There are 134 hits for ‘has role’ some psychotropic in ChEBI in February 2012. This screenshot (inter alia) shows Lithium (a mood stabilizer); chlorpromazine (an antipsychotic); valproate (antimanic); 5-methoxy-N,N-dimethyltryptamine (hallucinogen);
(Not the million dollar question, but the many billion dollars question!)We’re drowning in data and starving for knowledge! Not only different domains BUT different methods and different subjects (model organisms etc)Huge piles of different sorts of information coming out of different research areas. DIFFERENT PERSPECTIVES: if you try to get people to agree on names, they just don’t. But give them semantics-free identifiers and their own preferred (scoped) synonyms and you can get agreement on the definitions. Nobody is an expert in everything, most scientists are stuck in their narrow area of focus and expertise (which is a good thing for progress because you HAVE to become that specialised)
Different interpretations for the same results can ensue; based on the underlying theory of mental functioning. Linking the theory directly to the paradigm (tests) and the research results allows more straightforward generation of testable hypothesis for evaluating different theories… getting away from conceptual arguments, or at least helping to resolve them(Explicit logical formulation)
SNOMED, MeSH, ICD, ICF, Cognitive Atlas, Cognitive Paradigm Ontology, We will build on these vocabulary resources as sources, but maintain links so that we don’t lose mappings which have already been annotated to these sources.Most of these sources maintain controlled vocabularies but not real ontologies. There is a shortage of explicit relationships and formal (computable) definitions, so you can’t make computational inferences.
Mental functioning related anatomical structure: an anatomical structure in which there inheres the disposition to be the agent of a mental processBehaviour inducing state: a bodily quality inhering in a mental functioning related anatomical structure which leads to behaviour of some sortAffective representation: a cognitive representation sustained by an organism about its own emotionsCognitive representation: a representation which specifically depends on an anatomical structure in the cognitive system of an organismMental process: a bodily process which brings into being, sustains or modifies a cognitive representation or a behaviour inducing state
Arrows show ‘imports’ relationships between ontologies
Software engineering for integrative question-answering is made much easier by this approach, as the IDs are well-behaved strings – uniform length, numeric identifiers for quick lookup / indexing and so on.
Obviously, these questions leave aside the complexities of co-occurrences, but for the higher-level questions that would present no problem as long as aggregation occurred with the count of instances not the count of types. For the comparative questions at the lower level, you would want to exclude co-occurrences from the analysis if you were looking for genes that comparatively differed between the different classes.
BrainMap is a database of curated fMRI coordinates from published studies -- BrainMap.org.
These screenshots illustrate the search interface application for BrainMap
Examples of keywords which may be relevant – there are many others – e.g. heroin, opiate, … other sorts of drugs. No hierarchical relationships are expressed between these keywords, so a search would have to be assembled by adding them one by one – no automatic aggregation option is available.
Each database has different organisation and search criteria – here it is patient diagnosis and keywords, or at least those were the only two fields that I could find were relevant.
This desideratum may sound like wishful thinking but in fact it is ALREADY IN PLACE for the Gene Ontology and most biological databases. Databases listed here are a small selection of those that include fMRI coordinate data. For a discussion of the various brain imaging methods and results in studies of addiction, see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851068/ ‘Imaging the addicted human brain’
It would be useful, therefore, to compare data for addicted patients with data for patients with other preoccupations or failed goal-directed behaviours. But no computational methods facilitate this type of cross-searching at present. Again, it comes down to human effort to find or create the right sort of data. Targeted studies can be designed that do this on a one-by-one basis: see, for example, http://jnnp.bmj.com/content/68/6/731.full – which compares data on dysexecutive syndrome with patients who have alcoholism. Good study design is always a good idea, but the availability of published data on various conditions would allow re-use of that data in other contexts, if the links from symptoms to disorders were made more explicit.
Psychological standard test for ‘dysexective syndrome’ => failure of normal executive functions such as planning, organising, initiating … => http://www.dwp.gov.uk/docs/no2-sum-03-test-review-2.pdfFootnote: data should be compared only if it makes sense to do so! That’s the reason for explicitly characterising and classifying symptoms
Pathway illustration sourced from KEGG: http://www.kegg.jp/kegg-bin/highlight_pathway?scale=1.0&map=map05030&keyword=addictionNMR spectrum illustration (of a derivative of cocaine) comes from http://www.justice.gov/dea/programs/forensicsci/microgram/journal_v4_num14/pg5.html
This data on metabolites of cocaine was sourced from the Human Metabolome Database (HMDB): http://www.hmdb.ca/metabolites/HMDB06348
Canonical fear also involves an action tendency to fight-or-flight, a bad (powerless, negative, anxious) feeling, a behavioural response to the emotion that includes a characteristic fearful facial expression
Cognitive neuroscience uses research “paradigms” – experimental designs intended to allow comparison of brain activation between different conditions. The subtraction of the brain activation for the control condition from the brain activation for the test condition then gives the “net” activation, which is what is reported on in the literature, subject to statistical analysis.
This is, of course, just one tiny part of the story. The overall story would have to be built up out of many, many cross-ontology links.
Depression and bipolar disorder are paradigm affective disorders.
Mental functioning ontology for interdisciplinary research into mental disease, emotions and drugs
NIF Webinar, 24 April 2012Mental Functioning Ontology for interdisciplinary researchinto mental disease, emotions and drugs Janna Hastings1,2 (ChEBI, MF and the Emotion Ontology) 1 Cheminformatics and Metabolism, European Bioinformatics Institute, UK 2 Swiss Center for Affective Sciences, University of Geneva, Switzerland
Why mental functioning? I want…Oxytocin is believed to play a role in various behaviors,including orgasm, social recognition, pair bonding, anxiety …it is sometimes referred to as the "love hormone".The inability to secrete oxytocin and feel empathy is I think…linked to sociopathy, psychopathy, narcissism andgeneral manipulativeness. Tuesday, April 24, 2012 2
Many chemicals can affect mental functioning The Chemical OntologyTuesday, April 24, 2012 3
How does mental functioning actually work? EEGBiology Mouse Psychology Human Cognitive Science fMRI Genetic PET profiling GeneNeuroscience expression analysis Psychiatry Metabolic Chemistry Self-reports analysis Questionnaires
Theories of mental functioning have Abducted! testable implications for research Replaced! into mental diseaseCapgras delusion:a disorder in which a personholds a delusion that a friend,spouse, parent, or other closefamily member has been replacedby an identical-looking impostor. Faulty perception? Normal perception, faulty reasoning? Faulty emotional reaction to perception? Overactive imagination? TESTABLE IMPLICATIONS
Existing vocabularies don’t include computable definitions
Mental Functioning Ontology (MF)Tuesday, April 24, 2012 7
Modules under development: Mental diseases and emotions Domain-neutral BFO ontological upper level Mental Functioning OGMS MF Ontology Ontology for General Medical Science MFO-EM Emotion Ontology MD Mental Disease Ontology (Current focus on affective disorders and addiction)Tuesday, April 24, 2012 8
Bio-ontologies facilitate interdisciplinary scientific research1. Standardised vocabulary with definitions and synonyms for unified database annotations2. Hierarchical organisation for aggregation and multi- level comparison of results3. Community adoption for comparison of results to other project results worldwide4. Explicit relationships and underlying logic for automated reasoning to related entities5. Explicit bridging relationships between different ontologies for exploring underlying mechanismsTuesday, April 24, 2012 10
Modern scientific research relies on computational support Patient histories, EHR Synthesis Caregiver, Datapscyhiatric reports Analysis Genomic and Data metabolomic profiles Reporting Questionnaires Data Publication and self-reports Brain scans Tuesday, April 24, 2012 11
Ontology for standardisation Semantics-free unique identifiers that are stable and maintained MD:0000901 CODE (MD) indicates WHICH ONTOLOGY substance abuse A numeric identifier is unique per term is a Unambiguous preferred label together MD:0000902 with a textual definition guide the annotation marijuana abuse of this ontology term to associated data is abuse of substance S:09090909 Synonyms and other metadata are collected marijuana to facilitate searching, disambiguation and --------------------------- text processing Synonym: cannabis Synonym: THC Synonyms may be in several languages Synonym: dronabinol or reflect differing naming practices in different disciplinesTuesday, April 24, 2012 12
Ontology annotations are generic across multiple databasesID Patient Finding type Detail1111 Smith, John MF:0000902 Occasional (marijuana abuse)1111 Smith, John MF:0000903 Occasional (alcohol abuse)1111 Smith, John MF:0000904 Frequent (nicotine abuse) Same IDsSample ID Sample type Conditions Genotype1111 Illumina Golden Gate MF:0000903; MF:0000902 …Tuesday, April 24, 2012 13
Population-wide science depends on aggregation of dataAre there genes significantly enriched in all peoplewho suffer from some addiction?Are there differences between those people whosuffer from substance addiction compared to thosewho suffer from process addictions?Are there differences between those people whosuffer from opiate substance addictions and thosewho suffer from addictions to benzodiazepines?Tuesday, April 24, 2012 14
Ontology for hierarchical organisation MD:0000046 addiction MD:0000053 MD:0000053 process addiction substance addiction MD:0000054 MD:0000066 MD:0000065 gambling addiction benzodiazepine addiction opiate addiction MD:0000055 MD:0000067 MD:0000059 sex addiction diazepam addiction heroin addiction MD:0000064 MD:0000068 internet addiction morphine addictionEvery ‘sex addiction’ is a ‘process addiction’, every ‘process addiction’ is an ‘addiction’Every ‘heroin addiction’ is an ‘opiate addiction’, every ‘opiate addiction’ is a ‘substanceaddiction’, every ‘substance addiction’ is an ‘addiction’. And so on.Tuesday, April 24, 2012 15
Research involves comparison of results to existing data arising from other projects, stored in public databasesA researcher obtains brain scans for several addicted patients. In orderto determine how they compare to existing scans of other addictedpatients and to non-addicted patients, (s)he looks in public databases.Relating to addiction, manual examination of the BrainMap databasesearchcriteria suggests two patient diagnosis categories that maybe relevant: alcoholism and pathologicalgambling… as well as many unstructured keywordsTuesday, April 24, 2012 16
To amass the correct search criteria to find the data for each comparison requires careful manual examination … and that’s only one database out of hundredsTuesday, April 24, 2012 19
A shared community ontology for annotation allows unified searching across databases (e.g. GOA) RIKEN BrainMap Neuroimaging PlatformBrede NiftifMRI Data OpenfMRI NeuroSynth CenterTuesday, April 24, 2012 20
Computers can’t “see” implicit relationships between entities Substance addiction is characterised by symptoms such as preoccupation with substance and repeated failed attempts to control the use of the substance. These are non- canonical thinking and planning activities. But, there is no easy way to automatically compare with data from other conditions that have similar symptoms. Patient data – Patient data – Patient data – impaired rational preoccupation or addicted patients control of actions other compulsive or planning thinkingTuesday, April 24, 2012 21
Ontologies capture explicit computable relationships between entities MD:0001002 MD:0001001non-canonical (impaired) non-canonical (impaired) thinking process planning process MD:0001012 MD:0001011 Relationships preoccupation with failed attempts to are named substance use stop substance use and have definitions has part MD:0001053 They are used MD:0000053 realized in substance addiction substance addiction for automated disease course reasoning and questionTuesday, April 24, 2012 answering22
Related entities are themselves used in annotations MD:0001002 non-canonical (impaired) thinking process Patient data on Patient data on symptom symptom assessment assessment MD:0001001 (Dysexecutive (Addiction) non-canonical (impaired) syndrome) planning process … which allows patient data from disparate diseases (and research into normal functioning) to be comparedTuesday, April 24, 2012 23
Different domains operate at different levels of granularity and focus METABOLIC DATA (e.g. NMR) GENE EXPRESSION PATHWAYS, biological DATATuesday, April 24, 2012 24 processes
Urine samples of addicted patients reveal metabolites NMR data for metabolites of cocaine is found in metabolomics databases -- indexed by small moleculesTuesday, April 24, 2012 25
Ontology relationships can explicitly bridge across different ontologies at different levels MD:0000071 realized in MD:0010071 cocaine addiction cocaine addiction disease course has part S:00100100 has input MD:0020071 portion of cocaine use of cocaine has granular part CHEBI:27958 Chemical and cocaine metabolic dataTuesday, April 24, 2012 26
Current status and ongoing work in the Emotion OntologyTuesday, April 24, 2012 27
The Emotion Ontology (MFO-EM) BFO:Entity BFO MFO BFO:Continuant BFO:Occurrent MFO-EM BFO:Independent BFO:Dependent Continuant Continuant BFO:Process Organism BFO:Disposition Bodily Process Physiological Response to Emotion Process Mental Process Cognitiveinheres_in Representation Appraisal Process Emotional Action Tendencies Affective is_output_of Representation Appraisal Emotional Behavioural Process Subjective Emotional Feeling has_part agent_of Emotion Occurrent
To define the characteristics of different emotions start with canonical emotionsEmotion types (such as fear) show enormous variance across instancesJust as do anatomical types, e.g. human bodiesOntology expresses what is always true… But also aims to saysomething useful for representation of domain knowledge.Solution: encode such knowledge in ‘canonical’ types canonical Has part appraisal Has output Appraisal of fear process dangerousness Canonical fear results from an appraisal of dangerousness Tuesday, April 24, 2012 30
Canonical fear fear subtype canonical fear EMOTION COMPONENT CHARACTERISTIC FOR FEAR Action tendency Fight-or-flight Subjective emotional feeling Negative, tense, powerless Behavioural response Characteristic fearful facial expression Characteristic appraisal Something is dangerous to meTuesday, April 24, 2012 31
Canonical and non-canonical fearCanonical fear gives rise to action tendenciesthat are conformant to the perceived dangerPhobia =disposition giving rise to non-canonical fearlaridaphobia : intense fear of seagullsTuesday, April 24, 2012 32
Types of subjective feelingsTuesday, April 24, 2012 34
Types of physiological responsesTuesday, April 24, 2012 35
Types of emotional behaviourTuesday, April 24, 2012 36
Annotation of data from Cognitive Neuroscience of Emotion Study Task Annotation class in MFO/MFOEM Recognition of gender in emotional facial Visual perception of emotional facial expressions expressions (subClassOf perception) Recall of personal emotional memories Memory of emotional episodes with instructions to try re-create feeling (subClassOf memory) Listening to emotional sounds (e.g. grunts Auditory perception of emotional stimuli of disgust) (subClassOf perception) Viewing emotional film extracts Visual and auditory perception of emotional stimuli (subClassOf perception) The link from perception of emotional fear in facial expressions to canonical fear is subject to empirical researchTuesday, April 24, 2012 37
(Part of) the biochemical basis of emotion is in ChEBI Emotions are effected in part by neurotransmitters such as dopamine, tryptophanmolecular entity biological role Molecular function emotion (CHEBI:25375) (CHEBI:24432) (GO:0003674) (MFOEM:1) subtype neurotransmitter happiness dopamine neurotransmitter receptor activity (MFOEM:42) (CHEBI:25375) (CHEBI:25512) (GO:0030594) has role realized in part of Tuesday, April 24, 2012 38
Biological processes in affective disordersSome mental diseases involve altered emotionalfunctioning. (E.g. depression, bipolar disorder) Disposition Process mental emotion biological process disease Mechanism of action: complex down-regulation disturbances in non-canonical of dopaminergic depression underlying sadness system systems (GO:0032227) realized in has partTuesday, April 24, 2012 39
Availability, ContactsMental Functioning Ontology available at:http://mental-functioning-ontology.googlecode.com/svn/trunk/ontology/MF.owlEmotion Ontology available at:http://emotion-ontology.googlecode.com/svn/trunk/ontology/MFOEM.owlDiscussion mailing lists:firstname.lastname@example.org@googlegroups.comTuesday, April 24, 2012 40
Acknowledgements Thanks!Buffalo Ontologists Barry Smith, Werner Ceusters, Mark JensenEmotion Researchers in Geneva Kevin Mulligan, David Sander, Julien DeonnaChemistry, Biology, Neuroscience Christoph Steinbeck, Nicolas le Novère, Colin Batchelor, David Osumi-Sutherland, Jane Lomax, Jessica Turner, Angela LairdTuesday, April 24, 2012 41