Wiki » History » Version 73

Jason Bobe, 03/12/2010 11:08 AM
fixing LOD cut-offs to roughly match case/control cutoffs

1 36 Jason Bobe
 = Genotype + Environment = Trait Evidence (GET-E) Database = 
2 1 Jason Bobe
3 38 Jason Bobe
The '''GET-E''' project was started by Abraham Rosenbaum, Joe Thakuria, Xiaodi Wu and Alexander Wait Zaranek to help the [http://personalgenomes.org Personal Genome Project], the clinical genetics community, and, the general public interpret individual genomes.  The database is closely integrated with [wiki:Trait-o-matic].
4 1 Jason Bobe
5 1 Jason Bobe
You can find the PGP production server at:
6 1 Jason Bobe
 * http://evidence.personalgenomes.org
7 1 Jason Bobe
8 1 Jason Bobe
A development sandbox can be found at: 
9 1 Jason Bobe
 * http://evidence-dev.personalgenomes.org
10 1 Jason Bobe
11 37 Jason Bobe
Many contributors helped make '''GET-E''' possible. You can find specific contributions at: 
12 1 Jason Bobe
 * http://evidence.personalgenomes.org/editors
13 1 Jason Bobe
14 38 Jason Bobe
Please help the project by editing the database, writing software tools that use the database (eg. Trait-o-matic/AETAS) or by making suggestions on the wiki!  
15 1 Jason Bobe
16 28 Jason Bobe
 == Field Descriptions and Editing Guidelines ==
17 19 Jason Bobe
 === Short Summary === 
18 19 Jason Bobe
 * free text providing a one line summary of clinical action to be undertaken given this variant (possibly modified by known phenotypes). 
19 19 Jason Bobe
20 64 Jason Bobe
 === Variant Evidence === 
21 63 Jason Bobe
Each of these fields is a sliding scale of 0-5 where 0 represents no evidence and 5 strong evidence within the given category. Where the data is not entered the default is N/A. When Genetests and/or the literature correlate this variant with a number of phenotypes the impact should be reported for the most extreme condition
22 58 Jason Bobe
 a. Computational: One star for each consistent prediction and one star subtracted for conflicting results from:
23 26 Jason Bobe
  i. evolutionary conservation (minimum of three species)
24 26 Jason Bobe
  i. presence in active domain 
25 27 Jason Bobe
  i. SIFT 
26 27 Jason Bobe
  i. !PolyPhen 
27 44 Jason Bobe
  i. NBLOSUM >= 2
28 27 Jason Bobe
  i. GVGD
29 23 Jason Bobe
  i. Other variants in this gene cause similar disease 
30 23 Jason Bobe
  i. etc... 
31 58 Jason Bobe
 a. Functional: One star for each experiment supporting the result, and penalize one star for conflicting results from: 
32 23 Jason Bobe
  i. enzyme extracts 
33 23 Jason Bobe
  i. cell lines  
34 23 Jason Bobe
  i. animal models
35 23 Jason Bobe
  i. etc... 
36 50 Jason Bobe
 a. Case/Control: A combination of odds ratio and significance test (currently using Fisher's Exact Test). For protective alleles, use inverse OR = 1 / OR. Do not count related individuals, count probands -- ie. one per family
37 40 Jason Bobe
  i. 0 stars if no higher ranking is allowed
38 41 Jason Bobe
  i. 1 star if OR>1 and significance <= 0.1
39 41 Jason Bobe
  i. 2 stars if OR>=1.5 and significance <= 0.05
40 45 Jason Bobe
  i. 3 stars if OR>=2 and significance <= 0.025
41 45 Jason Bobe
  i. 4 stars if OR>=3 and significance <= 0.01
42 45 Jason Bobe
  i. 5 stars if OR>=5 and significance <= 0.0001
43 72 Jason Bobe
 a. Familial (you can read about LOD here: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hmg&part=A1378):
44 73 Jason Bobe
  i. -1 stars if best LOD < 1 and LOD < -2 for theta = 0.1
45 70 Jason Bobe
  i. 0 stars for no familial information
46 73 Jason Bobe
  i. 1 star for best LOD >= 1
47 73 Jason Bobe
  i. 2 stars for best LOD >= 1.3
48 73 Jason Bobe
  i. 3 stars for best LOD >= 1.5, more than one family
49 73 Jason Bobe
  i. 4 stars for best LOD >= 3, more than one family
50 73 Jason Bobe
  i. 5 stars for best LOD >= 5, more than one family
51 63 Jason Bobe
52 69 Jason Bobe
 === Disease Importance ===
53 63 Jason Bobe
As with the Variant Quality section, each of these fields is a sliding scale of 0-5. These two categories are not applicable for benign and protective variants.
54 63 Jason Bobe
55 69 Jason Bobe
 a. Severity: downgraded according to disease penetrance (eg. Crohn's disease would be moderate or severe, but "increased susceptibility" could only mean that the chances are increased by ~.15% and so would be called mild). For pharmacogenetic variants this is the severity of using the wrong drug/dosage.
56 51 Jason Bobe
  i. 0 stars for benign
57 60 Jason Bobe
  i. 1 star for very low expectation of having symptoms for this genotype, very low penetrance (eg. Susceptibility to crohn's with OR = 4.5, causing a ~.2% risk of Crohn's)
58 60 Jason Bobe
  i. 2 stars for mild effect on quality of life or unlikely to be symptomatic (Cystinuria)
59 60 Jason Bobe
  i. 3 stars for moderate effect on quality of life (eg. Familial mediterranean fever)
60 60 Jason Bobe
  i. 4 stars for severe effect: causes serious disability or reduces life expectancy (eg. Sickle-cell, Stargardt's disease)
61 60 Jason Bobe
  i. 5 stars for very severe effect: early lethal (eg. Familial adenomatous polypopsis, adrenoleukodystrophy)
62 51 Jason Bobe
 a. Treatability:
63 51 Jason Bobe
  i. 0 stars for no clinical evidence supporting intervention (eg. PAF acetylhydrolase deficiency)
64 51 Jason Bobe
  i. 1 star for uncurable: treatment only to alleviate symptoms (eg. adrenoleukodystrophy)
65 59 Jason Bobe
  i. 2 stars for potentially treatable: Treatment is in development or controversial
66 59 Jason Bobe
  i. 3 stars for treatable but a significant fraction do not require treatment (Cystinuria)
67 1 Jason Bobe
  i. 4 stars for treatable: Standard treatment reduces the amount of mortality/morbidity but does not eliminate it (eg. Sickle-cell disease)
68 54 Jason Bobe
  i. 5 stars for extremely treatable: Well-established treatment essentially eliminates the effect of the disease (eg. PKU)
69 1 Jason Bobe
70 47 Jason Bobe
 === Impact ===
71 64 Jason Bobe
This is filled in as one of the following:
72 32 Jason Bobe
 a. Pathogenic: Causative for disease. 
73 32 Jason Bobe
 a. Benign: No clinically significant phenotype. 
74 1 Jason Bobe
 a. Protective: Protective from disease.
75 1 Jason Bobe
 a. Pharmacogenetic: Clinically significant phenotype in the presence of a pharmacological agent.    
76 1 Jason Bobe
 a. NR: Not reviewed.
77 1 Jason Bobe
78 64 Jason Bobe
In addition to these categories, up to two qualifiers will be added automatically according to the variant quality scores. The first, "evidence", is based on the four "Variant Evidence" categories. The second, "importance", is based on the two "Clinical Importance" categories (not applicable for benign and protective categories).
79 1 Jason Bobe
80 64 Jason Bobe
An example for "pathogenic" follows:
81 64 Jason Bobe
|| - ||'''low evidence'''||'''moderate evidence'''||'''high evidence'''
82 64 Jason Bobe
||'''low importance'''|| uncertain pathogenic || likely pathogenic || pathogenic
83 64 Jason Bobe
||'''moderate importance'''|| uncertain important pathogenic || likely important pathogenic || important pathogenic
84 64 Jason Bobe
||'''high importance'''|| uncertain very important pathogenic || likely very important pathogenic || very important pathogenic 
85 61 Jason Bobe
86 64 Jason Bobe
Criteria for evidence:
87 64 Jason Bobe
 a. For no qualifier (ie, well-established): (1) at least 4 stars in either "Case/control evidence" or "Familial evidence" and (2) at least eight stars total
88 66 Jason Bobe
 a. For "likely": (1) at least 3 stars in either "Case/control evidence" or "Familial evidence" and (2) at least five stars total
89 64 Jason Bobe
 a. Otherwise "uncertain"
90 64 Jason Bobe
91 64 Jason Bobe
Criteria for importance (not used for benign and protective):
92 66 Jason Bobe
 a. For "very important": (1) at least 3 stars in severity and at least 4 stars in treatability, or (2) at least 4 stars in severity
93 66 Jason Bobe
 a. For "important": (1) at least 2 stars in severity and at least 3 stars in treatability, or (2) at least 3 stars in either severity
94 65 Jason Bobe
 a. Otherwise no qualifier
95 39 Jason Bobe
96 19 Jason Bobe
When Genetests and/or the literature give multiple phenotypes for a variant, the impact should be reported for the most extreme condition and annotated as such in the ''short summary''. In the future we hope to list different phenotypes separately.
97 19 Jason Bobe
98 19 Jason Bobe
 === Inheritance Pattern === 
99 19 Jason Bobe
 a. Dominant
100 19 Jason Bobe
 a. Recessive
101 19 Jason Bobe
 a. Other: A defined form of inheritance that is neither dominant or recessive (e.g. modifier, co-dominant, incomplete penetrance). These variants will get prioritized due to their potential phenotypic affect should the additional factors be present.
102 19 Jason Bobe
 a. Undefined: Undefined in the literature.
103 19 Jason Bobe
 a. Unknown: The default value for all variants and all variants without literature.
104 19 Jason Bobe
105 22 Jason Bobe
 === Summary of published research, and additional commentary === 
106 1 Jason Bobe
 * Free text providing a comprehensive review of the variant including youngest age of onset, oldest age of onset and oldest asymptomatic individual. 
107 21 Jason Bobe
108 22 Jason Bobe
 === Allele Frequency === 
109 21 Jason Bobe
 * Automatically generated frequencies for the !HapMap Project, 1000 Genomes Project and the weighted average of the two.  Sub-population frequencies and homozygous/heterozygous break-downs are currently not shown. 
110 21 Jason Bobe
111 21 Jason Bobe
 === Publications === 
112 21 Jason Bobe
113 21 Jason Bobe
 * User-entered publications and user entered synopses of the relevant details from the publication. A short summary is also entered for each paper (as above).
114 21 Jason Bobe
 
115 21 Jason Bobe
 === Genomes ===  
116 21 Jason Bobe
117 21 Jason Bobe
 * Automatically generated list of all genomes from Trait-o-matic in which this variant is seen. Additionally, specific actions taken by each individual harboring the variant can be reported.
118 21 Jason Bobe
 
119 21 Jason Bobe
 === Other External References === 
120 13 Jason Bobe
These are automatically generated by web "robots":  
121 12 Jason Bobe
   a. dbSNP: The link to the dbSNP entry for this nucleotide position (for this nucleotide change?)
122 12 Jason Bobe
   a. Genetests: Link to all clinical laboratories performing diagnostic tests on this gene and the list of diseases that the labs are looking for.
123 21 Jason Bobe
   a. Web Search Results: A web search for this exact variant using the Yahoo search engine
124 21 Jason Bobe
125 21 Jason Bobe
 === Edit History ===
126 20 Jason Bobe
 * Automatically generated history of all page edits with the contributor's name.
127 20 Jason Bobe
128 20 Jason Bobe
 == To Do ==
129 3 Jason Bobe
 * [wiki:GET-Evidence/23andWe]
130 1 Jason Bobe
131 1 Jason Bobe
 == Suggestions == 
132 1 Jason Bobe
133 1 Jason Bobe
 * your suggestion here.