GET-Evidence

 = Genotype + Environment = Trait Evidence (GET-E) Database = 

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].

You can find the PGP production server at:

 * http://evidence.personalgenomes.org

A development sandbox can be found at: 

 * http://evidence-dev.personalgenomes.org

Many contributors helped make '''GET-E''' possible. You can find specific contributions at: 

 * http://evidence.personalgenomes.org/editors

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!  

 == Field Descriptions and Editing Guidelines ==

 === Short Summary === 

 * free text providing a one line summary of clinical action to be undertaken given this variant (possibly modified by known phenotypes). 

 === Variant Quality Data === 

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

 a. Computational: One star for each consistent prediction and one star subtracted for conflicting results from:

  i. evolutionary conservation (minimum of three species)

  i. presence in active domain 

  i. SIFT 

  i. !PolyPhen 

  i. NBLOSUM >= 2

  i. GVGD

  i. Other variants in this gene cause similar disease 

  i. etc... 

 a. Functional: One star for each experiment supporting the result, and penalize one star for conflicting results from: 

  i. enzyme extracts 

  i. cell lines  

  i. animal models

  i. etc... 

 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

  i. 0 stars if no higher ranking is allowed

  i. 1 star if OR>1 and significance <= 0.1

  i. 2 stars if OR>=1.5 and significance <= 0.05

  i. 3 stars if OR>=2 and significance <= 0.025

  i. 4 stars if OR>=3 and significance <= 0.01

  i. 5 stars if OR>=5 and significance <= 0.0001

 a. Familial Disease Segregation

  i. 0 stars for no segregation (LOD < -2)

  i. 1 star if segregation exists in one family pedigree

  i. 2 stars for segregation in more than one family with some conflicting information (e.g. asymptomatic carrier of young age or possibility of second causative mutation)

  i. 3 stars for more than one family no conflicting information

  i. 4 stars for LOD > 2

  i. 5 stars for LOD > 3

 === Clinical Impact ===

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.

 a. Disease severity: downgraded according to disease penetrance (eg. Crohn's disease would be moderate or severe, but "increased susceptibility" is only increased the chances by ~.15% and so is called mild). For pharmacogenetic variants this is the severity of using the wrong drug/dosage.

  i. 0 stars for benign

  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)

  i. 2 stars for mild effect on quality of life or unlikely to be symptomatic (Cystinuria)

  i. 3 stars for moderate effect on quality of life (eg. Familial mediterranean fever)

  i. 4 stars for severe effect: causes serious disability or reduces life expectancy (eg. Sickle-cell, Stargardt's disease)

  i. 5 stars for very severe effect: early lethal (eg. Familial adenomatous polypopsis, adrenoleukodystrophy)

 a. Treatability:

  i. 0 stars for no clinical evidence supporting intervention (eg. PAF acetylhydrolase deficiency)

  i. 1 star for uncurable: treatment only to alleviate symptoms (eg. adrenoleukodystrophy)

  i. 2 stars for potentially treatable: Treatment is in development or controversial

  i. 3 stars for treatable but a significant fraction do not require treatment (Cystinuria)

  i. 4 stars for treatable: Standard treatment reduces the amount of mortality/morbidity but does not eliminate it (eg. Sickle-cell disease)

  i. 5 stars for extremely treatable: Well-established treatment essentially eliminates the effect of the disease (eg. PKU)

 === Impact ===

 a. Pathogenic: Causative for disease. 

 a. Benign: No clinically significant phenotype. 

 a. Protective: Protective from disease.

 a. Pharmacogenetic: Clinically significant phenotype in the presence of a pharmacological agent.    

 a. NR: Not reviewed.

In addition to these impacts, qualifiers will be added according to the variant quality information (ie. the stars). 

For pathogenic and pharmacogenetic:

 a. (no qualifier given): at least 4 stars in one of the human evidence categories (case/control or familial), at least 4 stars in one of the clinical categories (severity or treatability), and at least 12 stars total.

 a. "likely": at least 3 stars in one of the human evidence categories, at least 3 stars in one of the clinical categories, and at least 10 stars total.

 a. "uncertain": all the rest.

For benign and protective variants, severity and treatibility should be regarded as not applicable (NA) and not counted:

 a. (no qualifier given): at least 4 stars in one of the human evidence categories, and at least 8 stars total.

 a. "likely": at least 3 stars in one of the human evidence categories, and at least 6 stars total.

 a. "uncertain": all the rest.

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.

 === Inheritance Pattern === 

 a. Dominant

 a. Recessive

 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.

 a. Undefined: Undefined in the literature.

 a. Unknown: The default value for all variants and all variants without literature.

 === Summary of published research, and additional commentary === 

 * Free text providing a comprehensive review of the variant including youngest age of onset, oldest age of onset and oldest asymptomatic individual. 

 === Allele Frequency === 

 * 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. 

 === Publications === 

 * 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).

 === Genomes ===  

 * 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.

 === Other External References === 

These are automatically generated by web "robots":  

   a. dbSNP: The link to the dbSNP entry for this nucleotide position (for this nucleotide change?)

   a. Genetests: Link to all clinical laboratories performing diagnostic tests on this gene and the list of diseases that the labs are looking for.

   a. Web Search Results: A web search for this exact variant using the Yahoo search engine

 === Edit History ===

 * Automatically generated history of all page edits with the contributor's name.

 == To Do ==

 * [wiki:GET-Evidence/23andWe]

 == Suggestions == 

 * your suggestion here.