Substances Redesign Project update for Content Committee February 11, 2015

▪ Substance Hierarchy Redesign: ▪Reduce overloaded “is a” relationships ▪Correct inconsistent modeling of concepts resulting in inconsistent and/or incorrect inference and inheritance ▪Identify and retire grouper concepts representing roles ▪Identify and address ambiguous concepts ▪Meet criteria of Understandable, Reproducible, and Useful content Review of Project Goals

ChEBI – (Chemical Entities of Biological Interest)– Long time reference source Current scope = small molecules (excludes foods, environmental, biologicals etc.) Covers the majority of products currently in AMT. Other reference sources will be identified for subsequent phases. Current Scope

It was identified that substances are “collections of grains” To sufficiently define substances requires a source of these grains. For ChEBI molecules were identified as one source of ‘grains’. Options: 1.Map to external reference, classify and distribute as primitives. 2.Introduce Molecular Entity hierarchy, and have defined Substances distributed in SNOMED CT. Approach

Option 1 would involve substantial technical effort to either: A.Transform ChEBI to RF2 workbench format, manually define the substances, classify, then publish the Substances as primitives. B.Export the Substances to some other format (OWL), manually define the substances, classify, and then import the resultant inferred structure (as stated and primitive) and publish. This process would be have to be repeated each release. Approach

Option 2 allows the Substance hierarchy to be published as usual – with defined substances and genuine stated and inferred forms. It’s analogous to Option 1 a) however, only as much of the Molecular Entity hierarchy as is required is included. And it is manually curated (based on ChEBI). Automated process could be introduced, permitting resource availability. Substances are may then be defined as: Substance: hasGranularPart some ‘Molecular Entity’ Approach

The structure of the molecular entity hierarchy will reflect that of reference source (ChEBI), but only include the molecules necessary to define Substances. Examples

Molecular entities will not be created for groupers that are not useful for defining Substances (clinically useful) E.g. Amoxicillin has ChEBI ancestors ▪β-lactam ▪organonitrogen heterocyclic compound ▪carboxylic acid ▪And more… “organonitrogen heterocyclic compound” is not expected to be useful for SNOMED CT, so not included. These can be introduced in the future if required. Groupers and Dispositions

ChEBI defines molecular entities as having “role” realisable entities. Biological, Chemical, Application. Chemical and Biological roles, are generally considered intrinsic. And always applicable: “calcium channel blocker” “progesterone receptor agonist” These properties (Dispositions) are inherent in the molecule/substance and will be exhibited whenever the substance is given the opportunity. Groupers and Dispositions

Applications are almost always extrinsic and not applicable as defining properties in SNOMED CT. “Reagent”, “Cosmetic”, “Excipient” “Anti-inflammatory agent” “Laxative” Applications are uses for substances. They are: ▪ discovered/identified by people ▪ a result of the known dispositions ▪ associated with some therapeutic outcome. The properties may apply to products but not molecular entities or substances. Groupers and Dispositions

Proposed as sub-hierarchy in Qualifier value hierarchy ▪ A Disposition is an intrinsic, realizable property of an entity. While it is not always realised, the capacity to realize it must always present. ▪ Ice has the disposition to melt. ▪ A Role is a categorization applied to an entity. The presence or absence of this role, does not change the entity (aside from consequences of fulfilling the role). A role is usually assigned with some sort of intended outcome (e.g. treating a disease). Realisable Properties

Dispositions

As noted Substance will be defined as Substance : hasGranularPart some ‘Molecular Entity’ ▪ No Roles. (Only dispositions). Deprecated roles will reference “products” ▪ Ambiguous concept will be inactivated. ▪ Distinctions between ions and non-ions greatly reduced. ▪E.g |Alendronic acid vs |Alendronate Such terms are frequently used interchangeably and inconsistently. ▪ Substances that are target of “has active ingredient” relationships, should be disjoint. ▪ Groupers will be added as required (and existing ones reviewed) Defining Substances

Proposed future state The Amoxicillin variants may be related by a Grouper (e.g. Amoxicillin derivative) and/or relationship (e.g. “isModificationOf”). To be determined, based on feedback.

▪ Changes to the substance hierarchy will also impact existing concepts that are defined by these. ▪ The impacts will be a consequence of classification producing different inferred relationships. ▪ Currently |Amoxycillin trihydrate|<<< |Amoxycillin| Therefore: | Procedure |: | Using substance |= | Amoxycillin trihydrate | <<< | Procedure |: | Using substance |= | Amoxycillin | Making the Amoxycillin trihydrate and Amoxycillin disjoint will do the same to the procedures. Substance Hierarchy

▪ Alpha release April 2014 ▪ Alpha release used ChEBI subset to support proof of concept for separation of molecules and collectives (substances) ▪ Based on feedback recommendation is to develop new SNOMED CT Molecular Entity and Dispositions hierarchies ▪Proposed model is under review by IHTSDO Design Authority ▪Provides content, product delivery, tooling, implementation perspectives ▪Technology preview planned for February 2015 What’s happened so far…

▪ February/March 2015 ▪Molecular Entity Alpha Release and Technology Preview ▪ July 2015 ▪Molecular Entity Production Deployment ▪ September 2015 ▪Substance Hierarchy Technology Preview ▪ January 2016 ▪Substance Hierarchy Production Deployment Project Deliverables

▪ Deliverables include: ▪OWL and Human readable formats ▪Supporting documentation ▪Mechanism to submit feedback Molecular Entity Alpha Release

Deliverables include: ▪Technology Preview files and supporting documentation ▪Product development documentation ▪Includes Inception/Elaboration/Construction/Transition documents ▪Content development plan for 2015 ▪Content maintenance plan ▪Editorial Guide update ▪Stakeholder communications/presentations ▪Scope and proposal for inclusion of additional content ▪Ex: proteins, genes, antibodies, antigens Molecular Entity Technology Preview

▪ July 2015 ▪ Deliverables include: ▪Content from Technology Preview moved into Production ▪Editorial Guide update ▪Additional content per 2015 content development plan ▪Stakeholder engagement ▪Scoping plan Molecular Entity Production Deployment

▪ July 2015 ▪ Deliverables include: ▪Technology Preview files and supporting documentation ▪Product development documentation ▪Includes Inception/Elaboration/Construction/Transition documents ▪Content development plan for 2015 ▪Content maintenance plan ▪Editorial Guide update ▪Stakeholder communications/presentations ▪Scoping plan for additional content ▪Ex: proteins, genes, antibodies, antigens Substance Hierarchy Technology Preview

▪ January 2016 ▪ Deliverables include: ▪Editorial Guide update ▪Content from Technology Preview moved into Production ▪Additional content per 2015 content development plan ▪Stakeholder engagement ▪Scoping plan Substance Hierarchy Production Deployment

▪ Drug Concept Model ▪Pending updated requirements and input from Member Forum ▪ Multiple subprojects/dependent projects/maintenance and content clean up ▪Dose Form Hierarchy ▪Vaccine Model ▪Allergy/Allergens ▪Anticipate multiple small projects for content maintenance and revisions as we proceed through the product development process ▪Foods Other Deliverables Not Yet Scheduled

▪ Following slides provide further detail on items discussed Extra notes

▪ Proposed attributes and current working definitions ▪|Is conjugate base of| and |Is conjugate acid of| ▪Denotes relationship between acids and their conjugate bases ▪|Is enantiomer of| ▪Denotes cases where two entities are mirror images of and non-superposable upon each other ▪|Has part| ▪Denotes relationship between the whole and a part (e.g. between a salt and its components) ▪|Has disposition| ▪Denotes a role played by the molecular entity or part thereof within a biological or chemical context, but not within a therapeutic context Molecular entity Attributes

▪ At a molecular level, acids and their conjugate bases are different concepts Citric acidCitrate In practice, the terms are often used interchangeably Nomenclature of Acids

▪ The substances exist as ions (in solution) ▪ A citric acid solution contains citrate and hydrogen ions. ▪ Measurements are generally indirectly against the ion ▪A patient administered Sodium valproate or Semisodium valproate ▪Drug monitoring will measuring valproate. Nomenclature of Acids

▪ Propose to just to have either ‘acids’ OR ‘ates’ ▪ However, the alternate form as a synonym ▪ E.g. ▪Model “valproic acid” with synonym of “valproate” ▪Model “valproate” with synonym of “valproic acid” Nomenclature of Acids