| 摘要 |
Provided are methods of identifying biomarkers that cause or promote progression of disease. The successful application of the methods is demonstrated by the identification of biomarkers associated with and/or causative of the onset and/or progression and/or severity and/or recurrence of glaucoma and POAG. Many of these biomarkers were not previously associated with glaucoma or POAG. Predictive methods are also described, as well as applications in prognosis, diagnosis, and therapy. Testing for onset, progression, severity, and/or recurrence can be carried out. A key advantage in at least some embodiments is that a patient can receive earlier treatment for the disease such as POAG by use of the methods, screenings, and predictions described herein. Another key advantage in at least some embodiments is that a patient can receive more personalized or particular treatment for the disease such as POAG by use of the methods, screenings, and predictions described herein. |
| 主权项 |
1. A method of identifying genes whose alleles are associative with or causative of the onset and/or progression and/or severity and/or recurrence of a disease, comprising:
a) sequencing or reviewing multiple exomes from patients who have been diagnosed with the disease and one or more exomes from one or more individuals known not to have the disease, wherein the one or more exomes from one or more individuals known not to have the disease comprise one or more reference exomes; b) selecting exomes sequenced and read with a fidelity of 4 or fewer mismatches per 100 bases; c) selecting for genes having one or more site variants in the exomes from patients who have been diagnosed with the disease with one or more properties, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 properties, selected from:
i) site variant is found in one or more patients;ii) site variant is observed in a general population dataset;iii) site variant is found in three or more patients;iv) one or more reference exomes have the major allele;v) site variant is the minor allele in reference exomes;vi) site variant has only one alternate allele;vii) site is within genome region with balanced G+C and A+T content;viii) site is located outside low complexity genome regions;ix) site is located in genome region with no paralog within 95% identity; andx) site variant is located on chromosomes 1-22 or site variant is located on chromosome X or Y only if disease incidence is gender-biased;xi) site was measured in 25 or more patients;xii) site variant frequency in patients differs from general populations by more than expected measurement error, e.g., 0.05 (on a frequency scale from 0.00-1.00);xiii) site variant frequency in patients exceeds general populations, e.g., by more than 0.10;xiv) site variant is within a gene or regulatory regions influencing its expression as RNA or protein;xv) site variant is within or near a gene expressed in tissues relevant to disease;xvi) odds ratio 95% confidence interval lower bound calculated for the site from patient and reference general population frequencies is above 1.00;xvii) frequency of site variant in patients is above a line fitted to filtered sites represented as datapoints where X is reference general population frequency and Y is patient frequency, e.g., fit with least squares linear regression; andxviii) a p-value calculated with a 2×2 statistical test, e.g., Fisher's Exact Test, from numbers of alternate and reference alleles observed for the site in patients and in general population remains significant after correction for multiple testing. |
