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1. AI driven analysis of MRI to measure health and disease progression in FSHD

Author

Lara Riem, Olivia DuCharme, Matthew Cousins, Xue Feng, Allison Kenney, Jacob Morris, Stephen J. Tapscott, Rabi Tawil, Jeff Statland, Dennis Shaw, Leo Wang, Michaela Walker, Leann Lewis, Michael A. Jacobs, Doris G. Leung, Seth D. Friedman, and Silvia S. Blemker

Subjects
MRI, FSHD, Fat fraction, Muscle volume, Progression, Atrophy, Medicine, Science
Abstract

Abstract Facioscapulohumeral muscular dystrophy (FSHD) affects roughly 1 in 7500 individuals. While at the population level there is a general pattern of affected muscles, there is substantial heterogeneity in muscle expression across- and within-patients. There can also be substantial variation in the pattern of fat and water signal intensity within a single muscle. While quantifying individual muscles across their full length using magnetic resonance imaging (MRI) represents the optimal approach to follow disease progression and evaluate therapeutic response, the ability to automate this process has been limited. The goal of this work was to develop and optimize an artificial intelligence-based image segmentation approach to comprehensively measure muscle volume, fat fraction, fat fraction distribution, and elevated short-tau inversion recovery signal in the musculature of patients with FSHD. Intra-rater, inter-rater, and scan-rescan analyses demonstrated that the developed methods are robust and precise. Representative cases and derived metrics of volume, cross-sectional area, and 3D pixel-maps demonstrate unique intramuscular patterns of disease. Future work focuses on leveraging these AI methods to include upper body output and aggregating individual muscle data across studies to determine best-fit models for characterizing progression and monitoring therapeutic modulation of MRI biomarkers.

Published
2024
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2. Longitudinal cerebellar diffusion tensor imaging changes in posterior fossa syndrome

Author

Sean D. McEvoy, MD, Amy Lee, MD, Andrew Poliakov, PhD, Seth Friedman, PhD, Dennis Shaw, MD, Samuel R. Browd, MD/PhD, Richard G. Ellenbogen, MD, Jeffrey G. Ojemann, MD, and Christine L. Mac Donald, PhD

Subjects
Diffusion tensor imaging, Posterior fossa syndrome (PFS), Cerebellar mutism syndrome (CMS), Tumor, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Posterior fossa syndrome is a severe transient loss of language that frequently complicates resection of tumors of the cerebellum. The associated pathophysiology and relevant anatomy to this language deficit remains controversial. We performed a retrospective analysis of all cerebellar tumor resections at Seattle Children's Hospital from 2010 to 2015. Diffusion tensor imaging was performed on each of the patients as part of their clinical scan. Patients included in the study were divided into groups based on language functioning following resection: intact (N = 19), mild deficit (N = 19), and posterior fossa syndrome (N = 9). Patients with posterior fossa syndrome showed white matter changes evidenced by reductions in fractional anisotropy in the left and right superior cerebellar peduncle following resection, and these changes were still evident 1-year after surgery. These changes were greater in the superior cerebellar peduncle than elsewhere in the cerebellum. Prior to surgery, posterior fossa patients did not show changes in fractional anisotropy however differences were observed in mean and radial diffusivity measures in comparison to other groups which may provide a radiographic marker of those at greatest risk of developing post-operative language loss.

Published
2016
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3. A Phase 2 Trial of Response-Based Radiation Therapy for Localized Central Nervous System Germ Cell Tumors: Patterns of Failure and Radiation Dosimetry for Nongerminomatous Germ Cell Tumors

Author

Erin S. Murphy, Girish Dhall, Jason Fangusaro, Ute Bartels, Maryam Fouladi, Dennis Shaw, Soumen Khatua, Chris Williams Hughes, Ashok Panigraphy, Myrsini Ioakeim-Ioannidou, Mark Souweidane, David Morris, Amar Gajjar, Shengjie Wu, Arzu Onar-Thomas, Daphne A. Haas-Kogan, and Shannon M. MacDonald

Subjects
Central Nervous System, Male, Cancer Research, Radiation, Neoplasms, Germ Cell and Embryonal, Radiation Dosage, Combined Modality Therapy, Article, Central Nervous System Neoplasms, Testicular Neoplasms, Oncology, Antineoplastic Combined Chemotherapy Protocols, Humans, Female, Radiology, Nuclear Medicine and imaging, Prospective Studies, Neoplasm Recurrence, Local, Child
Abstract

PURPOSE: Children’s Oncology Group study ACNS1123 tested the efficacy of reduced dose and field of radiation therapy (RT) for patients with localized nongerminomatous germ cell tumors (NGGCT) who achieved a complete (CR) or partial response (PR) to chemotherapy. Here, we evaluate the quality of RT and patterns of failure for patients eligible for reduced RT in this phase 2 trial. METHODS AND MATERIALS: Patients with localized NGGCT with CR/PR after induction chemotherapy received reduced RT to 30.6 Gy whole ventricular irradiation and 54 Gy tumor-bed total dose. An atlas was provided to assist with complex RT volumes. Early interventional review was performed for the initial RT plan. Complete RT plans for all patients and images of relapsed patients were centrally reviewed at completion of therapy. RESULTS: Between May 2012 and September 2016, 107 eligible patients were enrolled and 66 achieved a CR/PR after induction chemotherapy (± second-look surgery) and were eligible for reduced RT. Median follow-up was 4.4 years. Median age was 11.0 years (3.7–21.6), and 75% were male. Progression-free survival and overall survival at 4 years were 87.9% ± 4.0% and 92.4% ± 3.3% for 66 evaluable patients, respectively. Eight patients relapsed: 6 with isolated spinal relapse and 2 with disease in the brain and spine. After central review, 62 (94%) patients had RT targets contoured and dose delivered per protocol. None of the patients with deviations (n = 4) have progressed. CONCLUSIONS: Patterns of failure suggest the spine is at risk for recurrence for patients with localized NGGCT who receive reduced RT after a CR/PR to induction chemotherapy. Although survival data are encouraging, the pattern of failure has influenced the next prospective trial design. RT compliance was excellent despite complexity of radiation volumes, suggesting that providing visual guidance in the form of an online atlas contributes to higher quality RT plans.

Published
2022

4. Motor Outcomes to Validate Evaluations in Facioscapulohumeral muscular dystrophy (MOVE FSHD): Preliminary Baseline Characteristics (S7.004)

Author

Michaela Walker, Russell Butterfield, John Day, Katy Eichinger, Bakri Elsheikh, Seth Friedman, Angela Genge, Kiley Higgs, Nicholas Johnson, Peter Jones, Doris Leung, Leann Lewis, Hanns Lochmuller, Erin O'Ferrall, William Martens, Dennis Shaw, Perry Shieh, S Subramony, Jaya Trivedi, Leo Wang, Matthew Wicklund, Alrabi Tawil, and Jeffrey Statland

Published
2023

6. Imaging of pediatric brain tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee/ASPNR White Paper

Author

Alok Jaju, Yi Li, Hisham Dahmoush, Nicholas G Gottardo, Suzanne Laughlin, David Mirsky, Ashok Panigrahy, Noah D. Sabin, Dennis Shaw, Phillip B. Storm, Tina Young Poussaint, Zoltan Patay, and Aashim Bhatia

Subjects
Oncology, Pediatrics, Perinatology and Child Health, Hematology
Abstract

Tumors of the central nervous system are the most common solid malignancies in children and the most common cause of pediatric cancer-related mortality. Imaging plays a central role in diagnosis, staging, treatment planning, and response assessment of pediatric brain tumors. However, the substantial variability in brain tumor imaging protocols across institutions leads to variability in patient risk stratification and treatment decisions, and complicates comparisons of clinical trial results. This White Paper provides consensus-based imaging recommendations for evaluating pediatric patients with primary brain tumors. The proposed brain magnetic resonance imaging protocol recommendations balance advancements in imaging techniques with the practicality of deployment across most imaging centers.

Published
2022

8. Imaging response assessment for CNS germ cell tumours: consensus recommendations from the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group

Author

Giovanni Morana, Dennis Shaw, Shannon M MacDonald, Claire Alapetite, Thankamma Ajithkumar, Aashim Bhatia, Hervé Brisse, Camilo Jaimes, Thomas Czech, Girish Dhall, Jason Fangusaro, Cecile Faure-Conter, Maryam Fouladi, Darren Hargrave, Julie H Harreld, Dipayan Mitra, James C Nicholson, Mark Souweidane, Beate Timmermann, Gabriele Calaminus, Ute Bartels, Brigitte Bison, Matthew J Murray, Murray, Matthew [0000-0002-4480-1147], and Apollo - University of Cambridge Repository

Subjects
Diagnostic Imaging, Consensus, Treatment Outcome, Oncology, Brain Neoplasms, Medizin, Humans, Neoplasms, Germ Cell and Embryonal, Child
Abstract

Homogeneous and common objective disease assessments and standardised response criteria are important for better international clinical trials for CNS germ cell tumours. Currently, European protocols differ from those of North America (the USA and Canada) in terms of criteria to assess radiological disease response. An international working group of the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group was therefore established to review existing literature and current practices, identify major challenges regarding imaging assessment, and develop consensus recommendations for imaging response assessment for patients with CNS germ cell tumours. New clinical imaging standards were defined for the most common sites of CNS germ cell tumour and for the definition of locoregional extension. These new standards will allow the evaluation of response to therapy in patients with CNS germ cell tumours to be more consistent, and facilitate direct comparison of treatment outcomes across international studies.

Published
2022
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9. Phase II trial of response-based radiation therapy for patients with localized germinoma: a Children’s Oncology Group study

Author

Sarah Leary, Girish Dhall, Shannon M. MacDonald, Aashim Bhatia, James M. Boyett, Maryam Fouladi, Shengjie Wu, Amar Gajjar, Jason Fangusaro, Mark M. Souweidane, Soumen Khatua, Sunita K. Patel, Erin S Murphy, Ute Bartels, Leanne Embry, Christine L. Trask, Dennis Shaw, and Arzu Onar-Thomas

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Context (language use), Pineal Gland, chemistry.chemical_compound, Internal medicine, Clinical endpoint, Medicine, Humans, Progression-free survival, Child, Etoposide, Germinoma, business.industry, Brain Neoplasms, medicine.disease, Carboplatin, Regimen, chemistry, Cohort, Neurology (clinical), business, Pediatric Neuro-Oncology, medicine.drug
Abstract

Background The study aimed to evaluate whether simplified chemotherapy followed by dose-reduced irradiation was effective for treating patients (ages 3–21 years) with localized germinoma. The primary endpoint was 3-year progression-free survival (PFS) rate. Methods Patients with a complete response to chemotherapy with carboplatin and etoposide received 18 Gy WVI + 12 Gy boost to the tumor bed. Patients with partial response proceeded to 24 Gy WVI + 12 Gy. Longitudinal cognitive functioning was evaluated prospectively on ALTE07C1 and was a primary study aim. Results One hundred and fifty-one patients were enrolled; 137 were eligible. Among 90 evaluable patients, 74 were treated with 18 Gy and 16 with 24 Gy WVI. The study failed to demonstrate noninferiority of the 18 Gy WVI regimen compared to the design threshold of 95% 3-year PFS rate, where, per design, patients who could not be assessed for progression at 3 years were counted as failures. The Kaplan-Meier (KM)-based 3-year PFS estimates were 94.5 ± 2.7% and 93.75 ± 6.1% for the 18 Gy and 24 Gy WVI cohorts, respectively. Collectively, estimated mean IQ and attention/concentration were within normal range. A lower mean attention score was observed at 9 months for patients treated with 24 Gy. Acute effects in processing speed were observed in the 18 Gy cohort at 9 months which improved at 30-month assessment. Conclusions While a failure according to the prospective statistical noninferiority design, this study demonstrated high rates of chemotherapy responses, favorable KM-based PFS and OS estimates in the context of reduced irradiation doses and holds promise for lower long-term morbidities for patients with germinoma.

Published
2021

10. GCT-18. Endoscopic third ventriculostomy (ETV) and tumor biopsy are not associated with relapse rate or patterns in primary central nervous system (CNS) germ cell tumor (GCT)

Author

Rachel Yan, Tong Lin, Shannon MacDonald, Joseph Carnevale, Aashim Bhatia, Dennis Shaw, Erin Murphy, Sarah Leary, Ute Bartels, Soumen Khatua, Maryam Fouladi, Amar Gajjar, Girish Dhall, Jason Fangusaro, Arzu Onar-Thomas, and Mark Souweidane

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

BACKGROUND: ETV and tumor biopsy are central to the surgical management of children with primary CNS GCT. An ETV creates a communication between the intraventricular compartment and the subarachnoid spaces and decompartmentalizes the ventricular system. “Tumor spill” or shedding may result from surgical interventions, such as biopsy. ETV with simultaneous biopsy may impart a greater tendency for dissemination and possible distant relapse. This is a concern in CNS GCT given the attempts of irradiation field and dose reduction following chemotherapy. METHODS: We performed a retrospective review of the prospective database for the Children’s Oncology Group (COG) ACNS1123 study. Possible associations were explored among ETV, endoscopic biopsy, and combined ETV+biopsy with relapse, distant relapse, progression free survival (PFS), and time to distant relapse. RESULTS: Among 244 eligible patients, 97 ETV+/-biopsies were performed, and 30 relapses occurred. There were no associations among ETV and/or biopsy with relapse (Cochran-Mantel-Haenszel [CMH] test, with histology (germinoma vs. nongerminomatous germ cell tumor (NGGCT)) as stratification variable: ETV: p=0.3167, biopsy: p=0.3375, combined: p=0.3066), distant relapse (CMH test, ETV: p=0.4631, ETV+biopsy: p=0.6795), PFS (log-rank test, ETV: NGGCT p=0.1632, germinoma p=0.9288; biopsy: NGGCT p=0.1682, germinoma p=0.9701; ETV+Biopsy: NGGCT p=0.1306, germinoma p=0.7758), or time to distant relapse with death/local relapse as competing risk (Gray’s test, ETV: NGGCT p=0.5694, germinoma p=0.2327; biopsy: NGGCT p=0.3505, germinoma p=0.5747; ETV+Biopsy: NGGCT p=0.3988, germinoma p=0.6839). CONCLUSIONS: Based on a secondary analysis of prospective data from the ACNS1123 trial, ETV and biopsy did not impart a greater likelihood of relapse in children with primary CNS GCT treated with combined chemotherapy and irradiation. However, three tract recurrences did occur (all germinoma), suggesting that they may affect pattern of relapse. Current and future prospective trials should continue to explore associations among these variables and relapse, including patterns of relapse.

Published
2022

11. SURG-12. Endoscopic evaluation of ventricular dissemination in primary central nervous system (CNS) germ cell tumors (GCTs)

Author

Rachel Yan, Tong Lin, Joseph Carnevale, Aashim Bhatia, Dennis Shaw, Shannon MacDonald, Erin Murphy, Sarah Leary, Ute Bartels, Soumen Khatua, Maryam Fouladi, Amar Gajjar, Girish Dhall, Jason Fangusaro, Arzu Onar-Thomas, and Mark Souweidane

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

INTRODUCTION: Endoscopic third ventriculostomy and endoscopic tumor biopsy have become integral to the surgical management of children with primary CNS GCTs. Observing ependymal tumor dissemination at the time of endoscopic surgery has been anecdotally reported. The incidence and impact of this finding in CNS GCT has not been reported. METHODS: Baseline neurosurgery data capture forms and operative reports from the Children’s Oncology Group (COG) ACNS1123 study were reviewed for ventriculoscopic findings of suspected tumor dissemination. The association between these findings and relapse was determined using Fisher’s exact test for each stratum and the Cochran-Mantel-Haenszel test for the entire cohort. Progression-free survival (PFS) was defined as time from enrollment to relapse, progression, death, or last follow-up; and survival probabilities were estimated using the Kaplan-Meier method with log-rank tests for outcome comparisons. RESULTS: 110/244 patients (45.1%) underwent endoscopic neurosurgery. Twelve patients (10.9%) had a documented observation suggestive of metastatic disease within the ventricular compartment. Ten were in the third ventricle and two were in the lateral ventricle. Nine of 12 were nongerminomatous germ cell tumors (NGGCTs) and three were germinoma. Ventriculoscopic findings of metastatic tumor were not significantly associated with relapse in NGGCT (p=0.4091), germinoma (p=0.1832), or overall (p=0.1540); odds ratio 2.57 (95%CI:0.66–10.11). PFS was not influenced in NGGCT (Log-rank test, p=0.1953) but was negatively impacted in germinoma (p=0.0250) when tumor dissemination was found during ventriculoscopy. CONCLUSIONS: Ventriculoscopic observation of tumor dissemination was reported in 10.9% of cases. This may negatively influence outcomes in children with germinoma, though due to the small number of relapses, more data is needed to verify these findings. Ventriculoscopic observation of tumor dissemination may contribute toward more accurate staging and influence future therapy, but a larger sample size is needed. Prospective studies should routinely integrate documentation of endoscopic observation in the study protocol.

Published
2022

12. Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism

Author

Jed T. Elison, Sarah Paterson, Martin Styner, Sun Hyung Kim, Annette M. Estes, Stephen R. Dager, Joseph Piven, Lonnie Zwaigenbaum, Guido Gerig, Alan Evans, Dennis Shaw, Robert T. Schultz, Robert W. Emerson, VS Fonov, Robert C. McKinstry, Mark D. Shen, Martin A. Styner, C. Chappell, J. Pruett, D. Shaw, Kelly N. Botteron, D.L. Collins, Alan C. Evans, Meghan R. Swanson, David G. Amaral, P. Kostopoulos, Hongbin Gu, Heather C. Hazlett, R. McKinstry, Christine Wu Nordahl, V. Fonov, G.B. Pike, J. Constantino, Samir Das, and Annette Estes

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, Magnetic resonance imaging, medicine.disease, behavioral disciplines and activities, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Cerebrospinal fluid, medicine.anatomical_structure, Neuroimaging, Autism spectrum disorder, mental disorders, medicine, Etiology, Autism, Family history, Subarachnoid space, Psychology, 030217 neurology & neurosurgery, Biological Psychiatry
Abstract

Background We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. Methods A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. Results Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohen's d = 0.54). Extra-axial CSF volume remained elevated through 24 months ( d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. Conclusions This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

Published
2017

13. Quantifying the effects of 16p11.2 copy number variants on brain structure: A multisite genetic-first study

Author

Sandra Martin-Brevet, Borja Rodríguez-Herreros, Jared A. Nielsen, Clara Moreau, Claudia Modenato, Anne M. Maillard, Aurélie Pain, Sonia Richetin, Aia E. Jønch, Abid Y. Qureshi, Nicole R. Zürcher, Philippe Conus, Wendy K. Chung, Elliott H. Sherr, John E. Spiro, Ferath Kherif, Jacques S. Beckmann, Nouchine Hadjikhani, Alexandre Reymond, Randy L. Buckner, Bogdan Draganski, Sébastien Jacquemont, Marie-Claude Addor, Joris Andrieux, Benoît Arveiler, Geneviève Baujat, Frédérique Sloan-Béna, Marco Belfiore, Dominique Bonneau, Sonia Bouquillon, Odile Boute, Alfredo Brusco, Tiffany Busa, Jean-Hubert Caberg, Dominique Campion, Vanessa Colombert, Marie-Pierre Cordier, Albert David, François-Guillaume Debray, Marie-Ange Delrue, Martine Doco-Fenzy, Ulrike Dunkhase-Heinl, Patrick Edery, Christina Fagerberg, Laurence Faivre, Francesca Forzano, David Genevieve, Marion Gérard, Daniela Giachino, Agnès Guichet, Olivier Guillin, Delphine Héron, Bertrand Isidor, Aurélia Jacquette, Sylvie Jaillard, Hubert Journel, Boris Keren, Didier Lacombe, Sébastien Lebon, Cédric Le Caignec, Marie-Pierre Lemaître, James Lespinasse, Michèle Mathieu-Dramart, Sandra Mercier, Cyril Mignot, Chantal Missirian, Florence Petit, Kristina Pilekær Sørensen, Lucile Pinson, Ghislaine Plessis, Fabienne Prieur, Caroline Rooryck-Thambo, Massimiliano Rossi, Damien Sanlaville, Britta Schlott Kristiansen, Caroline Schluth-Bolard, Marianne Till, Mieke Van Haelst, Lionel Van Maldergem, Hanalore Alupay, Benjamin Aaronson, Sean Ackerman, Katy Ankenman, Ayesha Anwar, Constance Atwell, Alexandra Bowe, Arthur L. Beaudet, Marta Benedetti, Jessica Berg, Jeffrey Berman, Leandra N. Berry, Audrey L. Bibb, Lisa Blaskey, Jonathan Brennan, Christie M. Brewton, Randy Buckner, Polina Bukshpun, Jordan Burko, Phil Cali, Bettina Cerban, Yishin Chang, Maxwell Cheong, Vivian Chow, Zili Chu, Darina Chudnovskaya, Lauren Cornew, Corby Dale, John Dell, Allison G. Dempsey, Trent Deschamps, Rachel Earl, James Edgar, Jenna Elgin, Jennifer Endre Olson, Yolanda L. Evans, Anne Findlay, Gerald D. Fischbach, Charlie Fisk, Brieana Fregeau, Bill Gaetz, Leah Gaetz, Silvia Garza, Jennifer Gerdts, Orit Glenn, Sarah E. Gobuty, Rachel Golembski, Marion Greenup, Kory Heiken, Katherine Hines, Leighton Hinkley, Frank I. Jackson, Julian Jenkins, Rita J. Jeremy, Kelly Johnson, Stephen M. Kanne, Sudha Kessler, Sarah Y. Khan, Matthew Ku, Emily Kuschner, Anna L. Laakman, Peter Lam, Morgan W. Lasala, Hana Lee, Kevin LaGuerre, Susan Levy, Alyss Lian Cavanagh, Ashlie V. Llorens, Katherine Loftus Campe, Tracy L. Luks, Elysa J. Marco, Stephen Martin, Alastair J. Martin, Gabriela Marzano, Christina Masson, Kathleen E. McGovern, Rebecca McNally Keehn, David T. Miller, Fiona K. Miller, Timothy J. Moss, Rebecca Murray, Srikantan S. Nagarajan, Kerri P. Nowell, Julia Owen, Andrea M. Paal, Alan Packer, Patricia Z. Page, Brianna M. Paul, Alana Peters, Danica Peterson, Annapurna Poduri, Nicholas J. Pojman, Ken Porche, Monica B. Proud, Saba Qasmieh, Melissa B. Ramocki, Beau Reilly, Timothy P.L. Roberts, Dennis Shaw, Tuhin Sinha, Bethanny Smith-Packard, Anne Snow Gallagher, Vivek Swarnakar, Tony Thieu, Christina Triantafallou, Roger Vaughan, Mari Wakahiro, Arianne Wallace, Tracey Ward, Julia Wenegrat, Anne Wolken, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, CSIR-Institute of Microbial Technology [Chandigarh] (IMTech), Council of Scientific and Industrial Research [India] (CSIR), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Human Genetics, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), The Wellcome Trust Sanger Institute [Cambridge], Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Guglielmo Marconi University [Roma], Laboratoire de biomécanique (LBM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Systèmes de Référence Temps Espace (SYRTE), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medical Sciences, Università degli studi di Torino (UNITO), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Liège (CHU-Liège), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Department of Clinical Genetics, Vejle Hospital, Institute of Child Health, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, CHU Bordeaux [Bordeaux], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Genomics of Common Disease, Imperial College London, Regional Hospital, Department of Psychiatry and Behavioral Sciences! (UW psychiatry), University of Washington [Seattle], University of California, San Francisco (UCSF), UCSF, Unité de Recherches Zootechniques (URZ), Institut National de la Recherche Agronomique (INRA), University of California [San Francisco] (UCSF), University of California, UCL Institute of Neurology, Biomagnetic Imaging Laboratory - University of California, SFARI219193, Simons Foundation, 31003A160203, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Roger De Spoelberch, Partridge Foundations, Jeanne et Jean Louis Levesque Foundation, 604102, Seventh Framework Programme, Canada Research Chairs, CRSII33-133044, SNSF Sinergia, 32003B_159780, SNSF National Centre of Competence in Research Synapsy, Foundation Parkinson Switzerland, Foundation Synapsis, Université de Lausanne = University of Lausanne (UNIL), CHU Sainte Justine [Montréal], Harvard University [Cambridge], Odense University Hospital (OUH), Department of radiology (Massachusetts General Hospital), Department of Psychiatry Massachusetts General Hospital (MGH), Columbia University [New York], Simons Foundation, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Gothenburg (GU), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vejle Hospital [Danemark], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Harvard University, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), University of Lausanne (UNIL), Centre de recherche du CHU Sainte-Justine [Montreal], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Human genetics, Institute of Microbial Technology (IMTECH), Intitute of Microbial Technology, Gillberg Neuropsychiatry Centre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], PSL Research University (PSL)-PSL Research University (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [APHP], Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Addor, M.C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Béna, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J.H., Campion, D., Colombert, V., Cordier, M.P., David, A., Debray, F.G., Delrue, M.A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gérard, M., Giachino, D., Guichet, A., Guillin, O., Héron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaître, M.P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekær Sørensen, K., Pinson, L., Plessis, G., Prieur, F., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A.L., Benedetti, M., Berg, J., Berman, J., Berry, L.N., Bibb, A.L., Blaskey, L., Brennan, J., Brewton, C.M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A.G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J.E., Evans, Y.L., Findlay, A., Fischbach, G.D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S.E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F.I., Jenkins, J., Jeremy, R.J., Johnson, K., Kanne, S.M., Kessler, S., Khan, S.Y., Ku, M., Kuschner, E., Laakman, A.L., Lam, P., Lasala, M.W., Lee, H., LaGuerre, K., Levy, S., Cavanagh, A.L., Llorens, A.V., Campe, K.L., Luks, T.L., Marco, E.J., Martin, S., Martin, A.J., Marzano, G., Masson, C., McGovern, K.E., McNally Keehn, R., Miller, D.T., Miller, F.K., Moss, T.J., Murray, R., Nagarajan, S.S., Nowell, K.P., Owen, J., Paal, A.M., Packer, A., Page, P.Z., Paul, B.M., Peters, A., Peterson, D., Poduri, A., Pojman, N.J., Porche, K., Proud, M.B., Qasmieh, S., Ramocki, M.B., Reilly, B., Roberts, TPL, Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A.S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., and Wolken, A.

Subjects
Adult, Male, 0301 basic medicine, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Autism Spectrum Disorder/diagnostic imaging, Autism Spectrum Disorder/genetics, Brain/pathology, Child, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 16/genetics, Cognitive Dysfunction/diagnostic imaging, Cognitive Dysfunction/genetics, Female, Humans, Intellectual Disability/diagnostic imaging, Intellectual Disability/genetics, Language, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders/diagnostic imaging, Neurodevelopmental Disorders/genetics, Schizophrenia/diagnostic imaging, Schizophrenia/genetics, Young Adult, 16p11.2, Autism spectrum disorder, Copy number variant, Genetics, Imaging, Neurodevelopmental disorders, Biology, Biological Psychiatry, 03 medical and health sciences, 0302 clinical medicine, Transverse temporal gyrus, Neuroimaging, Intellectual Disability, medicine, Cognitive Dysfunction, Copy-number variation, ComputingMilieux_MISCELLANEOUS, Brain morphometry, Brain, medicine.disease, 16p112, 030104 developmental biology, Schizophrenia, Williams syndrome, Neuroscience, Insula, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.METHODS: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion < control; Cohen's d < -1), and the caudate and hippocampus (control > duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.

Published
2018

14. Vascular disease

Author

Catherine, Amlie-Lefond and Dennis, Shaw

Subjects
Diffusion Magnetic Resonance Imaging, Humans, Vascular Diseases, Magnetic Resonance Angiography
Abstract

The child presenting with possible sentinel transient ischemic event or stroke requires prompt diagnosis so that strategies to limit injury and prevent recurrent stroke can be instituted. Cerebral arteriopathy is a potent risk factor for arterial ischemic stroke in childhood. Though acute imaging study in the setting of possible stroke is often a head computed tomography, when possible magnetic resonance imaging (MRI) is recommended as the first-line study as confirmation and imaging evaluation of ischemic stroke will typically require MRI. The MRI scanning approach should include diffusion-weighted imaging (DWI) early in the sequence order, since normal DWI excludes acute infarct with rare exception. In most cases, arterial imaging with time-of-flight (TOF) magnetic resonance angiography (MRA) is warranted. Dedicated MRA may not be possible in the acute setting, but should be pursued as promptly as possible, particularly in the child with findings and history suggestive of arteriopathy, given the high risk of recurrent stroke in these children. MRA can overestimate the degree of arterial compromise due to complex/turbulent flow, and be insensitive to subtle vessel irregularity due to resolution and complex flow. In cases with high imaging suspicion for dissection despite normal MRA findings, catheter angiogram is indicated. A thoughtful, stepwise approach to arterial neuroimaging is critical to optimize diagnosis, treatment, and primary and secondary prevention of childhood stroke.

Published
2016

15. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Author

Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Heterozygote, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Biology, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Order, Genetics, medicine, Humans, Copy-number variation, Clinical genetics, Obesity, Young adult, Child, Genetics (clinical), 030304 developmental biology, Child Development Disorders, Pervasive/diagnosis, Child Development Disorders, Pervasive/genetics, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities/diagnosis, Developmental Disabilities/genetics, Female, Intelligence Tests, Phenotype, Syndrome, 2. Zero hunger, Psychiatry, 0303 health sciences, Intelligence quotient, Neuropsychology, Complex traits, medicine.disease, Comorbidity, 3. Good health, Autism spectrum disorder, Child Development Disorders, Pervasive, Autism, Medical genetics, Human medicine, Copy-Number Variation, 030217 neurology & neurosurgery
Abstract

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Published
2012

16. Multipurpose Poetry: Introducing Science Concepts and Increasing Fluency

Author

Sarah Dennis‐Shaw

Subjects
Pharmacology, Linguistics and Language, Science instruction, Multimedia, Poetry, Teaching method, Primary education, computer.software_genre, Language and Linguistics, Fluency, English second language, Evaluation methods, Mathematics education, Pharmacology (medical), Student research, Psychology, computer
Published
2011

18. Principles of medical biochemistry

Author

Dennis Shaw

Subjects
business.industry, Library science, Academic community, Electronic publishing, Sociology, business, Biochemistry
Published
1999

19. Geography in higher education in the USSR

Author

Dennis Shaw

Subjects
Higher education, business.industry, Geography, Planning and Development, Subject (philosophy), Relevance (law), Sociology, Social science, business, Education
Abstract

Soviet geography in higher education stems from a solid tradition long pre‐dating 1917, but in Soviet times the subject's practical relevance to environmental problems has been especially emphasised. University courses are very specialised, yet in certain respects they are also extraordinarily broad by British standards. Geography graduates usually enter either teaching or scientific/ research bodies, to which they are readily suited by their training. The practical emphasis of geographical education, however, occasionally produces certain strains in the discipline.

Published
1977

20. Investigations of the library usage and information needs of clinical medicine and related disciplines

Author

Brember, Virginia Lovelace., Leggate, P. (Peter), Shaw, Dennis F., Dr. Dennis Shaw, and Dr. Peter Leggate

Subjects
Information resources, England, Clinical medicine, Medical libraries, Medical personnel, Information services, Oxford
Abstract

The relationships between medical libraries and the main users of medical information in the teaching hospitals and University departments in Oxford is examined. Systems ideas are used to define the sort of model or picture of the users that a library manager needs in order to provide the appropriate services, and to provide a formal means of incorporating users and their information needs into a management control system. Data were gathered by several methods and combined into a rich picture of the users and their information-seeking behaviour. The systems methodology developed by Checkland at the University of Lancaster was used to test this rich picture and link it with monitoring for library effective- ness. Application of the Checkland methodology was a crucial step which shifted the emphasis of the project from quantitative to conceptual modelling. The methods of data collection and the results are described as the User Survey. The following techniques were used: questionnaires, semi-structured interviews, direct observation, feedback forms (a critical incident technique), a reference tracing experiment and analysis of existing library records. The data gathered by those methods presented a consistent picture in which the nature of the users' work, ie research or clinical practice, was the dominant influence on information-seeking patterns. Application of the Checkland methodology and the conceptual models derived from it are described as the Systems Study. This revealed that the formal processes for monitoring and control expected by the conceptual models did not appear in identifiable form in the real world. Further examination showed that a detailed description of the library function was necessary and that this statement could be used to generate performance criteria. In addition, the rich picture from the User Survey was found to be a fair representation of reality. Conclusions for systems thinking, user studies, library managers and medical librarianship are presented.

Published
1982

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