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1. Mixture modeling for identifying subtypes in disease course mapping

Author

Stanley Durrleman, Pierre-Emmanuel Poulet, Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This research has received funding from the program 'Investissements d’avenir' ANR-10-IAIHU-06. This work was also funded in part by the French government under management of Agence Nationale de la Recherche as part of the 'Investissements d’avenir' program, reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute)., Aasa Feragen, Stefan Sommer, Julia Schnabel, Mads Nielsen, ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-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), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This paper is funded in part by grant number 678304 (ERC), 826421 (TVB-Cloud) from H2020 programme, and ANR-10-IAIHU-06 (IHU ICM), ANR-19-P3IA-0001 (PRAIRIE) and ANR-19-JPW2-000 (E-DADS) from ANR., Poulet, Pierre-Emmanuel, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Sorbonne Université (SU)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-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)

Subjects
Computer science, Population, Stochastic approximation, Machine learning, computer.software_genre, 01 natural sciences, Synthetic data, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Alzheimer's disease subtypes, mixed-effect models, 0101 mathematics, Cognitive decline, mixture models, education, Cluster analysis, Non-linear mixed-effect model, ComputingMilieux_MISCELLANEOUS, Mixture model, Ground truth, education.field_of_study, MCMC-SAEM, business.industry, Contrast (statistics), Disease course mapping, Disease progression modelling, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Artificial intelligence, business, computer, [STAT.ME]Statistics [stat]/Methodology [stat.ME], 030217 neurology & neurosurgery
Abstract

International audience; Disease modeling techniques summarize the possible trajectories of progression from multimodal and longitudinal data. These techniques often assume that individuals form a homogeneous cluster, thus ignoring possible disease subtypes within the population. We extend a non-linear mixed-effect model used for disease course mapping with a mixture framework. We jointly estimate model parameters and subtypes with a tempered version of a stochastic approximation of the Expectation Maximisation algorithm. We show that our model recovers the ground truth parameters from synthetic data, in contrast to the naive solution consisting in post hoc clustering of individual parameters from a one-class model. Applications to Alzheimer's disease data allows the unsupervised identification of disease subtypes associated with distinct relationship between cognitive decline and progression of imaging and biological biomarkers.

Published
2021

2. Cluster Analysis of Physical Activity Patterns, and Relationship with Sedentary Behavior and Healthy Lifestyles in Prepubertal Children: Genobox Cohort

Author

Gloria Bueno, Francisco Jesus Llorente-Cantarero, Concepción M. Aguilera, Juan Jose Bedoya-Carpente, Augusto Anguita-Ruiz, Mercedes Gil-Campos, Jose Manuel Jurado-Castro, Rosaura Leis, Azahara Iris-Rupérez, Rocío Vázquez-Cobela, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, [Leis,R, Bedoya-Carpente,JJ, Vázquez-Cobela,R] Unidad de Investigación en Nutrición, Crecimiento y Desarrollo Humano de Galicia, Departamento de Pediatría, Hospital Clínico Universitario de Santiago, Universidad de Santiago de Compostela, IDIS, Santiago de Compostela, Spain. [Leis,R, Llorente-Cantarero,FJ, Anguita-Ruiz,A, Vázquez-Cobela,R, Aguilera,CM, Bueno,G, Gil-Campos,M] CIBEROBN, (Physiopathology of Obesity and Nutrition) Institute of Health Carlos III (ISCIII), Madrid, Spain. [Jurado-Castro,JM, Gil-Campos,M] Metabolism and Investigation Unit, Reina Sofia University Hospital, Maimónides Institute of Biomedicine Research of Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain. [Llorente-Cantarero,FJ] Department of Artistic and Corporal Education, Faculty of Education, University of Córdoba, Córdoba, Spain. [Anguita-Ruiz,A, Aguilera,CM] Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology 'José Mataix', Center of Biomedical Research, University of Granada, Armilla, Granada, Spain. [Anguita-Ruiz,A, Aguilera,CM] Instituto de Investigación Biosanitaria ibs, Granada, Spain. [Iris-Rupérez,A] GENUD Research Group, University of Zaragoza, Instituto Agroalimentario de Aragón (IA2), Instituto de Investigación Sanitaria (IIS) Aragón, Zaragoza, Spain. [Bueno,G] Unidad de Endocrinología Pediátrica, Hospital Clínico Lozano Blesa, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain., and This work was supported bythe Plan Nacional de Investigación Científica, Desarrollo e InnovaciónTecnológica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) (PI051968, PI1102042 and PI1600871) and Redes temáticas de investigación cooperativa RETIC (Red SAMID RD12/0026/0015). The authors also acknowledge Instituto de Salud Carlos III for personal funding of A.A.-R: Contratos i-PFIS: doctorados IIS empresa en ciencias y tecnologías de la salud de la convocatoria 2017 de la Acción Estratégica en Salud 2013–2016 (IFI17/00048).This paper will be included in J.M.J.-C. doctorate, under the 'Social and Legal Sciences Program' at theUniversity of Córdoba, Spain.

Subjects
Male, obesity, Mediterranean diet, Health Behavior, Obesidad, Child Behavior, Diet, Mediterranean, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Cohort Studies, 0302 clinical medicine, Surveys and Questionnaires, Cluster Analysis, Insulin, 030212 general & internal medicine, skin and connective tissue diseases, Child, Chemicals and Drugs::Lipids::Glycerides::Triglycerides [Medical Subject Headings], Nutrition and Dietetics, exercise, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Health Behavior [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Nutrition Therapy::Diet Therapy::Diet, Mediterranean [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Equipment and Supplies::Electrical Equipment and Supplies [Medical Subject Headings], Conducta sedentaria, Ejercicio físico, Cardiovascular diseases, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Child Behavior [Medical Subject Headings], Cohort, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Health Surveys::Nutrition Surveys::Diet Surveys [Medical Subject Headings], Female, Anthropology, Education, Sociology and Social Phenomena::Human Activities::Leisure Activities::Recreation::Sports [Medical Subject Headings], Club, Enfermedades cardiovasculares, lcsh:Nutrition. Foods and food supply, Sports, musculoskeletal diseases, Electrical Equipment and Supplies, Anatomy::Digestive System::Pancreas::Islets of Langerhans::Insulin-Secreting Cells [Medical Subject Headings], Physical activity, Check Tags::Male [Medical Subject Headings], 030209 endocrinology & metabolism, lcsh:TX341-641, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Cluster Analysis [Medical Subject Headings], Disease cluster, Article, Information Science::Information Science::Data Collection::Questionnaires [Medical Subject Headings], 03 medical and health sciences, Screen time, Environmental health, Anthropology, Education, Sociology and Social Phenomena::Human Activities::Exercise [Medical Subject Headings], medicine, Humans, Persons::Persons::Age Groups::Child [Medical Subject Headings], Healthy Lifestyle, Obesity, Exercise, Triglycerides, business.industry, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Psychology, Social::Life Style [Medical Subject Headings], Anthropometry, medicine.disease, Dieta mediterránea, cardiovascular diseases, stomatognathic diseases, Check Tags::Female [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Sedentary Behavior, business, Food Science
Abstract

The authors would like to thank the children and parents who participated in the study and Ana Yara Postigo-Fuentes for the assistance with the English editing., Sedentary habits during childhood are associated with adverse health outcomes. The aim of this work was to cluster lifestyle behaviors and metabolic biomarkers to establish different patterns in children. Their physical and sedentary activities were evaluated by accelerometry, and questionnaires that included lifestyle behaviors, such as adherence to a Mediterranean diet, anthropometry and blood biochemical markers. Cluster analysis was performed to establish different groups based on physical activity levels. A total of 489 children were finally selected. Cluster 1 included children with a mostly sedentary state, whereas Cluster 3 included the most active children and Cluster 2 included children that did not fit into either the sedentary or the highly active groups. In Cluster 3, 56% of children were in a sports club, and a lower percentage used electronic devices in their rooms compared to the other groups. Cluster 1 children exhibited higher insulin, HOMA-IR and triacylglycerides with respect to the other groups. No differences were found regarding adherence to a Mediterranean diet. The choice to practice an extracurricular sport could be an influencing factor to increase exercise and ensure an active lifestyle in children. Reducing or limiting screen time mainly in children’s rooms could contribute to an active lifestyle., Plan Nacional de Investigacion Cientifica, Desarrollo e InnovacionTecnologica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI051968 PI1102042 PI1600871, Redes tematicas de investigacion cooperativa RETIC (Red SAMID) RD12/0026/0015, Instituto de Salud Carlos III IFI17/00048

Published
2020

3. Use of a New High Resolution Melting Method for Genotyping Pathogenic Leptospira spp

Author

Amélie Desvars, Alain Michault, Florence Naze, Pascale Bourhy, Mathieu Picardeau, Laboratoire de Bactériologie-Parasitologie-Virologie-Hygiène, Groupe Hospitalier Sud Réunion (GHSR), Centre Collaborateur FAO/OMS pour l'épidémiologie de la leptospirose, Institut Pasteur [Paris] (IP), Centre National de Référence de la Leptospirose - National Reference Center Leptospirosis (CNR), Biologie des Spirochètes / Biology of Spirochetes, The authors have no support or funding to report., Conceived and designed the experiments: AM MP PB. Performed the experiments: FN AD. Analyzed the data: AD MP AM PB. Contributed reagents/materials/analysis tools: FN PB. Wrote the paper: FN AD MP PB AM., and Institut Pasteur [Paris]

Subjects
Serotype, DNA, Bacterial, Genotype, Genotyping Techniques, [SDV]Life Sciences [q-bio], lcsh:Medicine, Minisatellite Repeats, Nucleic Acid Denaturation, Real-Time Polymerase Chain Reaction, Melting curve analysis, High Resolution Melt, Species Specificity, Leptospira, medicine, Cluster Analysis, Humans, lcsh:Science, Genotyping, Genetics, Multidisciplinary, biology, lcsh:R, biology.organism_classification, medicine.disease, Leptospirosis, Virology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, lcsh:Q, Leptospira interrogans, Software, Research Article
Abstract

Background Leptospirosis is a worldwide zoonosis that is endemic in tropical areas, such as Reunion Island. The species Leptospira interrogans is the primary agent in human infections, but other pathogenic species, such as L. kirschner and L. borgpetersenii, are also associated with human leptospirosis. Methods and Findings In this study, a melting curve analysis of the products that were amplified with the primer pairs lfb1 F/R and G1/G2 facilitated an accurate species classification of Leptospira reference strains. Next, we combined an unsupervised high resolution melting (HRM) method with a new statistical approach using primers to amplify a two variable-number tandem-repeat (VNTR) for typing at the subspecies level. The HRM analysis, which was performed with ScreenClust Software, enabled the identification of genotypes at the serovar level with high resolution power (Hunter-Gaston index 0.984). This method was also applied to Leptospira DNA from blood samples that were obtained from Reunion Island after 1998. We were able to identify a unique genotype that is identical to that of the L. interrogans serovars Copenhageni and Icterohaemorrhagiae, suggesting that this genotype is the major cause of leptospirosis on Reunion Island. Conclusions Our simple, rapid, and robust genotyping method enables the identification of Leptospira strains at the species and subspecies levels and supports the direct genotyping of Leptospira in biological samples without requiring cultures.

Published
2015

4. Characterization of Staphylococcus aureus strains associated with food poisoning outbreaks in France

Author

Jacques-Antoine Hennekinne, Annaëlle Kerouanton, L. Petit, C. Letertre, Anne Brisabois, O. Chesneau, M.L. De Buyser, Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Agents antibactériens, Institut Pasteur [Paris], We acknowledge the technical assistance of Trinh Tam Dao, Marie-Odile Delbart, Muriel Marault, and Anne Morvan. We dedicate this paper to the memory of Névine El Solh who contributed to the phage-typing and who passed away in January 2005., and Institut Pasteur [Paris] (IP)

Subjects
Salmonella, Enterotoxin, MESH: Base Sequence, medicine.disease_cause, SmaI, Disease Outbreaks, MESH: Genotype, Enterotoxins, Genotype, MESH: Staphylococcus aureus, MESH: Enterotoxins, Cluster Analysis, MESH: Disease Outbreaks, MESH: Phylogeny, Phylogeny, 2. Zero hunger, 0303 health sciences, General Medicine, PFGE, 3. Good health, Electrophoresis, Gel, Pulsed-Field, Phenotype, MESH: Electrophoresis, Gel, Pulsed-Field, Staphylococcus aureus, MESH: Staphylococcal Food Poisoning, France, Staphylococcal Food Poisoning, Food Contamination, Biology, MESH: Phenotype, Microbiology, Food-poisoning, 03 medical and health sciences, medicine, Pulsed-field gel electrophoresis, Humans, MESH: Food Microbiology, 030304 developmental biology, MESH: Humans, Base Sequence, 030306 microbiology, Outbreak, MESH: Food Contamination, MESH: Cluster Analysis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: France, Food Microbiology, Food Science
Abstract

International audience; Enterotoxins produced by Staphylococcus aureus are responsible for staphylococcal food-poisoning outbreaks (SFPO). In France, SFPO are the second cause of food-borne diseases after Salmonella. However, very little is known about the strains involved. The objective of this study was to characterize the staphylococcal strains related to these SFPO through phenotypic and genotypic analyses. A total of 178 coagulase-positive staphylococcal isolates recovered from 31 SFPO (1981-2002) were screened through biotyping. Thirty-three strains representative of the different biotypes in each SFPO were further examined for SmaI macrorestriction-type, phage-type, resistance to various antimicrobial drugs, presence of staphylococcal enterotoxin (se) genes sea to sei, and production of enterotoxins SEA to SED. All these 33 strains were identified as S. aureus species: 27 were of human biotypes and six ovine or non-host-specific biotypes. Most (74.1%) strains reacted with group III phages. Eleven strains were resistant to at least two classes of antibiotics and among them, two were resistant to methicillin. Twenty-nine strains carried one or several of the eight se genes tested; the gene sea was most common (n=23), and often linked to sed (n=12) or seh (n=5). The novel se genes seg-i were in all cases associated with se genes sea to sed except for one strain which carried only seg and sei. Pulsed-Field Gel Electrophoresis (PFGE) of SmaI macrorestriction digests of the 33 strains discriminated 32 PFGE patterns grouped into nine biotype-specific clusters. All five strains carrying sea and seh were grouped together into the same sub-cluster. Three of the four se-gene-negative strains were in one PFGE cluster: all four should be tested for se genes not included in this study and, if negative, be further investigated for the presence of unidentified SEs.

Published
2007