Day 1: Phenotypes: Orion Buske, PhenoTips

Orion Buske, CEO of Phenotypes, gave a presentation at the CORD Spring Conference in June 2022 about using patient phenotypes to drive genomic diagnostics for rare diseases. He explained that while genome sequencing can diagnose thousands of genetic conditions at once, clinicians need detailed phenotypic information to determine which are relevant to each patient's condition. PhenoTips is a digital platform that uses structured phenotypic data from sources like the Human Phenotype Ontology to help match patients to potential diagnoses, genes, and other related information to support precision medicine. It allows data sharing between hospitals, clinics, and research initiatives to help solve more rare disease cases.

Healthcare

Orion Buske, CEO
orion@phenotips.com
Phenotypes
(and their role in rare disease diagnosis)
CORD Spring Conference
June 2022

How to provide a timely and accurate diagnosis?
Genome sequencing allows us to diagnose
1000s of genetic conditions with a single test
But it’s not really a single test, it’s thousands
or millions of them, all in parallel
We need to know which are relevant to the patient’s
condition

Labs frequently have to re-contact the ordering clinician to get more
detailed information
— GeneDx XomeDx
— Invitae Exome
The patient phenotype drives genomic diagnostics

phe·no·type /ˈfēnəˌtīp/
4
noun BIOLOGY
the set of observable characteristics
of an individual resulting from the
interaction of its genotype with the
environment.
What is a phenotype?
One eye
Short stature
Yellow skin
Sparse scalp hair
Conspicuously
happy disposition

Human Phenotype Ontology
13,000+ terms; 156,000+ associations to
7,000 rare diseases and 4,000 common diseases
eye disease
abnormal eye
morphology
coloboma
globe
abnormality
neurologic skeletal
...
abnormality
5

Structured data helps computers help us
6
diagnosis
phenotype–disease
genome analysis
phenotype–gene
matchmaking
phenotype–phenotype

7
Patient
Specialist
Genetic
Counselor
EHR
PhenoTips
Labs
Digital
transformation
Data interoperability
Workflow efficiency
Patient safety
Precision
medicine
PhenoTips: digital infrastructure for genomic medicine

Features to simplify deep phenotyping
Smart search Smart measurements
Microcephaly [HP:0000252]
[...] The patient presents with osseous maturation
and mild intellectual disability. Craniofacial
features include flat nasal bridge, large ears, long
philtrum, micrognathia, loose skin, and a triangular
face. [...]
Text mining

genes
rare diseases
family history
phenotype
genotype
9
PhenoTips is the genomic medicine platform
with phenotype at its core

Hospitals
Portable data enables matchmaking
Research Clinics
National and International Initiatives
Matchmaking
Unsolved Cases
10
Check out the May 2022
special issue in Human
Mutation! [open access]

A huge thank you to our team, and
all the people and organizations
that have supported the project,
and the patients, providers and
researchers we are trying to benefit
through it.
Thank you.
orion@phenotips.com
11

The Human Phenotype Ontology (HPO) was developed to describe phenotypic abnormalities, aka, “deep phenotyping”, whereby symptoms and characteristic phenotypic findings (a phenotypic profile) are captured. The HPO has been utilized to great success for assisting computational phenotype comparison against known diseases, other patients, and model organisms to support diagnosis of rare disease patients. Clinicians and geneticists create phenotypic profiles based on clinical evaluation, but this is time consuming and can miss important phenotypic features. Patients are sometimes the best source of information about their symptoms that might otherwise be missed in a clinical encounter. However, HPO primarily use medical terminology, which can be difficult for patients and their families to understand. To make the HPO accessible to patients, we systematically added non-expert terminology (i.e., layperson terms) synonyms. Using semantic similarity, patient-recorded phenotypic profiles can be evaluated against those created clinically for undiagnosed patients to determine the improvement gained from the patient-driven phenotyping, as well as how much the patient phenotyping narrows the diagnosis. This patient-centric HPO can be utilized by all: in patient-centered rare disease websites, in patient community platforms and registries, or even to post one’s hard-to-diagnosed phenotypic profile on the Web.

The Application of the Human Phenotype Ontology

Patient-led deep phenotyping using a lay-friendly version of the Human Phenot...

Presented at AMIA TBI CRI 2018. Rare disease patients are expert in their medical history and these patients not only are some of the most engaged, but also they can themselves provision data for use in clinical evaluation. We therefore created a lay-person version of our clinical deep phenotyping instrument, the Human Phenotype Ontology. Here, we evaluate the diagnostic utility of this lay-HPO, and debut a new software tool for patient-led deep phenotyping.

Genetic Disorders and Variations on Mendel's Principles

ilanasaxe

Example OneDiscuss how new discoveries in genetics are contr.docx

SANSKAR20

Example One Discuss how new discoveries in genetics are contributing to our understanding of the HIV virus and how some folks exposed to HIV have been able to escape developing AIDS. The HIV virus daily infects 14,000 people, however some individuals’ odds of contracting the virus are very low. Dr. Donald Mosier of the Script Institute was puzzled by this and launched a genetic study to determine why certain individuals are resistant to the HIV virus. What Dr. Mosier discovered was the resistant people inherited a deletion mutation that gave them protection. Within the deletion mutation, the receptor CCR5, is excluded. This deleted section of the CCR5 receptor functions as a lock, therefore people born with the mutation will not get the HIV virus. Those individuals that are homozygous – have two copies of the same deletion gene, are immune to the virus and are protected. Individuals that are heterozygous – have two different genes – have some protection from HIV because their body have half the “locks.” Dr. Mosier further studied populations and discovered the deleted mutation was higher in certain parts of the world and among Caucasians. Explain the genetic connection between phenotype and genotype discovered by Mendel in the 19th century. Genetics helps to understand human diversity, not only in today’s world but in the past as well. When studying genetics it is important to understand the relationship between phenotype and genotype. A phenotype is defined as an observable physical characteristic whereas a genotype is the set of specific genes an organism carries (Allen, Anton, Stanford 60). In the video lesson, Anne Stone commented the phenotype can be impacted by the environment. For example, if there is not sufficient food or there is disease, this can impact an individual’s height which is a phenotype. Anthropologist Geneticist Joanna Mountain explained a phenotype can be “measurements and anything we can describe about a person from appearance to metabolism.” Utilizing the garden pea plant to conduct his experiment, Gregor Mendel was able to recognize traits were passed on from parents to offspring. He knew traits were inherited but did not know how this inheritance worked. Mendel’s Principles of Segregation which states in an organism, alleles occurs in pairs and when gametes sex cells get produced, alleles separate so each gamete contains one member of each pair. Further experiments by Mendel lead him to conclude in a unit of inheritance, meaning offspring received receive genes from each parent. Theses principles laid the foundation for future scientists to study inheritance. Vocabulary Phenotype – observable characteristics; expression of genetic instructions; something you can measure Genotype – genetic make-up of an individual; every person has a unique genotype made of genes inherited from parents Recessive – a masked trait or covered up Dominant – mask recessive characteristics P ...

chapter 3Traveon Brassfield

GA4GH Phenotype Ontologies Task team update

Berger ls 7e ch 3Jenna Ave-Lallemant

Presented at the IRDiRC 2017 conference in Paris, Feb 9th, 2017 (http://irdirc-conference.org/). This talk reviews use of the Human Phenotype Ontology for phenotype comparisons against other patients, known diseases, and animal models for diagnostic discovery. It also discusses the new Phenopackets Exchange mechanism for open phenotypic data sharing. www.monarchinitiative.org www.phenopackets.org www.human-phenotype-ontology.org

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Webinar: PMPRB NEW Guidelines and Impact on Rare Diseases

On this webinar, we’ll hear from experts on the issue and invite an open conversation with stakeholders. We need discussion, shared questions and answers and a review of case studies, which is why we are hosting this session. Panelist: Neil Palmer, Principal Consultant, WN Palmer & Co. and former PMPRB staff Michael Dietrich, Executive Director, Policy, Innovative Medicines Canada Laurene Redding, Global Head, Strategic Pricing (ex-China), BeiGene Durhane Wong-Rieger, President & CEO, CORD Moderator: Bill Dempster, CEO, 3Sixty Public Affairs

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Day 1: IAM RARE: Pamela Gavin, NORD

Day 2: Rare Disease & Drug Access Pathway

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Dar 2: Patient Engagement and Patient Empowerment Panel

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