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cohort.jinja
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cohort.jinja
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{% extends "./base.jinja" %}
{% block navbarbegin %}
<span class="navbar-brand mb-0 h1">{{cohort.cohortid}}
{% if cohort.title %}<span class="d-none d-md-inline small">— {{cohort.title}}</span>{% endif %}
</span>
{% endblock %}
{% block body %}
<script src="https://ajax.googleapis.com/ajax/libs/angularjs/1.8.0/angular.min.js"></script>
<script src="https://d3js.org/d3.v5.min.js"></script>
<script>
angular.module("cohortApp", []).filter('escape', function() {
return function(input) {
if(input) {
return window.encodeURIComponent(input);
}
return "";
}
}).controller("CohortController", ['$scope', function($scope) {
$scope.variantsets = [];
Promise.allSettled([
d3.tsv("http://100humans/cohorts/analysis/{{cohort.cohortid}}/slivar/{{cohort.cohortid}}.GRCh38.deepvariant.phased.slivar.tsv"),
d3.tsv("http://100humans/cohorts/analysis/{{cohort.cohortid}}/slivar/{{cohort.cohortid}}.GRCh38.deepvariant.phased.slivar.compound-hets.tsv")
]).then(function(tsvs) {
var singlevariants = [];
var compoundhets = [];
if (tsvs[0].status == "fulfilled") {
singlevariants = singlevariants.concat(tsvs[0].value);
}
if (tsvs[1].status == "fulfilled") {
compoundhets = compoundhets.concat(tsvs[1].value);
}
// Clean up the variant objects
singlevariants.concat(compoundhets).forEach(variant => {
// Parse the variant allele
variant.chrom = variant["chr:pos:ref:alt"].split(":")[0];
variant.pos = parseInt(variant["chr:pos:ref:alt"].split(":")[1], 10);
variant.ref = variant["chr:pos:ref:alt"].split(":")[2];
variant.alt = variant["chr:pos:ref:alt"].split(":")[3];
if (variant.ref.length == variant.alt.length) {
variant.allele = variant.ref + ">" + variant.alt;
}
else if (variant.ref.length > variant.alt.length) {
variant.allele = "-" + (variant.ref.length - variant.alt.length).toFixed(0) + " del" + variant.ref.substr(1);
}
else {
variant.allele = "+" + (variant.alt.length - variant.ref.length).toFixed(0) + " ins" + variant.alt.substr(1);
}
if (variant.allele.length > 12) {
variant.shortallele = variant.allele.substr(0,12) + "...";
}
else {
variant.shortallele = variant.allele;
}
variant.mode = variant["#mode"]
variant.highest_impact_rank = (variant.highest_impact == "" ? 999 : parseInt(variant.highest_impact));
variant.impact = variant.highest_impact.substr(3).replace("_", " ");
if (variant.gene_description_1.search("oe_lof") != -1) {
variant.oe_lof = parseFloat(variant.gene_description_1.split(";")[1].split("=")[1]);
}
else {
variant.oe_lof = -1;
}
variant.phrank = variant.gene_description_3 || -1;
variant.gnomad_nhomalt = Math.max(variant.gnomad_nhomalt, 0);
variant.hprc_nhomalt = Math.max(variant.hprc_nhomalt, 0);
variant.gnomad_ac = Math.max(variant.gnomad_ac, 0);
variant.hprc_ac = Math.max(variant.hprc_ac, 0);
variant.max_nhomalt = Math.max(variant.gnomad_nhomalt, variant.hprc_nhomalt);
variant.max_ac = Math.max(variant.gnomad_ac, variant.hprc_ac);
var genotypes = variant["genotype(sample,dad,mom)"].split(",").map(function(s) { return (s=="." ? 0 : parseInt(s, 10)); }).map(function(x) { return (x < 0 ? 0 : x); });
var depths = variant["depths(sample,dad,mom)"].split(",").map(function(s) { return (s=="." ? 0 : parseInt(s, 10)); });
var allele_balances = variant["allele_balance(sample,dad,mom)"].split(",").map(function(s) { return (s=="." ? 0 : parseFloat(s, 10)); });
variant.genotypes = [];
variant.depths = [];
variant.allele_balances = [];
variant.allele_depths = [];
for (var i = 0; i < {{ cohort.samples|length }} && i < 3; i++) {
variant.genotypes.push(genotypes[i]);
variant.depths.push(depths[i]);
variant.allele_balances.push(allele_balances[i]);
variant.allele_depths.push(Math.round(variant.allele_balances[i]*variant.depths[i]));
}
variant.highest_impact_rank = (variant.highest_impact == "" ? 999 : parseInt(variant.highest_impact, 10));
variant.lof = variant.highest_impact_rank <= 7;
});
// Create "variant sets", a combination of variants that satisfy an inheritance models.
// For dominant and homozygous recessive, a variants set is a single variants.
// For compound het, a variant set is a pair of variants.
var variantsets = [];
singlevariants.forEach((variant) => {
variantsets.push({ mode: variant["#mode"], gene: variant.gene, oe_lof: variant.oe_lof, phrank: variant.phrank, variants: [variant] });
});
// Slivar assigns the same "mode" to variants that make a compound het pair.
var compoundhetpairs = {};
compoundhets.forEach((variant) => {
var m = variant["#mode"];
if (variant.slivar_comphet) {
var cols = variant.slivar_comphet.split("/");
variant.orientation = cols[cols.length-1];
}
compoundhetpairs[m] = compoundhetpairs[m] || [];
compoundhetpairs[m].push(variant);
});
Object.values(compoundhetpairs).forEach((variants) => {
variantsets.push({ mode: "compoundhet", orientation: variants[0].orientation, gene: variants[0].gene, oe_lof: variants[0].oe_lof, phrank: variants[0].phrank, variants: variants });
});
// Tag variant sets that include a loss-of-function variant.
variantsets.forEach((variantset) => {
variantset.lof = false;
for (var i = 0; i < variantset.variants.length; i++) {
if (variantset.variants[i].lof) {
variantset.lof = true;
break;
}
}
});
// Tag "interesting" variant sets
variantsets.forEach((variantset) => {
variantset.interesting = [];
// LOF with ALCT=0 in a LOF-intolerant gene
if (variantset.lof && variantset.oe_lof >= 0 && variantset.oe_lof < 0.35) {
for (var i = 0; i < variantset.variants.length; i++) {
if (variantset.variants[i].lof && variantset.variants[i].max_ac == 0) {
variantset.interesting.push("LOF in LOF-intolerant gene");
break;
}
}
}
// Compound het where both variant have HMCT==0
if (variantset.mode == "compoundhet" && variantset.orientation != "cis" && variantset.variants[0].max_nhomalt == 0 && variantset.variants[1].max_nhomalt == 0) {
variantset.interesting.push("Compound het where both variants have HMCT=0");
}
// Homozygous where variant has HMCT==0
if ((variantset.mode == "recessive" || variantset.mode == "x_recessive") && (variantset.variants[0].max_nhomalt == 0)) {
variantset.interesting.push("Homozygous variant with HMCT=0");
}
});
$scope.variantsets = variantsets;
updateCandidateGenes();
$scope.$apply();
});
$scope.filter = {
gene: "",
hmct: 1,
alct_dominant: 1
};
$scope.$watch(function(scope) { return scope.filter; }, function() {
updateCandidateGenes();
}, true);
// Variant-level filter
function variantFilter(variant, mode) {
var filter = $scope.filter;
if (variant.highest_impact_rank > 20) {
return false;
}
if (mode == "dominant" || mode == "x_dominant") {
if (variant.max_ac > filter.alct_dominant) {
return false;
}
}
if (mode == "recessive" || mode == "x_recessive" || mode == "compoundhet") {
if (variant.max_nhomalt > filter.hmct) {
return false;
}
}
return true;
}
// Retain a variant set if it meets the variant set filter criteria and all of its variants meet the variant filters.
var geneBlacklist = { "MUC4": true, "MUC6": true, "MUC3A": true, "MUC12": true, "CT47A3": true, "CT47A4": true, "CT47A7": true, "EPPK1": true, "NPIPB3": true, "NPIPB5": true, "NBPF14": true, "NBPF20": true };
$scope.variantSetFilter = function(item) {
// Filter cis compound hets
if (item.mode == "compoundhet" && item.orientation == "cis") {
return false;
}
var filter = $scope.filter;
gene = item.gene.toUpperCase();
if (filter.gene != "" && gene.search(filter.gene.toUpperCase()) == -1) {
return false;
}
if (gene.startsWith("HLA") || gene.startsWith("TRBV") || geneBlacklist[gene]) {
return false;
}
for (var i = 0; i < item.variants.length; i++) {
if (!variantFilter(item.variants[i], item.mode)) {
return false;
}
}
return true;
};
$scope.variantSetOrderBy = function(item) {
var variantsetimpact = 999;
for (var i = 0; i < item.variants.length; i++) {
if (item.variants[i].highest_impact_rank < variantsetimpact) {
variantsetimpact = item.variants[i].highest_impact_rank;
}
}
return variantsetimpact;
};
$scope.geneOrderBy = function(item) {
var impact = 999;
for (var i = 0; i < item.variants.length; i++) {
if (item.variants[i].highest_impact_rank < impact) {
impact = item.variants[i].highest_impact_rank;
}
}
return impact;
};
$scope.candidateGenes = [];
function updateCandidateGenes() {
var genes = {};
// Filter variant sets then group them by gene.
$scope.variantsets.filter(variantset => $scope.variantSetFilter(variantset)).forEach((vs) => {
genes[vs.gene] = genes[vs.gene] || { gene: vs.gene, oe_lof: vs.oe_lof, phrank: vs.phrank, transcomphet: false, variantsets: [] };
if (vs.mode == "compoundhet" && vs.orientation == "trans") {
genes[vs.gene].transcomphet = true;
}
genes[vs.gene].variantsets.push(vs);
});
// Uniquify the variants for a given gene.
// Mark the gene as having LOF if at least one variant is LOF.
Object.values(genes).forEach(gene => {
var interesting = {};
var variants = {};
gene.variantsets.forEach(vs => {
vs.interesting.forEach(reason => {
interesting[reason] = true;
});
vs.variants.forEach(v => {
var vkey = v.chrom + "$" + v.pos.toFixed(0) + "$" + v.ref + "$" + v.alt;
variants[vkey] = v;
});
});
gene.interesting = Object.values(interesting);
gene.variants = Object.values(variants);
gene.lof = false;
gene.variants.forEach(v => {
if(v.lof) {
gene.lof = true;
}
});
});
$scope.candidateGenes = Object.values(genes);
};
}]);
</script>
<div ng-app="cohortApp">
<div ng-controller="CohortController as cohort">
{% if cohort.notes or cohort.solved or cohort.igv %}
<h5>Notes</h5>
<ul class="small pl-4">
{% for note in cohort.notes %}
<li>{{ note }}</li>
{% endfor %}
{% if cohort.solved %}
<li><b class="text-success">Solved</b> {{cohort.solved}}</li>
{% endif %}
{% if cohort.igv %}
<li><span class="font-weight-bold">IGV</span> <a href="http://100humansfs/cohorts/{{cohort.cohortid}}/{{cohort.cohortid}}_igv.xml">http://100humansfs/cohorts/{{cohort.cohortid}}/{{cohort.cohortid}}_igv.xml</a></li>
{% endif %}
</ul>
{% endif %}
<h5>Phenotype</h5>
<table class="table table-sm table-borderless">
<tbody class="small">
{% for bodysystem,phenotypes in cohort.bodysystems.items() %}
<tr>
<td class="text-nowrap font-weight-bold">{{bodysystem}}</td>
<td>
<ul class="list-inline mb-0">
{% for phenotype in phenotypes %}
<li class="list-inline-item" {% if phenotype.definition != "" %} data-toggle="tooltip" title="{{phenotype.definition|e}} [{{"{:,.0f}".format(phenotype.genect)}} genes]" {% endif %}>
<a href="https://hpo.jax.org/app/browse/term/{{phenotype.hpoid}}" target="_blank">{{phenotype.name}}</a>
</li>
{% endfor %}
</ul>
</td>
</tr>
{% endfor %}
</tbody>
</table>
<div class="card mb-3">
<div class="card-body">
<form>
<div class="form-group row mb-1">
<label for="term" class="col-sm-3 col-form-label col-form-label-sm">Search term</label>
<div class="col-sm-4">
<input class="form-control form-control-sm" type="text" id="gene" ng-model="searchTerm">
</div>
</div>
<div class="form-group row mb-1">
<label for="gene" class="col-sm-3 col-form-label col-form-label-sm">Gene</label>
<div class="col-sm-2">
<input class="form-control form-control-sm" type="text" id="gene" ng-model="filter.gene">
</div>
</div>
<div class="form-group row mb-1">
<label for="alct_dominant" class="col-sm-3 col-form-label col-form-label-sm">Dominant ALCT ≤</label>
<div class="col-sm-2">
<input class="form-control form-control-sm" type="number" id="alct_dominant" min=0 max=4 step=1 ng-model="filter.alct_dominant">
</div>
</div>
<div class="form-group row mb-0">
<label for="alct_dominant" class="col-sm-3 col-form-label col-form-label-sm">Recessive HMCT ≤</label>
<div class="col-sm-2">
<input class="form-control form-control-sm" type="number" id="hmct" min=0 max=4 step=1 ng-model="filter.hmct">
</div>
</div>
</form>
</div>
</div>
<table class="table table-sm small">
<thead>
<tr>
<th></th>
<th>Gene</th>
<th title="Phrank gene-phenotype similarity score">Phrank</th>
<th>O/E LOF</th>
<th>GRCh38</th>
<th>Variant</th>
<th>Impact</th>
<th>gnomAD</th>
<th>HPRC</th>
{% for sample in cohort.samples %}
<th class="text-center {{ 'text-primary' if sample.diseasestatus == "affected" }}">{{sample.sampleid}} <i class="fa fa-{{ 'male' if sample.sex=='MALE' else 'female' if sample.sex=='FEMALE' else 'question' }}"></i></th>
{% endfor %}
</tr>
</thead>
<tbody ng-repeat="gene in candidateGenes|orderBy:geneOrderBy">
<tr ng-repeat="variant in gene.variants">
<td>
<span ng-show="$first">
<i ng-show="gene.transcomphet" class="fa fa-exchange" title="trans compound het"></i>
</span>
</td>
<td>
<span ng-show="$first">
<a href="https://www.google.com/search?q={{ '{{gene.gene}}' }}+{{ '{{searchTerm | escape}}' }}" target="_blank">{{ '{{gene.gene}}' }}</a>
</span>
</td>
<td>
<span ng-show="$first && gene.phrank >= 0">
<span ng-class="{ 'text-success': gene.phrank && gene.phrank >= 10 }">{{ '{{gene.phrank|number:2}}' }}</span>
</span>
</td>
<td>
<span ng-show="$first && gene.oe_lof >= 0">
<span ng-class="{ 'text-success': gene.lof && gene.oe_lof <= 0.35, 'text-danger': gene.lof && gene.oe_lof >= 0.9 }">{{ '{{gene.oe_lof|number:2}}' }}</span>
</span>
</span>
</td>
<td>
{{ '{{variant.chrom}}' }}:{{ '{{variant.pos|number}}' }}
</td>
<td>
<span title="{{ '{{variant.allele}}' }}">{{ '{{variant.shortallele}}' }}</span>
</td>
<td>
{{ '{{variant.impact}}' }}
</td>
<td>
<span ng-show="variant.gnomad_ac <= 0">-</span>
<span ng-class="{ 'text-danger': variant['mode']=='dominant' }" ng-show="variant.gnomad_ac > 0">ALCT {{ '{{variant.gnomad_ac|number:0 }}' }}</span>
<span class="text-danger" ng-show="variant.gnomad_nhomalt > 0">HMCT {{ '{{variant.gnomad_nhomalt|number:0 }}' }}
</td>
<td>
<span ng-show="variant.hprc_ac <= 0">-</span>
<span ng-class="{ 'text-info': variant['mode']!='dominant', 'text-danger': variant['mode']=='dominant' }" ng-show="variant.hprc_ac > 0">ALCT {{ '{{variant.hprc_ac|number:0 }}' }}</span>
<span "text-danger" ng-show="variant.hprc_nhomalt > 0">HMCT {{ '{{variant.hprc_nhomalt|number:0 }}' }}
</td>
<td ng-repeat="genotype in variant.genotypes track by $index" class="text-center">
<span ng-class="{ 'text-black-50': genotype > 0 && variant.allele_balances[$index]<0.33 }" data-toggle="tooltip" title="AD/DP {{ "{{ variant.allele_depths[$index] }}" }}/{{ "{{ variant.depths[$index] }}" }}">
<i class="fa fa-circle" ng-show="genotype==2"></i>
<i class="fa fa-adjust" ng-show="genotype==1"></i>
<i class="fa fa-circle-o" ng-show="genotype==0"></i>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
{% endblock %}