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  1. Book ; Online: On the Challenges of using Reinforcement Learning in Precision Drug Dosing

    Basu, Sumana / Legault, Marc-André / Romero-Soriano, Adriana / Precup, Doina

    Delay and Prolongedness of Action Effects

    2023  

    Abstract: Drug dosing is an important application of AI, which can be formulated as a Reinforcement Learning (RL) problem. In this paper, we identify two major challenges of using RL for drug dosing: delayed and prolonged effects of administering medications, ... ...

    Abstract Drug dosing is an important application of AI, which can be formulated as a Reinforcement Learning (RL) problem. In this paper, we identify two major challenges of using RL for drug dosing: delayed and prolonged effects of administering medications, which break the Markov assumption of the RL framework. We focus on prolongedness and define PAE-POMDP (Prolonged Action Effect-Partially Observable Markov Decision Process), a subclass of POMDPs in which the Markov assumption does not hold specifically due to prolonged effects of actions. Motivated by the pharmacology literature, we propose a simple and effective approach to converting drug dosing PAE-POMDPs into MDPs, enabling the use of the existing RL algorithms to solve such problems. We validate the proposed approach on a toy task, and a challenging glucose control task, for which we devise a clinically-inspired reward function. Our results demonstrate that: (1) the proposed method to restore the Markov assumption leads to significant improvements over a vanilla baseline; (2) the approach is competitive with recurrent policies which may inherently capture the prolonged effect of actions; (3) it is remarkably more time and memory efficient than the recurrent baseline and hence more suitable for real-time dosing control systems; and (4) it exhibits favorable qualitative behavior in our policy analysis.

    Comment: Accepted to AAAI 2023
    Keywords Computer Science - Machine Learning
    Subject code 006
    Publishing date 2023-01-01
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: ExPheWas: a platform for cis-Mendelian randomization and gene-based association scans.

    Legault, Marc-André / Perreault, Louis-Philippe Lemieux / Tardif, Jean-Claude / Dubé, Marie-Pierre

    Nucleic acids research

    2022  Volume 50, Issue W1, Page(s) W305–W311

    Abstract: Establishing the relationship between protein-coding genes and phenotypes has the potential to inform on the molecular etiology of diseases. Here, we describe ExPheWas (exphewas.ca), a gene-based phenome-wide association study browser and platform that ... ...

    Abstract Establishing the relationship between protein-coding genes and phenotypes has the potential to inform on the molecular etiology of diseases. Here, we describe ExPheWas (exphewas.ca), a gene-based phenome-wide association study browser and platform that enables the conduct of gene-based Mendelian randomization. The ExPheWas data repository includes sex-stratified and sex-combined gene-based association results from 26 616 genes with 1746 phenotypes measured in up to 413 133 individuals from the UK Biobank. Interactive visualizations are provided through a browser to facilitate data exploration supported by false discovery rate control, and it includes tools for enrichment analysis. The interactive Mendelian randomization module in ExPheWas allows the estimation of causal effects of a genetically predicted exposure on an outcome by using genetic variation in a single gene as the instrumental variable.
    MeSH term(s) Mendelian Randomization Analysis/methods ; Phenotype ; Genetic Association Studies ; Causality ; Phenomics ; Genome-Wide Association Study/methods ; Polymorphism, Single Nucleotide
    Language English
    Publishing date 2022-04-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkac289
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pharmacogenomics of blood lipid regulation.

    Legault, Marc-André / Tardif, Jean-Claude / Dubé, Marie-Pierre

    Pharmacogenomics

    2018  Volume 19, Issue 7, Page(s) 651–665

    Abstract: Blood lipids are important modifiable risk factors for coronary heart disease and various drugs have been developed to target lipid fractions. Considerable efforts have been made to identify genetic variants that modulate responses to drugs in the hope ... ...

    Abstract Blood lipids are important modifiable risk factors for coronary heart disease and various drugs have been developed to target lipid fractions. Considerable efforts have been made to identify genetic variants that modulate responses to drugs in the hope of optimizing their use. Pharmacogenomics and new biotechnologies now allow for meaningful integration of human genetic findings and therapeutic development for increased efficiency and precision of lipid-lowering drugs. Polygenic predictors of disease risk are also changing how patient populations can be stratified, enabling targeted therapeutic interventions to patients more likely to derive the highest benefit, marking a shift from single variant to genomic approaches in pharmacogenomics.
    MeSH term(s) Cholesterol, HDL/blood ; Cholesterol, HDL/genetics ; Cholesterol, LDL/blood ; Cholesterol, LDL/genetics ; Coronary Disease/blood ; Coronary Disease/drug therapy ; Coronary Disease/genetics ; Gene Expression Regulation ; Humans ; Hypolipidemic Agents/adverse effects ; Hypolipidemic Agents/pharmacokinetics ; Hypolipidemic Agents/therapeutic use ; Membrane Transport Proteins/genetics ; Pharmacogenetics ; Polymorphism, Single Nucleotide ; Triglycerides/blood ; Triglycerides/genetics
    Chemical Substances Cholesterol, HDL ; Cholesterol, LDL ; Hypolipidemic Agents ; Membrane Transport Proteins ; Triglycerides
    Language English
    Publishing date 2018-04-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2019513-8
    ISSN 1744-8042 ; 1462-2416
    ISSN (online) 1744-8042
    ISSN 1462-2416
    DOI 10.2217/pgs-2018-0007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Study of effect modifiers of genetically predicted CETP reduction.

    Legault, Marc-André / Barhdadi, Amina / Gamache, Isabel / Lemaçon, Audrey / Lemieux Perreault, Louis-Philippe / Grenier, Jean-Christophe / Sylvestre, Marie-Pierre / Hussin, Julie G / Rhainds, David / Tardif, Jean-Claude / Dubé, Marie-Pierre

    Genetic epidemiology

    2023  Volume 47, Issue 2, Page(s) 198–212

    Abstract: Genetic variants in drug targets can be used to predict the long-term, on-target effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of genetically predicted lower CETP levels on biomarkers and ... ...

    Abstract Genetic variants in drug targets can be used to predict the long-term, on-target effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of genetically predicted lower CETP levels on biomarkers and cardiovascular outcomes. We found sex and body mass index (BMI) to be modifiers of the association between genetically predicted lower CETP and lipid biomarkers in UK Biobank participants. Female sex and lower BMI were associated with higher high-density lipoprotein cholesterol and lower low-density lipoprotein cholesterol for the same genetically predicted reduction in CETP concentration. We found that sex also modulated the effect of genetically lower CETP on cholesterol efflux capacity in samples from the Montreal Heart Institute Biobank. However, these modifying effects did not extend to sex differences in cardiovascular outcomes in our data. Our results provide insight into the clinical effects of CETP inhibitors in the presence of effect modification based on genetic data. The approach can support precision medicine applications and help assess the external validity of clinical trials.
    MeSH term(s) Humans ; Male ; Female ; Cholesterol Ester Transfer Proteins/genetics ; Cholesterol, HDL ; Cholesterol, LDL ; Biomarkers
    Chemical Substances Cholesterol Ester Transfer Proteins ; Cholesterol, HDL ; Cholesterol, LDL ; Biomarkers ; CETP protein, human
    Language English
    Publishing date 2023-01-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605785-8
    ISSN 1098-2272 ; 0741-0395
    ISSN (online) 1098-2272
    ISSN 0741-0395
    DOI 10.1002/gepi.22514
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: genipe: an automated genome-wide imputation pipeline with automatic reporting and statistical tools

    Lemieux Perreault, Louis-Philippe / Legault, Marc-André / Asselin, Géraldine / Dubé, Marie-Pierre

    Bioinformatics. 2016 Dec. 01, v. 32, no. 23

    2016  

    Abstract: Summary: Genotype imputation is now commonly performed following genome-wide genotyping experiments. Imputation increases the density of analyzed genotypes in the dataset, enabling fine-mapping across the genome. However, the process of imputation using ... ...

    Abstract Summary: Genotype imputation is now commonly performed following genome-wide genotyping experiments. Imputation increases the density of analyzed genotypes in the dataset, enabling fine-mapping across the genome. However, the process of imputation using the most recent publicly available reference datasets can require considerable computation power and the management of hundreds of large intermediate files. We have developed genipe, a complete genome-wide imputation pipeline which includes automatic reporting, imputed data indexing and management, and a suite of statistical tests for imputed data commonly used in genetic epidemiology (Sequence Kernel Association Test, Cox proportional hazards for survival analysis, and linear mixed models for repeated measurements in longitudinal studies). Availability and Implementation: The genipe package is an open source Python software and is freely available for non-commercial use (CC BY-NC 4.0) at https://github.com/pgxcentre/genipe. Documentation and tutorials are available at http://pgxcentre.github.io/genipe. Contact: louis-philippe.lemieux.perreault@statgen.org or marie-pierre.dube@statgen.org Supplementary information: Supplementary data are available at Bioinformatics online.
    Keywords automation ; bioinformatics ; computer software ; data collection ; epidemiology ; genome ; genotype ; genotyping ; longitudinal studies ; statistical analysis
    Language English
    Dates of publication 2016-1201
    Size p. 3661-3663.
    Publishing place Oxford University Press
    Document type Article
    ZDB-ID 1468345-3
    ISSN 1460-2059 ; 1367-4811 ; 1367-4803
    ISSN (online) 1460-2059 ; 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btw487
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: Simultaneous Electrophysiological Recording and Micro-injections of Inhibitory Agents in the Rodent Brain.

    Lai, Jimmy / Legault, Marc-André / Thomas, Sébastien / Casanova, Christian

    Journal of visualized experiments : JoVE

    2015  , Issue 101, Page(s) e52271

    Abstract: Here we describe a method for the construction of a single-use "injectrode" using commercially accessible and affordable parts. A probing system was developed that allows for the injection of a drug while recording electrophysiological signals from the ... ...

    Abstract Here we describe a method for the construction of a single-use "injectrode" using commercially accessible and affordable parts. A probing system was developed that allows for the injection of a drug while recording electrophysiological signals from the affected neuronal population. This method provides a simple and economical alternative to commercial solutions. A glass pipette was modified by combining it with a hypodermic needle and a silver filament. The injectrode is attached to commercial microsyringe pump for drug delivery. This results in a technique that provides real-time pharmacodynamics feedback through multi-unit extracellular signals originating from the site of drug delivery. As a proof of concept, we recorded neuronal activity from the superior colliculus elicited by flashes of light in rats, concomitantly with delivery of drugs through the injectrode. The injectrode recording capacity permits the functional characterization of the injection site favoring precise control over the localization of drug delivery. Application of this method also extends far beyond what is demonstrated here, as the choice of chemical substance loaded into the injectrode is vast, including tracing markers for anatomic experiments.
    MeSH term(s) Animals ; Brain/drug effects ; Brain/physiology ; Electrophysiology/instrumentation ; Electrophysiology/methods ; Infusion Pumps ; Microelectrodes ; Microinjections/instrumentation ; Microinjections/methods ; Rats ; Syringes ; gamma-Aminobutyric Acid/administration & dosage
    Chemical Substances gamma-Aminobutyric Acid (56-12-2)
    Language English
    Publishing date 2015-07-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
    ISSN 1940-087X
    ISSN (online) 1940-087X
    DOI 10.3791/52271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Genetic meta-analysis of cancer diagnosis following statin use identifies new associations and implicates human leukocyte antigen (HLA) in women.

    Sun, Maxine / Lemaçon, Audrey / Legault, Marc-André / Asselin, Géraldine / Provost, Sylvie / Aschard, Hugues / Barhdadi, Amina / Zada, Yassamin Feroz / Valois, Diane / Mongrain, Ian / Tardif, Jean-Claude / Dubé, Marie-Pierre

    The pharmacogenomics journal

    2021  Volume 21, Issue 4, Page(s) 446–457

    Abstract: We sought to perform a genomic evaluation of the risk of incident cancer in statin users, free of cancer at study entry. Patients who previously participated in two phase IV trials (TNT and IDEAL) with genetic data were used ( ... ...

    Abstract We sought to perform a genomic evaluation of the risk of incident cancer in statin users, free of cancer at study entry. Patients who previously participated in two phase IV trials (TNT and IDEAL) with genetic data were used (n
    MeSH term(s) Adult ; Aged ; Cohort Studies ; Coronary Artery Disease/drug therapy ; Coronary Artery Disease/genetics ; Female ; Genetic Variation/genetics ; Genomics/methods ; HLA Antigens/genetics ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Male ; Middle Aged ; Neoplasms/diagnosis ; Neoplasms/genetics ; Proportional Hazards Models ; Randomized Controlled Trials as Topic ; Risk Factors
    Chemical Substances HLA Antigens ; Hydroxymethylglutaryl-CoA Reductase Inhibitors
    Language English
    Publishing date 2021-03-01
    Publishing country United States
    Document type Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
    ZDB-ID 2106831-8
    ISSN 1473-1150 ; 1470-269X
    ISSN (online) 1473-1150
    ISSN 1470-269X
    DOI 10.1038/s41397-021-00221-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Simultaneous electrophysiological recording and micro-injections of inhibitory agents in the rodent brain

    Lai, Jimmy / Legault, Marc-André / Thomas, Sébastien / Casanova, Christian

    Journal of visualized experiments. 2015 July 07, , no. 101

    2015  

    Abstract: Here we describe a method for the construction of a single-use “injectrode” using commercially accessible and affordable parts. A probing system was developed that allows for the injection of a drug while recording electrophysiological signals from the ... ...

    Abstract Here we describe a method for the construction of a single-use “injectrode” using commercially accessible and affordable parts. A probing system was developed that allows for the injection of a drug while recording electrophysiological signals from the affected neuronal population. This method provides a simple and economical alternative to commercial solutions. A glass pipette was modified by combining it with a hypodermic needle and a silver filament. The injectrode is attached to commercial microsyringe pump for drug delivery. This results in a technique that provides real-time pharmacodynamics feedback through multi-unit extracellular signals originating from the site of drug delivery. As a proof of concept, we recorded neuronal activity from the superior colliculus elicited by flashes of light in rats, concomitantly with delivery of drugs through the injectrode. The injectrode recording capacity permits the functional characterization of the injection site favoring precise control over the localization of drug delivery. Application of this method also extends far beyond what is demonstrated here, as the choice of chemical substance loaded into the injectrode is vast, including tracing markers for anatomic experiments.
    Keywords brain ; drugs ; electrophysiology ; glass ; injection site ; neurons ; pharmacodynamics ; rats ; silver
    Language English
    Dates of publication 2015-0707
    Size p. e52271.
    Publishing place Journal of Visualized Experiments
    Document type Article
    ZDB-ID 2259946-0
    ISSN 1940-087X
    ISSN 1940-087X
    DOI 10.3791/52271
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: genipe: an automated genome-wide imputation pipeline with automatic reporting and statistical tools.

    Lemieux Perreault, Louis-Philippe / Legault, Marc-André / Asselin, Géraldine / Dubé, Marie-Pierre

    Bioinformatics (Oxford, England)

    2016  Volume 32, Issue 23, Page(s) 3661–3663

    Abstract: Genotype imputation is now commonly performed following genome-wide genotyping experiments. Imputation increases the density of analyzed genotypes in the dataset, enabling fine-mapping across the genome. However, the process of imputation using the most ... ...

    Abstract Genotype imputation is now commonly performed following genome-wide genotyping experiments. Imputation increases the density of analyzed genotypes in the dataset, enabling fine-mapping across the genome. However, the process of imputation using the most recent publicly available reference datasets can require considerable computation power and the management of hundreds of large intermediate files. We have developed genipe, a complete genome-wide imputation pipeline which includes automatic reporting, imputed data indexing and management, and a suite of statistical tests for imputed data commonly used in genetic epidemiology (Sequence Kernel Association Test, Cox proportional hazards for survival analysis, and linear mixed models for repeated measurements in longitudinal studies).
    Availability and implementation: The genipe package is an open source Python software and is freely available for non-commercial use (CC BY-NC 4.0) at https://github.com/pgxcentre/genipe Documentation and tutorials are available at http://pgxcentre.github.io/genipe CONTACT: louis-philippe.lemieux.perreault@statgen.org or marie-pierre.dube@statgen.orgSupplementary information: Supplementary data are available at Bioinformatics online.
    MeSH term(s) Automatic Data Processing ; Computational Biology/methods ; Genome ; Genomics/methods ; Genotype ; Humans ; Software
    Language English
    Publishing date 2016-12-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btw487
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Book ; Online: Deep interpretability for GWAS

    Sharma, Deepak / Durand, Audrey / Legault, Marc-André / Perreault, Louis-Philippe Lemieux / Lemaçon, Audrey / Dubé, Marie-Pierre / Pineau, Joelle

    2020  

    Abstract: Genome-Wide Association Studies are typically conducted using linear models to find genetic variants associated with common diseases. In these studies, association testing is done on a variant-by-variant basis, possibly missing out on non-linear ... ...

    Abstract Genome-Wide Association Studies are typically conducted using linear models to find genetic variants associated with common diseases. In these studies, association testing is done on a variant-by-variant basis, possibly missing out on non-linear interaction effects between variants. Deep networks can be used to model these interactions, but they are difficult to train and interpret on large genetic datasets. We propose a method that uses the gradient based deep interpretability technique named DeepLIFT to show that known diabetes genetic risk factors can be identified using deep models along with possibly novel associations.

    Comment: Accepted at ICML 2020 workshop on ML Interpretability for Scientific Discovery
    Keywords Computer Science - Machine Learning ; Quantitative Biology - Genomics ; Statistics - Applications ; Statistics - Machine Learning
    Publishing date 2020-07-03
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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