studies conducted in previous years showed that repeated exposure to GAS injections resulted in behavioural and neurochemical alterations isomorphic to TS/PANDAS symptoms. In previous studies our partners also demonstrated that neonatal exposure to corticosterone (an experimental paradigm to mimic neonatal stress) compensated for most of the identified abnormalities.

An independent study was performed to investigate whether exposure to social stress during development (i.e. at the same time in which mice were exposed to GAS administration) modulated the TS-like phenotype in a different way compared to neonatal exposure to stress. Social stress was operationalised through the presence of an aggressive mouse in the same cage in which the focal mouse was housed: although mice were constantly in visual contact, physical interaction was limited to a maximum of 10 minutes per day. In this study our partners replicated the finding that GAS exposure induces alterations in phenotypes isomorphic to TS symptoms. Exposure to social stress altered the individual phenotype independently of GAS administration. However, exposure to social stress neither normalised nor deteriorated the GAS-dependent phenotype.

Blood and brain samples from these mice will be investigated through immunological and neurochemical analyses.

 

We are all looking forward to the crucial work that will be undertaken in the next months and to the final general assembly that will take place in Mallorca (date to be confirmed)!

 

Here you can find our

Our Grant Agreement and Art. II.30.4 / II.12.2 of our grant agreement lay down the following rules:

  • The following standard disclaimer and acknowledgement is to be written on all publications of EMTICS:

„The project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 278367.

This paper reflects only the author’s views and the European Union is not liable for any use that may be made of the information contained therein.”

This means for you: Do not forget to include this information in your manuscripts or on your posters or books. It is a contractual duty!

  • Any dissemination activity shall be reported in the plan for the use and dissemination of foreground, including sufficient details/references to enable the Commission to trace the activity.

This means for you: Please keep track of your publications as they need to be reported on in the frame of our periodic reports.

  • With regard to scientific publications relating to foreground published before or after the final report, such details/references and an abstract of the publication must be provided to the Commission at the latest two months following publication. Furthermore, an electronic copy of the published version or the final manuscript accepted for publication shall also be provided to the Commission at the same time for the purpose set out in Article II.12.2 if this does not infringe any rights of third parties.

This means for you: Please send an abstract of your publication to the project office at concentris the moment when it is accepted for publication. concentris will forward it to the relevant services at the EC for you.

  • According to Special Clause 39 of our grant agreement, we are furthermore bound to the following provisions:

In addition to Article II.30.4, beneficiaries shall deposit an electronic copy of the published version or the final manuscript accepted for publication of a scientific publication relating to foreground published before or after the final report in an institutional or subject-based repository at the moment of publication.

Beneficiaries are required to make their best efforts to ensure that this electronic copy becomes freely and electronically available to anyone through this repository:

  • immediately if the scientific publication is published "open access", i.e. if an electronic version is also available free of charge via the publisher, or
  • within 6 months of publication.


In addition to this, the EMTICS Consortium Agreement contains the following provisions:

  • 8.4.1 Publications

Dissemination activities including but not restricted to publications and presentations shall be governed by the procedure of Article II.30.3 of the EC-GA subject to the following provisions.

(1) Prior notice of any planned publication shall be made 45 days before the publication. Any objection to the planned publication shall be made in accordance with the EC-GA in writing to the Coordinator and to any Party concerned within 30 days after receipt of the notice. If no objection is made within the time limit stated above, the publication is permitted.

(2) An objection is justified if

  • the objecting Party's legitimate academic or commercial interests are compromised by the publication; or
  • the protection of the objecting Party's Foreground or Background is adversely affected.

The objection has to include a precise request for necessary modifications.

(3) If an objection has been raised the involved Parties shall discuss how to overcome the justified grounds for the objection on a timely basis (for example by amendment to the planned publication and/or by protecting information before publication) and the objecting Party shall not unreasonably continue the opposition if appropriate actions are performed following the discussion.

This means for you: Please send any manuscript resulting from EMTICS work to the Consortium before publishing it. The Consortium members may object within 30 days.

  • 8.4.2 Publication of another Party’s Foreground or Background

For the avoidance of doubt, a Party shall not publish Foreground or Background of another Party, even if such Foreground or Background is amalgamated with the Party’s Foreground, without the other Party’s prior written approval, which shall not be unreasonably withheld. If the other Party has not raised an objection within 30 (thirty) calendar days after receiving the manuscript, consent to the publication is deemed to be granted.

The following was agreed by the EMTICS Consortium at the Kick-off Meeting in AMSTERDAM:

  • The whole consortium is last author through “the EMTICS consortium”
  • The data base is open to all for publication proposals; the Coordinator will draft and circulate a proposal about publication topic divisions and more detailed publication rules
  • *The group felt that the 45 days until green light of a manuscript for submission is too long in practice. The group agreed on 2 weeks for comments.
  • All centres to send information to the project office (Dr. Sara Stöber) on who is part of the EMTICS consortium from their centre (standard). Of course, people can withdraw from authorship for publications on a case by case basis.

European Multicentre Tics in Children Studies: translating pre-clinical results into therapies



EMTICS aims to identify the genetic and environmental susceptibility factors of tic disorders and will greatly contribute to a better understanding of the underlying mechanisms, especially by elucidating the role of autoimmunity and infections. EMTICS is a project funded by the EU programme FP7 and combines 27 partners from 11 different countries.

Read more

Tic disorders

Tics are characterised by the presence of multiple sudden, rapid, recurrent, and non-rhythmic movements and/or utterances.

About EMTICS

.

Aims of study

EMTICS wants to elucidate the causes of tics in children and to find an effective treatment for the disorder.

About EMTICS

.