Deep Phenotyping for Translational Research and Precision Medicine NIH Symposium: Linking Disease Model Phenotypes to Human Conditions

Home , Alexander disease, CADASIL, Hidrocystoma, Melorheostosis, Osteopoikilosis, Syringoma

Peter Robinson

Charit´e Universit¨atsmedizin Berlin

September 10–11, 2015

Peter Robinson (Charite)´ Deep Phenotyping 1/50 September 10–11, 2015 1 / 50 Thanks!

Matthew Brush Nathan Dunn Melissa Haendel Harry Hochheiser

Sebastian K¨ohler Suzanna Lewis Julie McMurry Christopher Mungall

Peter Robinson Damian Smedley Nicole Vasilevsky Kent Shefchek

Nicole Washington Zhou Yuan

1 http://monarchinitiative.org

Peter Robinson (Charite)´ Deep Phenotyping 2/50 September 10–11, 2015 2 / 50 Plan

1 Human Phenotype Ontology (HPO)

2 Ontology Algorithms: The Bare-Bones Basics

3 The Phenomizer

4 The HPO for translational research

5 PhenIX: Clinical Diagnostics in Medical Genetics

6 HPO: Semantic Uniﬁcation of Common and Rare Disease

7 Pressing Needs and Goals for Future Impact

Peter Robinson (Charite)´ Deep Phenotyping 3/50 September 10–11, 2015 3 / 50 Bioinformatics

Since the beginnings of the ﬁeld of Bioinformatics in the 1960s, a central theme has been the development of algorithms that calculate similarity scores between biological entities and use them to rank lists

Margaret Dayhoﬀ, originator of PAM matrices BLAST: Find and rank homologous sequences

Peter Robinson (Charite)´ Deep Phenotyping 4/50 September 10–11, 2015 4 / 50 Bioinformatics for medicine?

But how exactly do we calculate the similarity between diseases, symptoms, patients,...?

Peter Robinson (Charite)´ Deep Phenotyping 5/50 September 10–11, 2015 5 / 50 The Human Phenotype Ontology

11,030 terms 117,348 annotations for ∼ 7000 mainly monogenic diseases

http://www.human-phenotype-ontology.org

Widely used in rare disease community: UK 100,000 genomes; NIH Undiagnosed Diseases Network; DDD/DECIPHER, GA4GH, etc. Applications:

� linking human diseases to animal models � inferring novel drug interactions � prioritizing gene-disease targets � describing rare clinical disorders

Interoperable with model organism data and basic research standards A computable representation of human disease

Peter Robinson (Charite)´ Deep Phenotyping 6/50 September 10–11, 2015 6 / 50 Why HPO?

Substantially better coverage of phenotype concepts than any other terminology

Winnenburg and Bodenreider,

ISMB PhenoDay, 2014

Peter Robinson (Charite)´ Deep Phenotyping 7/50 September 10–11, 2015 7 / 50 Widely used in the community

Databases & Bioinformatics Resources Using HPO DECIPHER (Sanger Institute) DDD (Sanger Institute) ECARUCA FORGE (Genome Canada) GWAS Central IRDiRC ISCA NCBI Genetic Testing Registry NIH Undiagnosed diseases program UK 100,000 Genomes Program UMLS Phenotips (Brudno Group, U Toronto) ... Major credits go to OMIM and Orphanet

Peter Robinson (Charite)´ Deep Phenotyping 8/50 September 10–11, 2015 8 / 50 Plan

1 Human Phenotype Ontology (HPO)

2 Ontology Algorithms: The Bare-Bones Basics

3 The Phenomizer

4 The HPO for translational research

5 PhenIX: Clinical Diagnostics in Medical Genetics

6 HPO: Semantic Uniﬁcation of Common and Rare Disease

7 Pressing Needs and Goals for Future Impact

Peter Robinson (Charite)´ Deep Phenotyping 9/50 September 10–11, 2015 9 / 50 What’s The Problem?

Phenotypic descriptions that are very evocative for humans but meaningless for computers:

� myopathic electromyography � still walking 25 years after onset The following descriptions mean the same thing to you: “generalized amyotrophy”, “generalized muscle atrophy”, “muscular atrophy, generalized” (etc)1 Many publications have little2 information about the actual phenotypic features seen in patients with particular mutations Databases cannot talk to one another about phenotypes

Peter Robinson (Charite)´ Deep Phenotyping 10/50 September 10–11, 2015 10 / 50 A tale of two footballs

A football ... A football ...

American Football = Football = Football = European Football = Soccer

When you see “football”, your computer sees:

0100011001101111011011110111010001100010011000010110110001101100

Peter Robinson (Charite)´ Deep Phenotyping 11/50 September 10–11, 2015 11 / 50 A tale of two ﬁbrillations

ﬁbrillation ... ﬁbrillation ...

muscle fibrillation = fibrillation = fibrillation = ventricular fibrillation

When you see “ﬁbrillation”, your computer sees:

01100110011010010110001001110010011010010110110001101100011000010111010001101001

0110111101101110

Peter Robinson (Charite)´ Deep Phenotyping 12/50 September 10–11, 2015 12 / 50 What is an Ontology?

“An ontology is a speciﬁcation of a conceptualization.” Tom Gruber, 1993

disjoint inverse part of value Catalog Thesaurus instances ... restrictions

Glossary subclassing properties logical constraints

Peter Robinson (Charite)´ Deep Phenotyping 13/50 September 10–11, 2015 13 / 50 Information content

Information Content of Clinical Features

carnivore n = 1000 IC=0 IC

canine feline −log(p) n = 450 n = 550 IC=0.799 IC=0.598

dog wolf fox cat n = 350 n = 60 n = 40 n = 550 IC=1.050 IC=2.813 IC=3.219 IC=0.598 0 1 2 3 4 5 6 7

beagle terrier husky big cat wildcat 1.0 0.8 0.6 0.4 0.2 0.0 n = 40 n = 5 n = 15 n = 250 n = 80 IC=3.219 IC=5.298 IC=4.200 IC=1.386 ic=2.526 p=Frequency of clinical feature

cheetah tiger lion n = 100 n = 40 n = 90 IC=2.303 IC=3.219 IC=2.408 IC(t) = − log p(t),

Information content of common ancestor: Similarity between ontology terms Average similarity between terms can be used to compare two diseases

Peter Robinson (Charite)´ Deep Phenotyping 14/50 September 10–11, 2015 14 / 50 The Human Phenome: Network of Human Diseases and Disease Genes

Muscular

Disorder class

Skeletal/Bone/ Bone Connective tissue/ Cancer Development Cardiovascular Neuro Connective Tissue Dermatological Developmental Ear, Nose, Throat Endocrine Gastrointestinal Hematological Heme/ Immuno Immunological Endo/Renal Metabolic Metab Muscular Neurological Nutritional CV Ophtamalogical Psychiatric Renal Respiratory Ophth Skeletal Multiple Cancer

Derma

b) c)

Annotated terms ⎡ ⎤ Mapped ⎡to parents ⎤ Added 50% random terms

sim(d1, d2) = 0.5 · avg ⎣ max sim(s, t)⎦ + 0.5 · avg ⎣ max sim(s, t)⎦

Density t∈d2 t∈d1 s∈d s∈d 1 Rank of OMIM entry 2 0 10 20 30 40

Peter Robinson (Charite)´ Deep Phenotyping0 10 20 30 4015/50 50 60 September 10–11, 2015 15 / 50

0.0 0.2 0.4 0.6 0.8 1 2 3 4 5 6

Network score Number of terms used FOL: Klingon Opera

(∀x)(Klingon(x) ⇒ OperaLover(x)) Klingon(W orf)

If Klingon(W orf) is true, we can infer that Worf is an opera lover. OperaLover(W orf)

Analogous algorithms are the basis for human ⇔ model organism comparisons Peter Robinson (Charite)´ Deep Phenotyping 16/50 September 10–11, 2015 16 / 50 What is a phenotype ontology?

Precise language (and thinking), interoperability, improved database models to reliably capture and interpret phenotype information.

A medical phenotype ontology describes the individual manifestations of diseases: 1 signs 2 symptoms 3 laboratory ﬁndings 4 imaging studies 5 etc. Deep phenotype: The precise and comprehensive analysis of phenotypic abnormalities Individual components of disease rather than ”gestalt”

Robinson PN, Webber C (2014) Phenotype ontologies and cross-species analysis for translational research. PLoS Genet 10:e1004268.

PN Robinson (2012) Deep phenotyping for precision medicine. Hum Mutat 33: 777–780 (Special Issue of Human Mutation on Deep Phenotyping) Peter Robinson (Charite)´ Deep Phenotyping 17/50 September 10–11, 2015 17 / 50 Plan

1 Human Phenotype Ontology (HPO)

2 Ontology Algorithms: The Bare-Bones Basics

3 The Phenomizer

4 The HPO for translational research

5 PhenIX: Clinical Diagnostics in Medical Genetics

6 HPO: Semantic Uniﬁcation of Common and Rare Disease

7 Pressing Needs and Goals for Future Impact

Peter Robinson (Charite)´ Deep Phenotyping 18/50 September 10–11, 2015 18 / 50 Ontological diagnostics

Noonan Syndrome Opitz Syndrome a) b)

abn. of abn. of abn. of the abn. of the the eye the eye ocular region ocular region

abn. of the abn. of the abn. of globe eyelid abn. of globe eyelid localization or size localization or size

telecanthus

abn. of the abn. of the hypertelorism hypertelorism palpebral fissures palpebral fissures

Syndrome term downward slanting downward slanting palpebral fissures palpebral fissures Query term Overlap between query and disease

Noonan Syndrome c) 3.78 downward slanting palpebral fissures sim(Q,Noonan) = 3.78 + 3.05 2 = 3.42 Query (Q) 3.05 hypertelorism

downward slanting palpebral fissures

hypertelorism Opitz Syndrome

3.05 sim(Q,Opitz) =2.45 + 3.05 hypertelorism 2 = 2.75 2.45 (IC of abn. of the eyelid) telecanthus

⎡ ⎤

sim(Q → d) = avg ⎣ max sim(s, t)⎦ t∈d s∈Q Peter Robinson (Charite)´ Deep Phenotyping 19/50 September 10–11, 2015 19 / 50

Q: Query terms d: Disease terms Basic idea of ontological search: Do not need exact match! But semantically similar diseases score well

Peter Robinson (Charite)´ Deep Phenotyping 20/50 September 10–11, 2015 20 / 50 The Phenomizer

Sebastian K¨ohler et al. (2009) Clinical Diagnostics with Semantic Similarity Searches in Ontologies. Am J Hum Genet, 85:457–64.

http://compbio.charite.de/Phenomizer

Peter Robinson (Charite)´ Deep Phenotyping 21/50 September 10–11, 2015 21 / 50 Plan

1 Human Phenotype Ontology (HPO)

2 Ontology Algorithms: The Bare-Bones Basics

3 The Phenomizer

4 The HPO for translational research

5 PhenIX: Clinical Diagnostics in Medical Genetics

6 HPO: Semantic Uniﬁcation of Common and Rare Disease

7 Pressing Needs and Goals for Future Impact

Peter Robinson (Charite)´ Deep Phenotyping 22/50 September 10–11, 2015 22 / 50 HPO for translational research

Translation Translation Basic Science mechanisms Clinical strategy drugs guidelines Clinical Care genetics treatments Research products genomics biomarkers trials diagnostics animal models epidemiology ... drugs proteomics ... deep phenotyping treatments metabolomics ... quality of care cell biology ......

The HPO is a sophisticated computational resource that can be used to link data from anatomy, histology, pathology, gene function, model organisms, etc., in order to perform integrative computationally driven translational research

Peter Robinson (Charite)´ Deep Phenotyping 23/50 September 10–11, 2015 23 / 50 Traditional view of CNV pathogenesis

Phenotype results from dosage effects of one or more affected genes Diagnostic problem: Distinguish pathogenic from neutral CNVs Scientific and medical problem: Decide which genes are responsible for the phenotypic features?

For instance, haploinsuﬃciency of TBX1 contributes to the heart defects seen in 22q11.2 deletion

syndrome

Peter Robinson (Charite)´ Deep Phenotyping 24/50 September 10–11, 2015 24 / 50 Liebenberg syndrome

Recent observations challenge the gene-dosage model

Spielmann et al., (2012) Homeotic Arm-to-Leg Transformation Associated with Genomic Rearrangements

at the PITX1 Locus. Am J Hum Genet 91:629–635 Peter Robinson (Charite)´ Deep Phenotyping 25/50 September 10–11, 2015 25 / 50 Long Range Control of Gene Expression

Re-examination of the Liebenberg deletion indicated deletion of a topological domain barrier between a forelimb enhancer and a PITX1 ... leading to ectopic gene expression (“enhancer adoption”)

Spielmann M, Mundlos S (2013) Bioessays 35:533-43.

Peter Robinson (Charite)´ Deep Phenotyping 26/50 September 10–11, 2015 26 / 50 Gene-Dosage vs. Enhancer adoption

Therefore, we decided to address the question of how common haploinsuﬃciency (gene-dosage; a) and TDB disruption (b) are amongst CNVs associated with congenital disease

a b HP1 HP2 HP3 HP4 HP3 HP5 HP6

HP3 HP1 HP3

HP4 HP6

Peter Robinson (Charite)´ Deep Phenotyping 27/50 September 10–11, 2015 27 / 50 Tissue-Speciﬁc Enhancers and Phenotypic categories

A B C

Fetal Adrenal Gland Fetal Brain Fetal Heart Fetal Intestine Fetal Kidney Fetal Lung promoter Fetal Muscle exonic Fetal Stomach intronic intergenic Fetal Thymus IMR90 Mobilized CD34 White Blood iPS 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 ubiquitous DHS GFRA1 Fetal Adrenal Gland Fetal Lung Mobilized CD34 Fetal Brain Fetal Muscle White Blood Fetal Heart Fetal Stomach iPS 0.0 0.2 0.4 0.6 0.8 1.0 118020000 118040000 118060000 118080000 Fetal Intestine Fetal Thymus Fetal Kidney IMR90 genomic position, chr10

Our genome: > 400,000 enhancers We identified cell type specific enhancers as DNase I hypersensitive sites (DHS) Assigned tissue-specific enhancers to HPO terms

Tissue HPO term name Term ID Descendant Genes Cases HPO terms Adrenal Abnormality of the adrenal glands HP:0000834 65 75 2 (0.217%) Brain Abnormality of the forebrain HP:0100547 213 640 276 (29.9%) Heart Abnormality of the heart HP:0001627 273 491 236 (25.6%) Intestine Abnormality of the intestine HP:0002242 121 260 17 (1.84%) Kidney Abnormality of the kidney HP:0000077 184 383 77 (8.35%) Lung Abnormality of the lung HP:0002088 149 529 9 (0.976%) Muscle Abnormality of the musculature HP:0003011 667 1079 291 (31.6%) Stomach Abnormality of the stomach HP:0002577 24 116 10 (1.08%) Thymus Abnormality of the thymus HP:0000777 9 26 0 (0.0%) WBC Abnormality of leukocytes HP:0001881 195 256 4 (0.434%)

Peter Robinson (Charite)´ Deep Phenotyping 28/50 September 10–11, 2015 28 / 50 How common is enhancer adoption?

Permuted CNV phenotypes p=8e−04 Permuted gene phenotypes p=0.003 DECIPHER

● ● ● ● ●● ● ●●● p<1e−04 p=0.014 ●

● ● p=0.33 ● ● ● ● ●●● p=0.86 ●●●●●●●●●● ●●● ● ● ● ● ● ●●● ●

●

Percent of all deletions Percent ●●● ●●●●●●●●●●●●●

●●●●●● ● ● ●

● ● ● 0 2 4 6 8

No boundary TDBD TDBD only enhancer adoption

6.7% of 922 DECIPHER deletion cases potentially related to TDBD Even higher rate of TDBD predicted by analysis that includes ontologically mapped model organism phenotype data (mouse, ﬁsh): 11.9%

No diﬀerence if we simulate deletions so as not to disrupt TDBs!

Ibn-Salem J, K¨ohler S, (13 coauthors), Spielmann M, Robinson PN (2014) Deletions of

chromosomal regulatory boundaries are associated with congenital disease. Genome Biology 15:423.

Peter Robinson (Charite)´ Deep Phenotyping 29/50 September 10–11, 2015 29 / 50 Plan

1 Human Phenotype Ontology (HPO)

2 Ontology Algorithms: The Bare-Bones Basics

3 The Phenomizer

4 The HPO for translational research

5 PhenIX: Clinical Diagnostics in Medical Genetics

6 HPO: Semantic Uniﬁcation of Common and Rare Disease

7 Pressing Needs and Goals for Future Impact

Peter Robinson (Charite)´ Deep Phenotyping 30/50 September 10–11, 2015 30 / 50 Clinical Diagnostics in Medical Genetics

Getting a precise diagnosis for individuals with rare disease can be diﬃcult

Roughly 7,000 Mendelian diseases. Although these diseases are individually rare, up to 8% of the population is aﬀected by a speciﬁc genetic disorder Diagnosis useful for avoiding unnecessary investigations, exact prognosis, personalised clinical management, recurrence risk, “closure” and reduction of feelings of guilt Diagnostic rate

� Cytogenetics: ∼ 4% � Array-CGH: ∼ 10–15 % � Targeted Sanger sequencing: ∼ 5–95% (depending on indication) 3 � Total with traditional workup: Less than 50% overall

Peter Robinson (Charite)´ Deep Phenotyping 31/50 September 10–11, 2015 31 / 50 PhenIX

Basic algorithm: (i) Identify predicted pathogenic mutations in (clinical) exome (typically up to 100); (ii) rank the corresponding genes according to phenotypic relevance with the Phenomizer PhenIX Phenotypic Interpretation of eXomes Designed for clinical diagnostics with exome or DAG panel

Peter Robinson (Charite)´ Deep Phenotyping 32/50 September 10–11, 2015 32 / 50 Phenotypic Interpretation of eXomes: PhenIX

In 10,000 simulations with mutations from HGMD and corresponding HPO terms, the correct gene was ranked in ﬁrst place in over 86% of cases

Peter Robinson (Charite)´ Deep Phenotyping 33/50 September 10–11, 2015 33 / 50 PhenIX: Workﬂow

Clinical/Bioinformatic workﬂow in ca. 60 min Peter Robinson (Charite)´ Deep Phenotyping 34/50 September 10–11, 2015 34 / 50 PhenIX: Prospective Validation

ID Age, Sex Presentation Gene Rank Diagnosis

P1 3y (f) Intellectual disability MLL 2 Wiedemann Steiner syndrome + complex phenotype P2 5y (f) Intellectual disability SYNGAP1 4 Mental retardation, MRD5 + complex phenotype (41) P3 6y (f) Skeletal phenotype FGFR2 1 Pfeiﬀer syndrome P4 d. 5.5m (f) Complex phenotype SH3PXD2B 6 Frank-ter Haar syndrome without intellectual disability P5 6m (f) Intellectual disability SLC6A3 1 Parkinsonism-dystonia + neurological abnor malities P6 Fetus Skeletal phenotype ALPL 2 Infantile hypophosphatasia P7 7y (m) Eye phenotype NHS 2 Nance-Horan Syndrome P8 14y (m) Intellectual disability MLL 1 Wiedemann-Steiner syndrome + complex phenotype P9 6y (f) Intellectual disability DYRK1A 4 Mental retardation, MRD7 + complex phenotype P10 1.5–7y Intellectual disability MCOLN1 1 Type IV mucolipidosis + complex phenotype P11 3y (m) Intellectual disability RBM10 3 TARP syndrome + complex phenotype

Diagnosis rate was 100% in 52 retrospective “solved” cases and 28% in the 40 “unknown” cases

Peter Robinson (Charite)´ Deep Phenotyping 35/50 September 10–11, 2015 35 / 50 PhenIX

http://compbio.charite.de/phenix

Zemojtel T et al (2014) Eﬀective diagnosis of genetic disease by computational phenotype analysis

of the disease-associated genome. Science Translational Medicine 6:252ra123

Peter Robinson (Charite)´ Deep Phenotyping 36/50 September 10–11, 2015 36 / 50 The value of models

We remain largely ignorant of the genetic basis of human disease Large scale mouse and zebraﬁsh programs are providing phenotype data for many thousands of genes for which no human disease is currently known A number of talks in this Symposium!

K¨ohler S, Schoeneberg U, et al (2014) Clinical interpretation of CNVs with cross-species phenotype data.

J Med Genet 51:766-72. Peter Robinson (Charite)´ Deep Phenotyping 37/50 September 10–11, 2015 37 / 50 Plan

1 Human Phenotype Ontology (HPO)

2 Ontology Algorithms: The Bare-Bones Basics

3 The Phenomizer

4 The HPO for translational research

5 PhenIX: Clinical Diagnostics in Medical Genetics

6 HPO: Semantic Uniﬁcation of Common and Rare Disease

7 Pressing Needs and Goals for Future Impact

Peter Robinson (Charite)´ Deep Phenotyping 38/50 September 10–11, 2015 38 / 50 HPO and Common Disease

Duodenitis Anemia, Sarcoidosis, Gastritis, Hepatitis B Pernicious Pulmonary Spondylitis, Atrophic Aortic Ankylosing Aneurysm, Hepatitis C Mixed Gastritis Abdominal Pulmonary Connective Stomach Aortic Edema Paraproteinemias Tissue Arthritis Arthritis, Brain Stem Ulcer Aneurysm, Aortitis CryoglobulinemiaDisease Lateral Bile Reflux Pyloric Aortic Respiratory Rheumatoid OchronosisAlkaptonuria Infarctions Thoracic Sarcoidosis Medullary Gastric Stenosis, Aneurysm Pulmonary Distress Immune Syndrome Outlet Hypertrophic Sclerosing Syndrome, Sjogren's Complex Vasculitis Obstruction Rheumatic Hemangioma Adult Syndrome Polyarteritis Sinus Peptic Ulcer Aortic Diseases Fever Nodosa Thrombosis, Moyamoya Scleroderma, Intestinal Frontal Rupture Endocarditis, Pyloric Glomerulonephritis Behcet Intracranial Disease Intracranial Localized Perforation Sinusitis Duodenogastric Subacute Pulmonary Glomerulonephritis, Anti-Glomerular Lupus Stenosis Pulmonary Endocarditis Hypertension, Syndrome Aneurysm Reflux Bacterial Embolism Membranous Basement Erythematosus, Vertebrobasilar Veno-Occlusive Mitral Valve Pulmonary Intracranial Intracranial Basal Scleroderma, DiGeorge NephroticNephritis Membrane Systemic Insufficiency Raynaud Peptic Ulcer Disease Stenosis Thrombosis Carotid Arterial Ganglia Systemic Sphenoid Syndrome Aortic Valve Syndrome Disease Disease Perforation Pericarditis, Artery Diseases Cerebrovascular DiverticulitisSinusitis Ethmoid Duodenal Mediastinitis Prolapse Thrombophlebitis Intracranial Aortic ValveScimitar Constrictive Glomerulonephritis, Thrombosis DiseaseInfarction, Scleroderma, Sinusitis Ulcer Esophagitis Embolism Infarction, Hernia, InsufficiencySyndrome Lutembacher Persistent Membranoproliferative Cerebral Anterior Diffuse Brain Middle Esophagitis, Hiatal Heart Septal Syndrome Fetal Infarction Cerebral Maxillary Dextrocardia Ischemia Cerebral Peptic Defects, Circulation Artery Scleroderma,Appendicitis Sinusitis Aortic Foramen Artery Cerebral Ventricular Antiphospholipid Carotid Limited Stenosis, EndomyocardialSyndrome Ovale, Nephrosis, Arterial Coronary Pulmonary Tricuspid Syndrome Stenosis Supravalvular Aortic Valve Fibrosis Patent Lipoid Stroke Diseases Aneurysm Aortic Subvalvular Valve Stenosis Ductus Heart Septal Glomerulonephritis, Protein C Barrett Stenosis, Stenosis Prolapse Esophagus Subvalvular Arteriosus, Defects, IGA Deficiency Gastroesophageal Mitral Valve Patent Protein S Discrete MyocarditisAtrial Reflux Insufficiency Nephrosis Deficiency Subaortic Factor V Heart Thrombophilia Antithrombin Intracranial Double Stenosis Deficiency Diaphragmatic Hypoplastic Tetralogy ofFailure, III Arteriosclerosis Anemia, Hepatopulmonary Esophageal Outlet Right Arrhythmogenic Left Heart Inferior Wall Diastolic Deficiency Myelophthisic Eventration Ventricle Fallot Right Brain Infarction, Syndrome Neoplasms Syndrome Myocardial Arteriolosclerosis Red-Cell Esophageal Ventricular Infarction Posterior CADASIL Liver TricuspidPulmonary Infarction Glomerulosclerosis, Aplasia, Achalasia Cardiomyopathy,Dysplasia Hemophilia Cerebral Fanconi Cirrhosis Valve Valve Ebstein Focal Ischemic Pure Erythema Hypertension, Restrictive B Artery Anemia StenosisStenosis Anomaly Segmental Attack, Anemia, Anemia, Infectiosum Portal Factor X Factor VII Hemoglobinuria Diverticulosis, Heart Heart AfibrinogenemiaTransient Neonatal Hemoglobin Aplastic Alagille Cardiomyopathy, Deficiency Deficiency Cholestasis, Esophageal Aneurysm Failure, Erythroblastosis, C Disease Liver Syndrome Hypertrophic BrugadaCardiomyopathy, Intrahepatic Composite Systolic Fetal Anemia, Kernicterus Cirrhosis, Endocardial Syndrome Alcoholic Hepatitis, Lymphoma Superior Duodenal Factor XIII Anemia, Hemolytic, Biliary Fibroelastosis Anterior Myofascial Anemia, Diamond-Blackfan Cholestasis Autoimmune Mesenteric Obstruction Hernia, Deficiency Autoimmune Cholangitis Wall Pain Dyserythropoietic, Crigler-Najjar Artery Diaphragmatic Myocardial Syndromes Congenital Syndrome Biliary Cholangitis, Syndrome Hirschsprung Asphyxia Hyperbilirubinemia Drug-Induced Colonic Infarction Coronary Cardiomyopathy, Atresia Sclerosing Pneumonia, Intestinal Disease Neonatorum Rh Anemia, Liver Injury, Pseudo-Obstruction Thrombosis Hypertrophic, Meconium Anemia, Aspiration Pseudo-Obstruction IsoimmunizationHemolytic Jaundice, Chronic CoronaryFamilial Aspiration Anemia, Sideroblastic Gilbert Jaundice, Esophageal Intestinal Cardiomyopathy, Syndrome Hyaline Disease Obstructive Megacolon VasospasmNephrosclerosis Hemolytic, Chronic Atresia Atresia Dilated Membrane Idiopathic Cholestasis, Ileus Anemia, Congenital Caroli Disease von Glucosephosphate Cerebral Porphyria, Extrahepatic Intestinal Wolff-Parkinson-White Hemolytic, Disease Willebrand Dehydrogenase Amyloid Hepatoerythropoietic Volvulus Intussusception Syndrome Diseases Congenital Spherocytosis, Deficiency Angiopathy, Nephritis, Favism Cardiac Pneumonia Atrioventricular Nonspherocytic Hereditary Familial Klatskin's Choledocholithiasis BlockInterstitial Tumor Tamponade Enterocolitis, Chagas Biliary Tract Glycogen Hemarthrosis Purpura, Pseudomyxoma Necrotizing Disease Sick Sinus Neoplasms Storage Glycogen Thrombocytopenic, Peritonei Syndrome Fibromyalgia Bile Duct Cholecystolithiasis Pericardial Myocardial Disease Leukomalacia,Storage Idiopathic Neoplasms Effusion Infarction Type IIb Disease Cholelithiasis Coronary Osteoarthropathy, Periventricular Ileal Cholangiocarcinoma Type IV Stenosis Secondary Bursitis Elliptocytosis, Neoplasms Common Cholecystitis Pericarditis Tuberculosis, Appendiceal Angina,Hypertrophic Hereditary Bile Duct OsteoarticularPeroneal Gastrointestinal Neoplasms Adenoma, Croup Unstable Neuropathies Neoplasms Bile Duct Postcholecystectomy Renal Artery DisseminatedMyocardial Stromal Peutz-Jeghers Epiglottitis Encephalomalacia Syndrome Bronchopneumonia Obstruction IntravascularIschemia Chondrocalcinosis Tumors Syndrome Pasteurella Femoral Radial Gallbladder Heart Infections Coagulation Tenosynovitis Neoplasms Laryngitis Endometritis Neuropathy Carpal Neuropathy Cecal Neoplasms Neoplasms Biliary Hyperostosis, Tunnel Duodenal Placenta Dyskinesia Rhinoscleroma Tracheitis Cortical, HELLP Shoulder Syndrome Neoplasms Previa Syndrome Impingement Jejunal Tracheal Congenital Intestinal Placenta Placental Coronary Syndrome Neoplasms Neoplasms Stenosis Melorheostosis Eclampsia MuscularPeriarthritis Brachial Accreta Insufficiency Restenosis Plexus Blindness, Kidney Cerebral Dystrophy,Tendinopathy Migraine Camurati-Engelmann Neuropathies Cortical Osteopoikilosis Papillary Palsy Emery-Dreifuss Thrombasthenia with Aura Syndrome Patellofemoral Ulnar Necrosis Chondromalacia De Brachial Polyhydramnios Pain Reflex Neuropathies Patellae Quervain Bernard-Soulier Plexus Kidney Syndrome Sympathetic Heart Failure Disease Syndrome Neuritis Tubular Dystrophy Platelet Calciphylaxis Osteopetrosis Osteosclerosis Necrosis, Arthropathy, Storage Poliomyelitis Osteochondrosis Muscular Creutzfeldt-Jakob Scrapie Acute Neurogenic Pool PostpoliomyelitisSpinal Hypertension,Hypertension, Dystrophy, Syndrome Deficiency SyndromeMuscular Alzheimer RenovascularRenal Duchenne Myopathies, Periapical Calcinosis Oligohydramnios Pleurodynia, Atrophies Disease Fetofetal Nemaline Granuloma Periapical Noma Osteitis Epidemic of Transfusion Glycosuria, Arthritis, Periodontitis Deformans Renal Coronary Muscular Childhood Burning Gingivitis, Uterine Infectious Pre-Eclampsia Myopathy, Dermatomyositis Legg-Calve-Perthes Myotonic Artery Dystrophy, Glycogen Kuru Mouth Necrotizing Pseudopseudohypoparathyroidism Cervical Hypertension, Central Periodontitis Disease Dystrophy Disease MyositisFacioscapulohumeral Storage Toxascariasis Syndrome Ulcerative MucopolysaccharidosisIncompetence Mucopolysaccharidosis Malignant Core Periapical III Disease Insomnia, Pseudohypoparathyroidism VI Myasthenia Muscular Muscular Abscess Cutis Laxa Thromboangiitis TypeCharcot-Marie-Tooth VIII Fatal Tongue, Dentinogenesis MucopolysaccharidosisCystinosis Gravis, Dystrophies, Atrophy, Disease Neurodegenerative Stomatitis Leukoedema, HyperphosphatemiaOsteogenesisMucopolysaccharidosis ArteriosclerosisObliterans Familial Hairy Root Caries DentinImperfecta Campomelic II Uremia Osteochondritis Neonatal Limb-Girdle Myasthenic Spinal Amyotrophic Diseases Oral Hypercalcemia Imperfecta VIIAnkylosis Mucopolysaccharidosis Glycogen Myositis, Dysplasia Dysplasia Obliterans Syndromes, Polyneuropathies Glossitis, Renal Mucopolysaccharidosis IV Renal Storage Lateral Clubfoot Congenital Inclusion Pulpitis Amelogenesis Pericoronitis Osteodystrophy I Insufficiency Disease Bulbo-Spinal Sclerosis Candidiasis,Benign Hyperparathyroidism, Smith-Lemli-Opitz Myotonia BodyStomach Stomatitis, Imperfecta Osteomalacia Type II Atrophy, OralMigratory Secondary Syndrome Congenita Neoplasms Pick Glossitis Denture Hypercementosis Hyperparathyroidism Aspartylglucosaminuria Carcinoma, Thanatophoric Hyperlipidemia, Sigmoid X-Linked Hereditary Polyradiculoneuropathy, Disease of Tooth Acidosis, Diabetes, Adenoid Dental Fluorosis, Dysplasia Kidney Fanconi Atherosclerosis Familial Neoplasms Sensory and Chronic the Brain Aggressive Hypoparathyroidism Renal Gestational Arteriosclerosis Caries Dental Ankylosis Dental Nephrocalcinosis Failure, Combined Carcinoma, Motor Inflammatory Tauopathies Cystic Periodontitis Osteitis Exostoses, Syndrome Tubular Paralyses, Polyradiculoneuropathy Enamel Chronic Signet Ring Neuropathy Demyelinating Mandibular Fibrosa MultipleOsteochondrodysplasias Familial Paralysis, Zellweger Cheilitis Hypoplasia Hyperlipoproteinemia Cell Pseudobulbar Gerstmann-Straussler-Scheinker Neoplasms Jaw Cystica Hereditary Periodic MetabolicHyperkalemic Syndromebeta-Mannosidosis Gitelman Type II Bulbar Palsy Disease Tracheal Goiter, Neoplasms Hyperparathyroidism, Hyperoxaluria SyndromePeriodic X Lipodystrophy, Guillain-Barre Achondroplasia BartterSyndrome Dandy-Walker FamilialHyperlipoproteinemia Tangier Palsy, Neoplasms Substernal Primary Cleidocranial Hypertension Discitis Diabetes Glycogen Glycogen Syndrome Syndrome Syndrome Diabetes Partial Type IVHyperlipoproteinemia Disease Progressive Fibroma, Rickets Dysplasia Mellitus, Storage Storage Striatonigral Nephrolithiasis Mellitus Diabetes Type III Adrenoleukodystrophy Lewy Body Leukoplakia, Adenocarcinoma, Ossifying Osteoporosis Type 2 Disease Disease Degeneration Mellitus, Xanthomatosis Pelizaeus-Merzbacher Disease Focal Oral Bronchiolo-AlveolarSolitary Glucose Lipodystrophy Type V Type VII Muscular Langer-Giedion PseudohypoaldosteronismHypokalemic Lipoatrophic Disease Epithelial Pulmonary Pierre Robinalpha-Mannosidosis Intolerance Dystrophy, MyomaParathyroid Syndrome Periodic Anterior Hyperplasia Nodule Refsum Syndrome Hyperostosis, Hyperlipoproteinemia Neoplasms Gynatresia Paralysis HyperlipoproteinemiaCompartment Oculopharyngeal Canavan Tongue Disease, Scheuermann Diffuse Lecithin Type V Cytochrome-c DiffuseLeukodystrophy, Parkinson Lip Acrocephalosyndactylia SyndromeType I Disease Neoplasms Papillon-Lefevre Anodontia Infantile Disease Idiopathic Acyltransferase Oxidase Leukodystrophy, CerebralGloboid Cell Disease, Neoplasms Syndactyly Hyperinsulinism Disease Skeletal Deficiency Deficiency Metachromatic Sclerosis of Postencephalitic EpidermolysisEpidermolysis Lingual Maxillary Hyperaldosteronism Epidural DiabeticDiabetic Schistosomiasis Schilder Sea-Blue Bullosa Bullosa, Goiter Neoplasms Abscess AngiopathiesNeuropathies MELAS Miller Fisher Goiter, haematobia Spinal Rectal Histiocyte Dystrophica Junctional Syndrome Syndrome Nodular Dysraphism Diabetes ProlapseAnus Syndrome Ureterocele Huntington Alexander Shy-Drager Adenocarcinoma, Ureterolithiasis Spondylosis Mellitus, Neoplasms Spastic Thyroiditis, ParaneoplasticDisease Supranuclear Disease Syndrome Thyroiditis, FollicularRothmund-Thomson Incontinentia Diabetes Type 1 Mitochondrial Paraplegia, Autoimmune Prediabetic Migraine Polyneuropathy Palsy, Subacute Syndrome Pigmenti LiddleInsipidus, Spondylolysis Cystinuria Myopathies Hereditary Gangliosidoses,Niemann-Pick Keratosis, Epidermolysis State without Progressive Tinea SyndromeNephrogenic GM2 Diseases Carcinoma, Actinic Bullosa Thyroid Aura Parkinson Versicolor Pinta Nesidioblastosis Kearns-Sayre Verrucous Struma Hashimoto Crisis Disease Keratoderma, Lipoma Blepharophimosis Spondylolisthesis Ovarii Thyrotoxicosis Hypotrichosis Mineralocorticoid Arcus Senilis Syndrome Keratoderma, Disease Palmoplantar Pyelitis Botulism Parkinson Hypohidrosis Lipomatosis Excess Hemorrhoids Dystonia Friedreich Palmoplantar, Disease, Carcinoma, Syndrome,Tuberculosis, Musculorum Ataxia Machado-Joseph Diffuse Graves Congenital Spinal Adenocarcinoma, Paraparesis, Secondary Laryngeal Epidermolysis Papillary, ApparentRenal Rectal Deformans DiseaseOlivopontocerebellar Hypopharyngeal Disease Hypothyroidism Pyelonephritis Hernia Stenosis ProctitisMucinous Tropical Neoplasms Bullosa Follicular Neoplasms Atrophies Neoplasms Erythrokeratodermia Adrenal Urethral Sciatic Spastic Simplex HyperthyroidismBronchial UrinaryUrinary Neurogenic Ophthalmoplegia, Variabilis Adenoma, Gland Neuropathy Tay-Sachs Fox-Fordyce Neoplasms Obstruction Bowel Syringomyelia Chronic Spinocerebellar Carcinoma, Insulinoma Bladder,Bladder Quadriplegia Leigh Disease Acanthoma Oxyphilic Neoplasms Progressive Disease Pemphigus, Papillary Cystitis NeurogenicCalculi MERRF Disease Ataxias Hyperkeratosis, Keratosis Thyroid Urinary External Benign Vesico-Ureteral Polyradiculopathy Syndrome Epidermolytic Goiter,Neoplasms Gastrinoma Ureteral Bladder Myelitis Pyruvate Sandhoff Familial Goiter Paraganglioma Hidrocystoma Reflux Ophthalmoplegia Cystadenocarcinoma Trombiculiasis Endemic Tuberculosis, Neoplasms Choanal Neoplasms Carboxylase Disease Adenocarcinoma, Multiple Propionic Pityriasis Pancreatic Urogenital Atresia Mobius Deficiency Ornithine Papillary Hyperthyroxinemia Acidemia Neoplasms Syndrome Carboxylase Carbamoyltransferase Cystadenoma Rubra Adenoma, Dermoid Disease Lichen Meige Deficiency Deficiency Pilaris Islet Cell UrinaryCyst Maxillary Brown-Sequard Carbamoyl-Phosphate Argininosuccinic PorokeratosisNitidus Menkes Blepharospasm Syndrome Trigeminal Disease Cystadenocarcinoma, Hypothyroidism Bladder Sinus Syndrome Hyperargininemia Aciduria Papilloma Kinky Hair Neuralgia Pyruvate Synthase I Mucinous Mediastinal Hematometra Neck Carcinoma,Neoplasms Uterine Xanthogranuloma, Trochlear Cystitis, Syndrome Epidural Arachnoiditis Horner Dehydrogenase Deficiency Psoriasis Neoplasms Obstruction Transitional Cervical Juvenile Nerve Maple Syrup Citrullinemia Euthyroid Darier Urethral Interstitial Neoplasms Syndrome Complex Disease Adrenal Cell NeoplasmsGenital Diseases Urine Keratoacanthoma Sick Disease Neoplasms Duane Deficiency Cortex Neoplasms, Disease Syndromes Neuroschistosomiasis Retraction Disease Neoplasms Tinea Prostatic Female Syndrome Myoclonic Adrenocortical Favosa Neoplasms Diabetic Retinopathy Hyperglycinemia, Cerebellar CarcinomaWarts Phenylketonurias Phenylketonuria, Hand Adenoma, Scalp Nonketotic Dyssynergia Maternal Eczema, Carcinoma, Dermatoses Keratosis, KallmannBasophil Cushing Dermatoses Balanitis Uterine Homocystinuria Myoclonic Dyshidrotic Squamous Seborrheic Syndrome Syndrome Spinal Cord Hartnup Cell Xerotica Neoplasms Melanoma, Epilepsies, Molluscum Neoplasms Amblyopia Optic Disease Retroperitoneal Obliterans Amelanotic Neuronal Progressive Contagiosum Pilomatrixoma Atrophy Refsum Neoplasms Phimosis Ceroid-Lipofuscinoses Disease Esthesioneuroblastoma, Angiolipoma Piedra Retinopathy Olfactory Nystagmus, Teratoma of Optic Disk Adrenocortical Diabetes Hydrocephalus Paranasal Hordeolum Congenital Folliculitis Prematurity Retinitis Addison Hyperfunction Insipidus Lichen Sinus Drusen Prostatic Pigmentosa Carcinoma Disease Planus Neoplasms Vitreous Hyperandrogenism Hyperplasia Retinoschisis Macular Epilepsies, Carcinoma, Meningitis Detachment Choroideremia Adrenal Lymphangioma Aniridia Degeneration Myoclonic Renal Cell Ganglioneuroma Pelvic HyperpituitarismACTH-SecretingPituitary Mucinosis, Retinal Retinal Salpingitis Rest Tumor Dry Eye Inflammatory PituitaryACTH Follicular Perforations Optic Dystrophies Screw WormEndometriosis Adenoma Syndromes Leber Disease Hypersecretion Balanitis Carcinoma, Orbital Astigmatism Vitreoretinopathy, Neuritis Adenocarcinoma Infection LeiomyomaLeiomyomatosis Panophthalmitis Congenital Optic Lafora Hypopituitarism Bronchogenic Neoplasms Facial ProliferativeMyopia,Macular Retinal Kidney Ovarian Amaurosis Atrophy, Disease Carcinoma,Paralysis Eye Hydrophthalmos RetinalDegenerative Edema Degeneration Neoplasms Polyendocrinopathies, Hyperstimulation AcromegalyOvarianAndrogen-Insensitivity Nelson Hereditary, Malaria Basal Cell Neoplasms Detachment Papilledema Retinal Epilepsy, Colonic Autoimmune SyndromeHerpes NeoplasmsSyndrome PenileSyndrome Sweat Gland Optic Nerve Choroiditis Leber Neuroblastoma Dermatitis, Endophthalmitis Ocular Pars Planitis Drusen Partial, Unverricht-Lundborg Pituitary NeoplasmsParaphimosis Neoplasms UveomeningoencephaliticDiseases Spasms, Neoplasms Wilms LeydigGenitalis Cell Seborrheic Conjunctival HypertensionGlaucoma, AngioidGyrate Apoplexy Xerophthalmia Syndrome Sensory Syndrome GanglioneuroblastomaBreast Tumor Pituitary Syringoma Neoplasms Neovascular StreaksAtrophy Infantile Tumor Hypogonadism Freemartinism Hemangioma Corneal Glaucoma Epilepsy, Neoplasms Adenoma, Neoplasms Keratoconjunctivitis Candidiasis, Rhinosporidiosis Chalazion Dacryocystitis NeovascularizationRetinal Uveitis, Reflex Chromophobe Sicca Eyelid Intermediate Chronic Trypanosomiasis, Eunuchism Prolactinoma Adenocarcinoma, Conjunctivitis, NeoplasmsOphthalmia, Exfoliation Retinitis Thrombocytosis Carcinoma, Lung Hypothalamic Neurilemmoma Neoplasms Fuchs' Retinal Vein Mucocutaneous African Sebaceous Bacterial Sympathetic SyndromeGlaucoma, Chorioretinitis Myoclonic Non-Small-CellNeoplasms Empty SellaNeoplasms Sebaceous Melanoma Endothelial Retinal Occlusion Lung Growth Lymphangioma, Angle-ClosureUveitis, Epilepsy, Epilepsy, Syndrome Gland Blepharitis Dystrophy Iritis Necrosis Retinal Polycythemia Hormone-Secreting Pemphigoid, Retinoblastoma Posterior Tonic-Clonic Juvenile Sertoli-Leydig Diabetes Cystic Neoplasms Keratoconjunctivitis Syndrome, Vasculitis Vera Pituitary Benign Keratitis Panuveitis Thrombocythemia, Cell Tumor Hyperprolactinemia Insipidus, Uveal Choroid Acute Epilepsy, Lymphoma Primary Mumps Prostatitis Adenoma Rosacea Nerve Mucous ConjunctivitisOptic Nerve Uveitis Optic Epilepsy, Essential Trichomonas Neurogenic Neoplasms Neoplasms Retinal Epilepsy, Benign Ovarian Adenoma, Craniopharyngioma Sheath Peripheral Membrane Neoplasms Corneal Neuropathy, Epilepsy, Rolandic Vaginosis, Infections Uveitis,Glaucoma, Artery Partial, Neonatal Insufficiency Acidophil NeoplasmsNervous Bell Palsy Edema Iris Ischemic Frontal Primary Leukemia, Leukemia Bacterial Sertoli Meningioma AnteriorOpen-Angle Occlusion LobeMotor Hodgkin Cell-Only System Trachoma Neoplasms Epilepsy,Epilepsy, Epilepsy, Myelofibrosis Myeloid, Gonorrhea Vulvar Cranial Optic Nerve Low Disease Menopause, Mesonephroma NeoplasmsMeningeal EncephalitisComplexGeneralized Absence Acute Syndrome Nerve Glioma Orbital Iridocorneal Tension Premature Sex DysgerminomaNeoplasms Partial Leukemia, Urethritis Granulosa Condylomata Neoplasms Neoplasms Pseudotumor Endothelial Glaucoma Landau-Kleffner Lymphoma, Cord-Gonadal Hemangioma, Megakaryoblastic, Leukemia, Cell Tumor Testicular Vaginal GonadoblastomaAcuminata Syndrome Epilepsy, Syndrome Non-Hodgkin Stromal Cavernous Acute Myeloid Neoplasms Neoplasms Herpes Temporal Leukemia, VaricoceleTumors Genital Scleritis Oophoritis Neoplasms, Pseudotumor Zoster Lobe Status Hairy Cell Leukemoid Epididymitis Germinoma Ependymoma Neuroma, Leukemia, Cerebri Conjunctivitis, Oticus Neoplasms, Epilepticus Gerstmann Reaction Male Acoustic Ganglioglioma Leukemia, Lymphoid Orchitis Sertoli CellSeminoma Neurofibrosarcoma Pinealoma Allergic Neuroepithelial Syndrome Carcinoma,Tumor Brain Edema Cerebral Cholesteatoma, Myelogenous, Intracranial LabyrinthitisMeniere Leukemia, SpermatoceleEmbryonal Ventricle Middle Ear Chronic, Hypertension Disease Prolymphocytic BCR-ABL Bone Spermatic Inappropriate Neoplasms Astrocytoma Intracranial Cerebellar Cholesteatoma Positive Leukemia, Neoplasms Cord ADH Syndrome Hypotension Neoplasms Otosclerosis Lymphocytic, Torsion Brain Oligodendroglioma Endolymphatic Leukemia-Lymphoma, Chronic, Neoplasms Conjunctivitis, Leukemia, Mesenchymoma Glioma, Hydrops B-Cell Medulloblastoma Inclusion Adult T-Cell Subependymal T-Cell Endodermal Central Otitis Hearing Gangliosidosis, Liposarcoma Dermatitis, Hemosiderosis Siderosis Necatoriasis Sinus Hemangiopericytoma Nervous Media, Loss, GM1 Fucosidosis Atopic Hemangioblastoma Neurocytoma Ancylostomiasis Tumor Neoplasms, System Suppurative Central Sarcoma, Uterine Neurodermatitis Endometrial Fibrosarcoma Nerve Neoplasms Choroid Synovial Inversion Vestibular Anterior Stromal Tissue Plexus Fatty Liver, Sarcoma Neuronitis Spinal Cord Spinal Mikulicz' Tumors Neoplasms Otitis Media Alcoholic Space Motion Paronychia Tinea Pedis Ischemia Artery Disease Papilloma, Motion Cholesterol Dermatitis, Sickness Syndrome Dermatitis, Glioma Choroid Sickness Ester Occupational Neuroectodermal Adenosarcoma Allergic Plexus Storage Smooth Tumors, Respiratory Giant Cell Polymyalgia Sialadenitis Contact Disease Muscle Primitive Glioblastoma Syncytial Arteritis Rheumatica Pleural Thymoma Virus Liver Tumor Dermatitis, Trichostrongylosis Neoplasms Infections Neoplasms Irritant Dermatitis, Mycosis Contact Chorea Sneddon Sezary Osteosarcoma Pulmonary Fungoides Syndrome Leiomyosarcoma Thymus Gravidarum Syndrome Carcinoma, Fibrosis Bronchiolitis Egg Trichostrongyloidiasis Mesothelioma Neoplasms Hepatocellular Hypersensitivity Femoral Gastric Neoplasms Urticaria Sarcoma, Anemia, Antral Mastocytosis, Angioedemas, Mastocytosis Pigmentosa Ewing Hypobetalipoproteinemias Iron-Deficiency Vascular Systemic Nut Hereditary Ectasia Hypersensitivity Angioedema Anemia, Abetalipoproteinemia Hypochromic Angiodysplasia Chordoma Rhabdomyosarcoma Chondroblastoma Leprosy, Sarcoma, Leprosy, Exocrine Borderline Pancreatitis Colitis, Chondrosarcoma Adamantinoma Small Cell Lepromatous Pancreatic Insufficiency Lymphocytic Ileitis Leprosy, Chondroma Milk Pancreatitis, Colitis, Peanut Leprosy Tuberculoid Hypersensitivity Alveolitis, Alcoholic Microscopic Colitis, Hypersensitivity Colitis, Giant Cell Extrinsic Steatorrhea Ulcerative Collagenous Tumor of Allergic Bone IgG Deficiency Wheat Glycogen Crohn IgA Hypersensitivity Storage Disease Osteosarcoma, Deficiency Rhinitis, Disease Juxtacortical Common Vasomotor Type III Osteomyelitis Variable Bronchiectasis Rhinitis Sarcoma, Immunodeficiency Nasopharyngitis Fructose-1,6-Diphosphatase Clear Cell Deficiency Severe Agammaglobulinemia Osteitis Sarcoma, Combined Glycogen Alveolar Immunodeficiency Asthma Pulmonary Rhabdomyosarcoma, Cryptogenic Common Storage Soft Part Dysgammaglobulinemia Eosinophilia Embryonal Organizing Cold Disease Tietze's Bird Legend: disease by infectious agent Pneumonia Type I Syndrome Bronchitis Fancier's Hyper-IgM Lung Rhabdomyosarcoma, Farmer's urinary system disease Immunodeficiency disease of metabolism Alveolar Lung Acquired Syndrome Porphyria, Porphyrias, Immunodeficiency integumentary system disease Acute endocrine system disease Bronchiolitis Hepatic Syndrome Pemphigus Intermittent Phagocyte Anthracosis Obliterans disease of cellular proliferation respiratory system disease Bactericidal HIV Protein-Losing Dysfunction Postphlebitic Enteropathies Sprue, Pneumoconiosis Pemphigoid, Syndrome Varicose Infections musculoskeletal system disease nervous system disease Tropical Bullous Veins Asbestosis Epidermolysis Idiopathic Blind Loop Giardiasis Bullosa cardiovascular system disease gastrointestinal system disease Pulmonary Syndrome Acquisita Cystadenocarcinoma, Fibrosis Papillary Cystadenocarcinoma, immune system disease reproductive system disease Lactose Serous Intolerance Celiac Silicosis Disease

Groza T, et al. (2015) The Human Phenotype Ontology: Semantic uniﬁcation of common and rare disease (Am J Hum Genet, 97:111-24) 132,006 annotations to terms of the HPO for 3,145 common human diseases

Peter Robinson (Charite)´ Deep Phenotyping 39/50 September 10–11, 2015 39 / 50 Phenotypic overlap: Rare and Common

Mutations in the coding sequence of PSEN1 are associated with early-onset familial Alzheimer’s disease

Mutations in the promoter of PSEN1 are associated with an increased risk of late-onset Alzheimer’s disease Question: How common is this across the spectrum of all Mendelian disease?

Peter Robinson (Charite)´ Deep Phenotyping 40/50 September 10–11, 2015 40 / 50 Phenotypic overlap: Rare and Common

We compared phenotypes of rare diseases and common dis eases with non-coding GWAS hits in the region of the gene

Hundreds of candidates Overlap was signiﬁcantly higher than randomized networks (p = 1.6 × 10−7)

Peter Robinson (Charite)´ Deep Phenotyping 41/50 September 10–11, 2015 41 / 50 Phenotypic Networks of Common Disease

GWAS studies have identiﬁed over 6,000 strong associations (p < 10−8) to common complex diseases

Some GWAS hits have been associated with multiple diseases For instance, rs1344706 is associated with both schizophrenia and bipolar disease Of 16,152 GWAS hits analysed (GWAS Central), 863 were associated with 2 or more diseases For these 863 GWAS hits, we compared the HPO annotations of the diseases and looked for overlap

Peter Robinson (Charite)´ Deep Phenotyping 42/50 September 10–11, 2015 42 / 50 Phenotypic Networks of Common Disease

We identiﬁed a substantial amount of phenotypic overlap including many dense subnetworks Highly statistically signiﬁcant (p = 2.3 × 10−57)

Peter Robinson (Charite)´ Deep Phenotyping 43/50 September 10–11, 2015 43 / 50 Common Disease Annotations: Browsing

The common disease annotations are available for browsing and download at http://pubmed-browser.human-phenotype-ontology.org

Peter Robinson (Charite)´ Deep Phenotyping 44/50 September 10–11, 2015 44 / 50 Plan

1 Human Phenotype Ontology (HPO)

2 Ontology Algorithms: The Bare-Bones Basics

3 The Phenomizer

4 The HPO for translational research

5 PhenIX: Clinical Diagnostics in Medical Genetics

6 HPO: Semantic Uniﬁcation of Common and Rare Disease

7 Pressing Needs and Goals for Future Impact

Peter Robinson (Charite)´ Deep Phenotyping 45/50 September 10–11, 2015 45 / 50 Cross species phenotype analysis

The full value of projects such as UDP/UDN, 100K Genomes, IMPC, and many others will not be gotten without comprehensive computational phenotype resources Monarch and HPO are growing into a comprehensive interlinked database of the human phenome and diseasome with relevant model organism data, but are still underfunded Some areas in HP and MP will require extension

� Behaviour � Metabolism (e.g., metabolomics) � Craniofacial

Peter Robinson (Charite)´ Deep Phenotyping 46/50 September 10–11, 2015 46 / 50 Precision Medicine

While current algorithms are working well for rare disease, more sophisticated representations of the phenotype will be required for common (complex) disease including cancer

� Time course � Multimorbidity � Medications and treatments � Side eﬀects Integrated algorithms for matching phenotype to molecular pathophysiology

� Enable & shorten time to diagnosis � Identify actionable subtypes � Understand natural history and gender diﬀerences Connect to molecular taxonomy of disease Animal models of common disease

Peter Robinson (Charite)´ Deep Phenotyping 47/50 September 10–11, 2015 47 / 50 Genome sequencing & Non-coding Variation

We are just beginning to explore the role of the entire genome in human disease Regulatory variation is probably more common than we think By understanding regulatory mutations in rare disease, we will have a path towards precision medicine – the great majority of GWAS hits are non-coding. How does phenotype diﬀer from that of coding mutations in rare disease (e.g., SHH or PTF1A) How do the myriad variants found in all of us contribute to the phenotypic spectrum of common disease? Animal models of gene regulation are many but not currently annotated in a way that could be integrated in medical analysis

Peter Robinson (Charite)´ Deep Phenotyping 48/50 September 10–11, 2015 48 / 50 Thank you for your attention ....

Computational Biology and Bioinformatics Group, Charité Max Planck Institute for Molecular Genetics, Sebastian Bauer (alumnus) Berlin Peter Hansen Marcel H. Schulz Verena Heinrich Jonas Ibn-Salem University of Cambridge UK Marten Jäger George V. Gkoutous Sebastian Köhler Michael Ashburner Peter Krawitz Paul Schofield Peter N. Robinson Oliver Stolpe MRC Harwell UK Na Tzu John Hancock Tomasz Zemojtel http://compbio.charite.de Berkeley Bioinformatics and Ontology Project (BBOP) California Suzi Lewis Institute of Medical Genetics, Charité Chris Mungall Johannes Grünhagen (alumnus) Nicole Washington Gao Guo (alumnus) Claus-Eric Ott Mouse Informatics Group, Sanger Institute Sandra Dölken (alumna) Damian Smedley Denise Horn Jules Jacobsen Ulrike Krüger Stefan Mundlos Oregon Health & Sciences University Melissa Haendel Nicole Vasilevsky ZFIN: The Zebrafish Model Organism Database, Eugene, OR, USA Monte Westerfield Barbara Ruef

Peter Robinson (Charite)´ Deep Phenotyping 49/50 September 10–11, 2015 49 / 50 HPO: Find out more

Overview articles Robinson PN et al 2008 The Human Phenotype Ontology: a tool for annotating and ana lyzing human hereditary disease. Am J Hum Genet 83:610-5. Robinson PN, Mundlos S 2010 The human phenotype ontology. Clin Genet 77:525-34. Köhler et al 2014 The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acids Res. 42:D966 74. Computational semantic reasoning over phenotypes Köhler et al (2013) Construction and accessibility of a cross-species phenotype on tology along with gene annotations for biomedical research. F1000Research 2:30 Köhler S et al. (2011) Improving ontologies by automatic reasoning and evaluation of log ical definitions. BMC Bioinformatics 12:418. Robinson PN, Webber C (2014) Phenotype ontologies and cross-species analysis for translational research. PLoS Genet 10:e1004268. Decision support/exome analysis Köhler S et al 2009 Clinical diagnostics in human genetics with semantic similarity searches in ontologies. Am J Hum Genet. 2009 Oct;85(4):457-64. Algorithms Schulz MH et al 2011 Exact score distribution computation for ontological similarity searches. BMC Bioinformatics. 12;12:441. Bauer S et al 2012 Bayesian ontology querying for accurate and noise-tolerant seman tic searches. Bioinformatics;28(19):2502-8. Robinson PN, Bauer S 2011 Introduction to Bio-Ontologies. Chapman & Hall/CRC Mathemat ical & Computational Biology

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