Alan Ruttenberg Melanie Courtot The Adverse Event Reporting Ontology (AERO) is designed to facilitate the representation of adverse event reports and their evaluation in relation to clinical guidelines written by various authorities. We take a realist approach in which findings in reports are information artifacts and are related to instances or types that represent patient, symptoms, diseases, etc. We intend that use of this ontology will result in data that interoperates well with OBO Foundry ontologies as we directly use terms from OBO ontologies wherever appropriate. The initial domain for this work are reports of adverse events following immunization (AEFIs). We represent the Brighton case definitions as our guidelines, show how findings can be assessed in terms of Brighton criteria and how diagnoses of adverse events with different levels of certainty can be obtained by use of the OWL reasoner. BrightonFormula SuddOnset = sudden onset An annotation property reflecting the string used by Brighton in their ABC tool to encode the term AngEdGenLoc - angioedema, localized or generalized PHAC definition The definition of the term as formalized in the PHAC user guide, http://www.phac-aspc.gc.ca/im/pdf/AEFI-ug-gu-eng.pdf. Those definitions are often very specific to adverse event following immunization and are intended for reporting personel. found to exhibit A funny kind of relation, as there is a sense in which this is really a made up relation so we can speak from a patient centric point of view. Really, the relation is established in the inverse direction - a process in which a patient or information about the patient is assessed leads to a finding about the patient. Alan Ruttenberg if something is 'found to exhibit' a clinical finding, then there is a clinical finding 'that 'is clinical finding about' that something. has component a VAERS report has_component MedDRA term 12345 indicates the constitutive elements of a document/guideline/specification. involves 20101115, MC: one difiiculty in defining this relation is how to "cut" the chain at the first system involved. Example (from AR): a patient has a stroke in a nexk artery, which causes brain damage. We would still say "stroke involves cardiovascular system" and NOT "stroke involves nervous system" A relation between a clinical finding and the anatomical system or entity in which it takes place, at least partly. is clinical finding about A clinician records a finding that the patient has nausea Relates a clinical finding to the patient or part about which the finding was made. a finding is made that the heart has a malfunctioning valve realizes begins to exist during located at diagnosis guideline A directive information entity that specifies how to establish a diagnosis based on clinical findings disorder resulting from an AEFI process MC, 20110120: AR mentioned that the use of is_specified_output is not appropriate, as this would indicate that the adverse event process is a planned process - specified output are things that are specified in the plan to realize a process. Adverse events are not planned process but processual entities, and therefore this should be updated. AR mentioned that BFO will include an appropriate relation. MC, 20110120: This class should have a different label for OBO Foundry unique label. "adverse event following immunization" is a term in use by the clinician community, however in the context if the Foundry it may be confusing to associate the word "event" which seem to refer to a process with the hierarchical position under continuant. Proposed OBO Foundry label: disorder resulting from an AEFI MC, 20110126: class renamed from "adverse event following immunization continuant" following AR suggestion Brighton case definition A diagnosis guideline specifying how to establish a diagnosis of adverse event with an associated degree of certainty, as developed by the Brighton Collaboration, http://www.brightoncollaboration.org/ MC, 20110126: this should be linked to the different adverse events reported. AR suggests using a new relation to appear in BFO2, maybe "ascription" Brighton diagnosis of generalized convulsive seizure as an adverse event following immunization PMID:14741144#Generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. 20121115, MC: originally "a categorical measurement datum whose instances are used to classify adverse events according to whether or not they have some likelihood of being a seizure and if so, to what degree" disorder resulting from an adverse event process MC, 20110120: AR mentioned that the use of is_specified_output is not appropriate, as this would indicate that the adverse event process is a planned process - specified output are things that are specified in the plan to realize a process. Adverse events are not planned process but processual entities, and therefore this should be updated. AR mentioned that BFO will include an appropriate relation. MC, 20110120: This class was initially labeled "adverse event continuant". After discussion with AR, and due to the fact that the word "event" implicitely refers to a process, we renamed this class. adverse event ICH Topic E 2 A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting An adverse event is an undesirable, unfavorable and unintended medical occurrence presenting in a predetermined time frame following administration of a compound or usage of a device I initialy made adverse event a defined class: is_a sign and preceded by administration. However, by doing so, and as the range of preceded by is processual entities, I was implicitely making adverse event a subclass of processual entity, therfore making adverse event rash (a continuant) inconsistent. adverse event following immunization Adapted from ICH Topic E 2 A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting An adverse event is an undesirable, unfavorable and unintended medical occurrence presenting in a predetermined time frame following administration of a vaccine _manifestations temporary placeholder - to be removed This class just helps me group some terms during development of the structure AEFI idiopathic thrombocytopenic purpura according to Brighton Idiopathic thrombocytopenic purpura (ITP) is the condition of having a low platelet count (thrombocytopenia) of no known cause (idiopathic).v http://en.wikipedia.org/wiki/Idiopathic_thrombocytopenic_purpura AEFI encephalitis according to Brighton Encephalitis is an inflammation of the brain. It may be caused by a number of different factors. One of the most common causes is direct infection of the brain by a virus or bacterium. Inflammation can also occur as a complication of some other disorder, such as mumps (see mumps entry) or herpes simplex (see herpes infections entry). http://www.faqs.org/health/Sick-V2/Encephalitis-Definition.html motor manifestation A _manifestation involving the motor system adverse event process An adverse event process is a processual entity occurring in a pre determined time frame following administration of a compound or usage of a device I included the usage of a device into the definition of adverse event as I am aiming at being inclusive, and cover cases such as those described by MAUDE - Manufacturer and User Facility Device Experience. See for example http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/detail.cfm?mdrfoi__id=1942591 - a patient get fitted with bioprosthetic heart valves and dies within the following 4 months. Note that this definition of adverse event doesn't imply any type of causality between the sign observed and the coumpond administration/device utilization. For our purposes, we consider any type of sign presenting within a specific time frame after the coumpound administration/device utilization to be an adverse event. adverse event following immunization process seizure level 1 of certainty according to the Brighton criteria MC, 20110126: this needs to be linked to the Brighton guideline defined under directive information entity witnessed sudden loss of consciousness AND generalized, tonic, clonic, tonic–clonic, or atonic motor manifestations. (atonic In the absence of: hypotonic hyporesponsive episode (as defined by the Brighton Collaboration), syncope, and myoclonic jerks. seizure level 2 of certainty according to the Brighton criteria MC, 20110126: this needs to be linked to the Brighton guideline defined under directive information entity history of unconsciousness AND generalized, tonic, clonic, tonic–clonic, or atonic motor manifestations. (atonic In the absence of: hypotonic hyporesponsive episode (as defined by the Brighton Collaboration), syncope, and myoclonic jerks. seizure level 3 of certainty according to the Brighton criteria MC, 20110126: this needs to be linked to the Brighton guideline defined under directive information entity history of unconsciousness AND other generalized motor manifestations. atonic motor manifestation finding A sudden loss of tone in postural muscle, often preceded by a myoclonic jerk and precipitated by hyperventilation Brighton Collaboration, http://www.brightoncollaboration.org/ generalized atonic motor manifestation finding clonic motor manifestation finding Brighton Collaboration, http://www.brightoncollaboration.org/ Sudden, brief (100ms) involuntary contractions of the same muscle groups, regularly repetitive at a frequency of about two to three contractions per second. generalized motor manifestation finding Brighton Collaboration, http://www.brightoncollaboration.org/ bilateral motor manifestation, more than minimal muscle involvement generalized clonic motor manifestation finding generalized tonic motor manifestation finding generalized tonic-clonic motor manifestation finding AEFI hypotonic-hyporesponsive episode according to Brighton HHE HHE is characterized by sudde onset of reduced muscle tone, hyporesponsiveness (i.e., less responsive than usual to verbal or other sensorial stimuli) and change of skin color (pallor or cyanosis) performing a diagnosis of generalized convulsive seizure according to Brighton guidelines performing a diagnosis specified by the Brighton case definition for convulsive seizure as an adverse event following immunization Brighton case definition of generalized convulsive seizure as an adverse event following immunization A Brighton case definition of generalized convulsive seizure as an adverse event following immunization PMID:14741144#Generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. shaking finding quivering repetitive, cyclical movements of the body or a body part; usually involuntary, but can also manifest in response to an attempt at movement shivering trembling tremor bilateral shaking finding A shaking process which unfolds in both sides of an organism syncope finding MC, 20110126: The Brighton guideline on which this is based needs to be checked. Email correspondance with Brighton: [MC] One thing is unclear to me: Level 1 of diagnostic certainty is defined as "witnessed sudden loss of consciousness AND generalized, tonic, clonic, tonic–clonic, or atonic motor manifestations." A footnote adds: atonic in the absence of: hypotonic hyporesponsive episode (as defined by the Brighton Collaboration), syncope, and myoclonic jerks. If we define syncope as being a loss of consciousness, how can I have a witnessed sudden loss of consciousness and a generalized atonic motor manifestation in the absence of syncope? [Brighton] Thank you for your question. You are right, that there is an overlap between the clinical presentation of an atonic seizure and a Syncope. This is also true for HHE. This is the very reasonf or the footnote to alert the user of the definition to this differential diagnosis. If you are working on a database and only have the clinical criteria vailable, you may have some false positives for the atonic seizure cases, unless you obtain additional information, e.g. that the Syncope was vasovagal or orthostatic, or arrhythmic, etc. http://en.wikipedia.org/wiki/Syncope_%28medicine%29 loss of consciousness, fainting myoclonic jerk finding A myoclonic jerk is the brief, involuntary twitching of a muscle or group of muscles. It may be caused either by a sudden muscle contraction, or a sudden lapse of contraction. This happens when a person is on the verge of falling asleep, and suddenly have a sensation or feeling that they are free falling through the air. Contractions are called positive myoclonus; relaxations are called negative myoclonus. When falling asleep, it is common for people to experience a type of myoclonic jerk known as a hypnic jerk. Hiccups are also a kind of myoclonic jerk specifically affecting the diaphragm. http://house.wikia.com/wiki/Myoclonic_jerk tonic motor manifestation finding A sustained increase in muscle contraction lasting a few seconds to minutes loss of consciousness finding Total suspension of conscious relationship with the outside world demonstrated by the inability to perceive and to respond to verbal, visual, and painful stimulus Vaccine 28 (2010) 4487-4498 history of unconsciousness Brighton Collaboration, http://www.brightoncollaboration.org/ MC, 20110126: AR suggest that "history of consciousness is not a process. definition reads "the sudden loss of consciousness was not observed, but the patient was found unconscious", so maybe updating the label would be better : "unwitnessed loss of consciousness with history of unconsciousness" would help the sudden loss of consciousness was not observed, but the patient was found unconscious witnessed sudden loss of consciousness finding Brighton Collaboration, http://www.brightoncollaboration.org/ bilateral site witness role A role inhering in a person that is realized when the bearer sees an event and reports what happened adapted from http://golovchenko.org/cgi-bin/wnsearch?q=witness adverse side effect side effect is an adverse event of a type that has been determined by a review board to be causally related to the intervention. while in some cases the particular may not be actually caused by the intervention, it is an adverse side effect nonetheless. device malfunction A process in which the device doesn't perform as expected device malfunction adverse event report A report as submitted in an adverse event reporting system MC, 20110719: not all adverse event report are about adverse event. See for example cases in MAUDE database that are about potential adverse events such as device malfunctions. adverse event report reporting process The process of creating documentation about something and adding it to a system allowing further analysis of the reported entity sudden onset SuddOnset Anaphylaxis: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 25 (2007) 5675–5684 The term sudden onsets refers to an event that occurred unexpectedly and without warning leading to a marked change in a subjects previously stable condition rapid progression RapidProgr Anaphylaxis: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 25 (2007) 5675–5684 The term rapid progression is a conventional clinical term. An exact timeframe sould not be offered since it would have to refer to a wide range of signs and symptoms without a scientific evidence base. Using an arbitrarily restrictive setpoint might bias future data collection unnecessarily. respiratory distress diagnosis 2 1 1 1 1 1 respiratory distress—2 or more of the following: • tachypnoea • increased use of accessory respiratory muscles (sternocleidomastoid, intercostals, etc.) • recession • cyanosis • grunting performing a diagnosis according to a Brighton case definition Brighton diagnosis result The diagnosis performed upon review of an adverse event report according to the Brighton case definitions adverse event reporting process The process of creating documentation about an adverse event and adding it to a system allowing further analysis of the event clinical diagnosis of uncompensated shock 3 1 1 1 1 combination of at least 3 of the following: - tachycardia - capillary refill time > 3s - reduced central pulse volume - decreased level of consciousness or loss of consciousness dermatologic or mucosal sign A clinical finding that involves the dermatological-mucosal system token respiratory-distress-token uncompensated-shock-token Brighton case definition of anaphylaxis as an adverse event following immunization PMID:17448577#Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. performing a diagnosis of anaphylaxis according to Brighton guidelines major dermatological criterion for anaphylaxis according to Brighton generalized urticaria or generalized erythema finding angioedema finding 20130423, MC: in the anaphylaxis case definition, angioedeme can be localized or generalized. There was no need as of today to create specialized subclasses representing those. AngEdGenLoc Areas of deeper swelling of the skin and/or mucosal tissues in either single or multiple sites which may not be well circumscribed and is usually not itchy. Reported symptoms of ‘swelling of the lip’ or ‘swelling of the tongue or throat’ should not be documented as angioedema unless there is visible skin or mucosal swelling. Vaccine 28 (2010) 4487-4498 generalized pruritus with skin rash finding _anaphylaxis according to Brighton criteria set of clinical findings 20120821, MC: placeholder for development the set of clinical findings that are classified as being relevant for the anaphylaxis diagnosis major cardiovascular criterion for anaphylaxis according to Brighton major respiratory criterion for anaphylaxis according to Brighton measured hypotension finding An abnormally low blood pressure and documented by appropriate measurement. Infants and children: age specific systolic BP of <3-5%percentile or greater than a 30% decrease from that person’s baseline; Adults: systolic BP of <90mm Hg or greater than 30% decrease from that person’s baseline. HypotensMeas Vaccine 28 (2010) 4487-4498 uncompensated shock sign finding tachycardia finding A heart rate that is abnormally high for age and circumstance (In beats per minute: <1year old: >160; 1 – 2 yrs: >150; 2-5 yrs: >140; 5-12 yrs: >120; >12 yrs: >100) Citation for norms is Don & Roberton; Physical examination; in Practical Pediatrics 2007; 6th ed TachyCard Vaccine 28 (2010) 4487-4498 capillary refill time > 3s finding CapRefillOver3 Capillary refill time is the time required for the normal skin colour to reappear after a blanching pressure is applied. It is usually performed by pressing on the nail bed to cause blanching and then counting the time it takes for the blood to return to the tissue, indicated by a pink colour returning to the nail. Normally it is <3 seconds. Vaccine 28 (2010) 4487-4498 reduced central pulse volume finding PulseVolRed decreased level of consciousness or loss of consciousness finding loss of counsciousness is a subclass of decreased consciousness, so saying "is about some decreased level of consciousness" I cover all cases bilateral wheeze finding WheezeBilat bronchospasm finding stridor finding A harsh and continuous sound made on breathing in. Stridor Vaccine 28 (2010) 4487-4498 upper airway swelling finding SwellUpAirways lip, tongue, throat, uvula or larynx tachypnoea finding Citation for norms is Don & Roberton; Physical examination; in Practical Pediatrics 2007; 6th ed Rapid breathing which is abnormally high for age and circumstance rapid breathing whichis abnormally high for age and circumstance (<1yr: >60; 1-2 yrs: >40; 2-5 yrs: >35; 5-12 yrs: >30: >12 yrs: >16) TachyPnea Vaccine 28 (2010) 4487-4498 tachypnea finding increased use of accessory respiratory muscles finding RespMuscAccIncr sternocleidomastoid, intercostals, etc recession finding Recess cyanosis finding A dark bluish or purplish discolouration of the skin and mucous membrane due to lack of oxygen in the blood. Cyanosis Vaccine 28 (2010) 4487-4498 grunting finding A sudden and short noise with each breath when breathing out. Grunting Vaccine 28 (2010) 4487-4498 respiratory distress sign finding Brighton diagnosis of anaphylaxis as an adverse event following immunization Level 1 of certainty of anaphylaxis according to Brighton patient generalized prickle sensation finding PrickleSens localized injection site urticaria finding Localized redness of superficial layers of skin that is itchy, raised, sharply demarcated and transient (that is skin changes at any location are usually present for less than 12 hours). UrticariaLOC Vaccine 28 (2010) 4487-4498 red and itchy eyes finding EyeRedItch reduced peripheral circulation finding capillary refill time > 3s finding without hypotension reduced peripheral circulation diagnosis 2 1 1 1 The reduced peripheral circulation diagnosis is the minor cardiovascular criterion for anaphylaxis according to Brighton. The diagnosis is established by observing the combination of at least 2 reduced peripheral circulation findings, but at most one of each type. generalized pruritus without skin rash finding persistent dry cough finding CoughPersisDry Rapid expulsion of air from the lungs to clear the lung airways and not accompanied by expectoration (a non-productive cough). Vaccine 28 (2010) 4487-4498 hoarse voice finding An unnaturally harsh cry of infant or vocalization in a child or adult. Vaccine 28 (2010) 4487-4498 VoiceHoarse sensation of throat closure finding ThroatCloseSens sneezing or rhinorrhea finding diarrhoea finding Diarrhea Loose and/or watery stool which may occur more frequently than usual. Vaccine 28 (2010) 4487-4498 diarrhea finding abdominal pain finding AbdoPain Sensation of discomfort or pain in the abdominal region. Vaccine 28 (2010) 4487-4498 nausea finding An unpleasant sensation vaguely referred to the upper abdominal region and the abdomen, with a tendency to vomit. Nausea vomiting finding The reflex act of ejecting the contents of the stomach through the mouth. Vaccine 28 (2010) 4487-4498 VomitUnspec mast cell tryptase elevation > upper normal limit finding MastCellTryp minor dermatological criterion for anaphylaxis according to Brighton minor cardiovascular criterion for anaphylaxis according to Brighton minor respiratory criteria set for anaphylaxis according to Brighton difficulty breathing without wheeze or stridor finding 20130319, MC: Here the ontology is more specific than Brighton formula which just states "DiffBreath" - we logically encode the restrictions mentioned in the guideline -> without wheeze or stridor DiffBreath minor gastrointestinal criterion for anaphylaxis according to Brighton minor laboratory criteria set for anaphylaxis according to Brighton Level 2 of certainty of anaphylaxis according to Brighton Level 3 of certainty of anaphylaxis according to Brighton cardiovascular sign respiratory sign gastrointestinal sign Reported anaphylaxis with insufficient evidence to meet the case definition not a case of anaphylaxis dry cough finding chest tightness finding indrawing finding rhinorrhea finding Discharge of thin nasal mucus. Rhinorrhea sore throat finding wheezing finding erythema finding generalized erythema finding ErythemaGen red eyes finding itchy eyes finding prickle sensation finding Tingling or smarting (stinging) sensation. pruritus finding generalized pruritus finding PruritusGen rash finding skin rash finding SkinRash urticaria finding generalized urticaria finding UrticariaGen hives finding decreased level of consciousness finding ConscDecr Reduced alertness or awareness of the outside world. tonic-clonic manifestation finding A sequence consisting of a tonic followed by a clonic phase sneezing finding An involuntary (reflex), sudden, violent, and audible expulsion of air through the mouth and nose. Sneeze Vaccine 28 (2010) 4487-4498 difficulty breathing finding reported anaphylaxis Level 3 of certainty of anaphylaxis - post ICPE Following the ICPE meeting in Montreal 2013, MC clarified with JB that the guideline should be understood as "if there is a minor cardiovascular criteria, then we need 2 other systems involved, including respiratory, dermatologic, gastrointestinal and laboratory" and similarly if there is a respiratory criteria. The first iteration was interpreted as (1 minor cardiovascular OR respiratory criterion) AND 2 minors from systems that are neither respiratory nor cardiovascular (dermatologic, gastrointestinal , laboratory systems) to mimic behavior of the ABC tool. minor respiratory criteria set for anaphylaxis according to Brighton - post ICPE Following meeting at ICPE Montreal 2013, MC and JB clairfied that "difficulty breathing without wheeze or stridor" should be understood as "difficulty breathing" minor dermatological criterion for anaphylaxis according to Brighton - post ICPE Following meeting at ICPE Montreal 2013, MC and JB clairfied that "genralized pruritus withou rash" should be understood as "generalized pruritus" Level 2 of certainty of anaphylaxis according to Brighton - post ICPE Level 3 of certainty of anaphylaxis - PHAC form 20130912: In the paper http://dx.doi.org/10.1016/j.vaccine.2010.04.041 "Can the Brighton Collaboration case definitions be used to improve the quality of Adverse Event Following Immunization (AEFI) reporting? Anaphylaxis as a case study", the form used by PHAC and shown in Appendix E states as a footnote "for level III, a skin MAJOR can count as a minor criterion" cynosis-token grunting-token increased use of accessory respiratory muscles-token recession-token tachypnoea-token tachycardia-token capillary refill time above 3s-token reduced central pulse volume-token decreased level of consciousness or loss of consciousness-token An acute hypersensitivity reaction with multi-organ-system involvement that can present as, or rapidly progress to, a severe life-threatening reaction.