![Page 1: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/1.jpg)
Benchmarking Methods for Identifying Causal MutationsTal Friedman
![Page 2: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/2.jpg)
Rare Genetic Diseases
•Our goal: identify and diagnose rare genetic diseases
•Difficult for clinicians due to incredibly low exposure
•Often not already documented
![Page 3: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/3.jpg)
PhenomeCentral
• Clinicians upload patient data
![Page 4: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/4.jpg)
PhenomeCentral
•Matchmaking algorithm displays most similar patients
•Get additional evidence from other clinicians
![Page 5: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/5.jpg)
Background
• Phenotype: Observable characteristics
•Human Phenotype Ontology (HPO)
Robinson et. al
![Page 6: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/6.jpg)
Exomiser
(Robinson et. al, 2014)
![Page 7: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/7.jpg)
Objectives
• Reproduce Exomiser performance
• Expand to new patient similarity domain
![Page 8: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/8.jpg)
Patient Simulation
Control Genome
Mutation
HPO Terms
Infected Patient
Disease
![Page 9: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/9.jpg)
Results
Series10
100
200
300
400
500
600
700
371
547
659
# of causal genes as top hit (N=999)
First attemptSecond attemptExomiser reported
![Page 10: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/10.jpg)
Patient Similarity
• Phenotypic similarity algorithm
•Hypothesis: same disease/causal gene
• Combine Exomiser results
![Page 11: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/11.jpg)
Patient Pair Simulation
Control Genome A
Sampled mutation
Sampled HPO terms
Patient 1
Control Genome B
Sampled mutation
Sampled HPO terms
Patient 2
Disease
Phenotypic Noise & Imprecision
Phenotypic Noise & Imprecision
![Page 12: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/12.jpg)
Results (preliminary)
Series10
100
200
300
400
500
600
700
800
900
397483
768
# of causal genes as top hit (N=890)
ExomiserAveragingPhenomeCentral
![Page 13: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/13.jpg)
Challenges
•Data
•Data
•More data
![Page 14: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/14.jpg)
ChallengesROC Curve for Phenotypic Similarity Algorithm
![Page 15: Benchmarking Methods for Identifying Causal Mutations](https://reader035.vdocument.in/reader035/viewer/2022062315/56816185550346895dd11c5d/html5/thumbnails/15.jpg)
Questions!