Explaining the Purpose of PGT-A. Nathan R. Treff PhD, HCLD(ABB) Chief Science Officer Clinical Laboratory Director

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1 Explaining the Purpose of PGT-A Nathan R. Treff PhD, HCLD(ABB) Chief Science Officer Clinical Laboratory Director

2 Disclosures Cofounder, Shareholder and CSO, Genomic Prediction Inc Director, Genomic Prediction Clinical Laboratories Inc Stephen Hsu SNP array (18) qpcr (22) NGS (19) Laurent Tellier

3 Aneuploidy is the most common genetic abnormality in humans (data from 15,169 trophectoderm biopsies) Franasiak et al., 2014 Fertil. Steril. 101(3):

Reproductive Technology (ART) Report: Section 4 ART

4 Reproductive potential decreases and aneuploidy incidence increases with age 2006 Assisted Reproductive Technology (ART) Report: Section 4 ART Cycles Using Donor Eggs (CDC Report) Hassold & Hunt, Nat.Rev.Gen. 2001

14 Mosaicism

15 Primarily maternal meiotic (not mosaic) Hassold and Hunt Nature :280

16 ~67% of errors from maternal meiosis n=358 Treff et al Fertil Steril 2008

17 Frequency of mosaicism is misconceived

18 Why are some mosaicism estimates so high?

19 Mosaicism or technical error? 0% consistency in embryos with aneuploidy!

20 acgh False Positives P=0.006 False Positive Rate Capalbo et al. EJHG 2014 n=159 embryos

21 Mosaicism or technical error? 9% FPR= 47% mosaicism

22 HR-NGS validation (~100% concordance with acgh)

23 36.8% discordance with acgh

24 Mosaicism is a gimmick

25 Mosaicism classification schemes Capalbo et al. Hum. Reprod. In Press

26 Reciprocal Aneuploidy

27 Mosaicism is not common Capalbo et al. Hum. Reprod. In Press

28 Positive Controls?! (Mixture Model) Goodrich et al. JARG 2016

29 Comparison of methods to detect aneuploidy in a mixture Goodrich et al. JARG 2016

30 sensitivity = specificity Goodrich et al. JARG % False Positive Rate

31 False negative uniform aneuploidy Mosaic range trisomy 13 Uniform trisomy 13 Uniform trisomy 13

32 False negative uniform aneuploidy Trisomy Disomy

33 Triploidy can also look like mosaicism NexCCS Allele Ratio Allele Ratio Copy Number Triploid (2:1 allele ratios) Diploid (1:1 allele ratios)

34 Conclusions Mosaicism is overestimated by inaccurate methods and weak criteria Intermediate copy number can originate from phenomena other than mosaicism Criteria for diagnosing mosaicism from a single biopsy needs evaluation for specificity prior to clinical utilization Results from a single biopsy should not be considered a definitive diagnosis of mosaicism

35 Would you use a new test: With a 60% false positive rate? Without knowing performance on positive controls? Without evidence of preclinical or clinical predictive value? Without a single true positive observed to date?

36 What should we do with mosaic embryos? Don t use a test which claims to diagnose mosaicism from a single biopsy! If you do, only report results as consistent with possible mosaicism

37 We don t know if these embryos are mosaic!

38 Future Directions? (non-invasive mosaicism prediction) Weak criteria Stringent criteria

39 Expanded Preimplantation Genetic Testing (epgt)

40 Monogenic Polygenic e.g. Type 1 e.g. Cystic 1% Fibrosis 15-25% Diabetes

41 monogenic polygenic

42 UK BioBank (500K Genome-wide Data)

43 Million Veterans Program

45 Modern Polygenic Risk Scores Algorithms Clinical Predictors (i.e. fracture risk assessment) GWAS one at a time Combined Testing? Polygenic Risk Scores machine learning Clinical Risk Out of Sample Validation Osteoporosis Variance Explained

46 Family History

47 Replication We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues. -

48 Disease Examples Atrial Fibrillation Type 2 Diabetes Inflammatory Bowel Disease Breast Cancer

49 Genotyping Accuracy on Limited Quantities 100% Concordance 99% 98% 97% 96% 95% Large qty Small qty

50 PGT-P Results: Hypothyroidism Risk (4945 SNPs) emerge-gwas Set n=219,000 n=2,019

51 PGT-P Results: Hypothyroidism Risk (4945 SNPs) n=219,000 n=43

52 PGT-P: Hypothyroidism Risk (83% Accuracy) Note: Heritability studies suggest that up to 67% of hypothyroidism is genetically determined.

53 epgt Circos Plot Schematic PGT-A >99% PGT-S >99% PGT-M >99.9% PGT-P 83%

54 epgt Initial Polygenic Risk Targets Type 1 Diabetes Type 2 Diabetes Coronary Artery Disease Atrial Fibrillation Breast Cancer Hypothyroidism Mental Disability Idiopathic Short Stature Inflammatory Bowel Disease Diabetes

55 epgt Conclusions and Implications Combined use of machine learning algorithms with novel molecular genetics for genome-wide analysis of the preimplantation embryo First method for simultaneous and accurate PGT of aneuploidy, monogenic and polygenic disorders, and structural abnormalities Polygenic risk scores may provide an additional embryo selection tool, increase utilization of IVF, and reduce the incidence of common genetic disease in humans

56 Utilization IVF population Higher risk of polygenic disorders (e.g. cancer risk in azoospermic males) Fewer embryos for selection General Population Family History Greater number of embryos for selection Genetic Counseling

58 CRISPR

59 Acknowledgements

ADVANCED PGT SERVICES

Genomic Prediction ADVANCED PGT SERVICES with PGT-A using SEQ is a cost-effective, rigorously validated, unambiguous, and streamlined test for aneuploidy in blastocyst biopsies, and uses state of the art