int HaploTree::Traverse(IntArray & pointer, IntArray & state) const
{
while (pointer.Length())
{
int branch = pointer.Peek();
int & allele = state[levels[branch]];
int next = -1;
while (++allele < alleleCounts[levels[branch]])
if ((next = PeekBranch(branch, allele)) != -1)
break;
if (next == -1)
{
allele = -1;
pointer.Pop();
continue;
}
if (levels[branch] == depth - 1)
return next;
pointer.Push(next);
}
return -1;
}
void PDF::WriteReferenceArray(const IntArray & array)
{
fprintf(file, " [ ");
for (int i = 0; i < array.Length(); i++)
WriteReference(array[i]);
fprintf(file, " ] ");
}
void Pedigree::Filter(IntArray & filter)
{
if (filter.Length() != count)
error("Pedigree:Size of pedigree filter doesn't match number of persons in pedigree");
for (int i = 0; i < count; i++)
if (filter[i] == 1)
{
persons[i]->WipePhenotypes();
persons[i]->filter = true;
}
}
void Family::ShowInvalidCycles()
{
// Try and identify key individuals responsible for
// pedigree mess-up ... when this function is called
// pedigree has been traversed top-down and individuals
// that are correctly specified have IDs of >= 0.
// This routine traverses the pedigree bottom up to
// identify a subset of individuals likely to be causing
// the problem
IntArray descendants(ped.count);
descendants.Zero();
for (int i = first; i <= last; i++)
if (ped[i].traverse == -1)
{
descendants[ped[i].father->serial]++;
descendants[ped[i].mother->serial]++;
}
IntArray stack;
for (int i = first; i <= last; i++)
if (ped[i].traverse == -1 && descendants[i] == 0)
{
stack.Push(i);
do {
int j = stack.Pop();
if (ped[j].traverse != -1) continue;
ped[j].traverse = 9999;
if (--descendants[ped[j].father->serial] == 0)
stack.Push(ped[j].father->serial);
if (--descendants[ped[j].mother->serial] == 0)
stack.Push(ped[j].mother->serial);
} while (stack.Length());
}
printf("The structure of family %s requires\n"
"an individual to be his own ancestor.\n\n"
"To identify the problem(s), examine the\n"
"following key individuals:\n\n",
(const char *) famid);
for (int i = first; i <= last; i++)
if (ped[i].traverse == -1)
printf("Problem Person: %s\n", (const char *) ped[i].pid);
error("Invalid pedigree structure.");
}
void InverseNormalTransform(Pedigree & ped)
{
Vector phenotypes;
IntArray individuals;
QuickIndex index;
phenotypes.Dimension(ped.count);
individuals.Dimension(ped.count);
for (int trait = 0; trait < ped.traitCount; trait++)
{
phenotypes.Dimension(0);
individuals.Dimension(0);
for (int i = 0; i < ped.count; i++)
if (ped[i].traits[trait] != _NAN_)
{
phenotypes.Push(ped[i].traits[trait]);
individuals.Push(i);
}
int count = individuals.Length();
if (count == 0) continue;
index.Index(phenotypes);
double scale = 1.0 / count;
for (int i = 0, j; i < index.Length(); i++)
{
for (j = i; j + 1 < index.Length(); j++)
if (ped[individuals[index[i]]].traits[trait] !=
ped[individuals[index[j]]].traits[trait] )
break;
if (ped[individuals[index[i]]].traits[trait] !=
ped[individuals[index[j]]].traits[trait] )
j--;
double z = ninv(((i + j) * 0.5 + 0.5) * scale);
for (int k = i; k <= j; k++)
ped[individuals[index[k]]].traits[trait] = z;
i = j;
}
}
}
void HaploTree::MakeEmptyTree(const IntArray & counts)
{
alleleCounts = counts;
depth = counts.Length();
leafs = 0;
}
int main(int argc, char ** argv)
{
setbuf(stdout, NULL);
time_t start = time(NULL);
printf("MiniMac - Imputation into phased haplotypes\n"
"(c) 2011 Goncalo Abecasis\n");
#ifdef __VERSION__
printf("VERSION 5.0\n");
#else
printf("UNDOCUMENTED RELEASE\n");
#endif
int rounds = 5, states = 200, cpus = 0;
bool em = false, gzip = false, phased = false;
String referenceHaplotypes, referenceSnps;
String haplotypes, snps;
String prefix("minimac");
String firstMarker, lastMarker;
String recombinationRates, errorRates;
BEGIN_LONG_PARAMETERS(longParameters)
LONG_PARAMETER_GROUP("Reference Haplotypes")
LONG_STRINGPARAMETER("refHaps", &referenceHaplotypes)
LONG_STRINGPARAMETER("refSnps", &referenceSnps)
LONG_PARAMETER_GROUP("Target Haplotypes")
LONG_STRINGPARAMETER("haps", &haplotypes)
LONG_STRINGPARAMETER("snps", &snps)
LONG_PARAMETER_GROUP("Starting Parameters")
LONG_STRINGPARAMETER("rec", &recombinationRates)
LONG_STRINGPARAMETER("erate", &errorRates)
LONG_PARAMETER_GROUP("Parameter Fitting")
LONG_INTPARAMETER("rounds", &rounds)
LONG_INTPARAMETER("states", &states)
LONG_PARAMETER("em", &em)
LONG_PARAMETER_GROUP("Output Files")
LONG_STRINGPARAMETER("prefix", &prefix)
LONG_PARAMETER("phased", &phased)
LONG_PARAMETER("gzip", &gzip)
// LONG_PARAMETER_GROUP("Clipping Window")
// LONG_STRINGPARAMETER("start", &firstMarker)
// LONG_STRINGPARAMETER("stop", &lastMarker)
#ifdef _OPENMP
LONG_PARAMETER_GROUP("Multi-Threading")
LONG_INTPARAMETER("cpus", &cpus)
#endif
END_LONG_PARAMETERS();
ParameterList pl;
pl.Add(new LongParameters("Command Line Options", longParameters));
pl.Read(argc, argv);
pl.Status();
#ifdef _OPENMP
if (cpus > 0)
omp_set_num_threads(cpus);
#endif
// Read marker list
printf("Reading Reference Marker List ...\n");
StringArray refMarkerList;
refMarkerList.Read(referenceSnps);
// Index markers
StringIntHash referenceHash;
for (int i = 0; i < refMarkerList.Length(); i++)
referenceHash.Add(refMarkerList[i].Trim(), i);
printf(" %d Markers in Reference Haplotypes...\n\n", refMarkerList.Length());
// Load reference haplotypes
printf("Loading reference haplotypes ...\n");
HaplotypeSet reference;
reference.markerCount = refMarkerList.Length();
reference.LoadHaplotypes(referenceHaplotypes);
printf(" %d Reference Haplotypes Loaded ...\n\n", reference.count);
// Read framework marker list
printf("Reading Framework Marker List ...\n");
StringArray markerList;
markerList.Read(snps);
ClipReference(reference, refMarkerList, referenceHash, markerList,
firstMarker, lastMarker);
// Crossref Marker Names to Reference Panel Positions
IntArray markerIndex;
markerIndex.Dimension(markerList.Length());
int matches = 0;
for (int i = 0; i < markerList.Length(); i++)
{
markerIndex[i] = referenceHash.Integer(markerList[i].Trim());
if (markerIndex[i] >= 0) matches++;
}
printf(" %d Markers in Framework Haplotypes Overlap Reference ...\n", matches);
if (matches == 0)
error("No markers overlap between target and reference\n"
"Please check correct reference is being used and markers are named consistently");
printf(" %d Other Markers in Framework Haplotypes Discarded ...\n\n", markerList.Length() - matches);
// Check for flips in reference vs. target haplotypes
int flips = 0;
int previous = -1;
for (int i = 0; i < markerIndex.Length(); i++)
if (markerIndex[i] >= 0)
if (markerIndex[i] < previous)
{
if (flips++ < 10)
printf(" -> Marker %s precedes %s in reference, but follows it in target\n",
(const char *) refMarkerList[previous],
(const char *) markerList[i]);
previous = markerIndex[i];
}
if (flips > 10)
printf(" -> %d Additional Marker Order Changes Not Listed\n", flips - 10);
if (flips)
printf(" %d Marker Pairs Change Order in Target vs Framework Haplotypes\n", flips);
// Load target haplotypes
printf("Loading target haplotypes ...\n");
HaplotypeSet target;
target.markerCount = markerList.Length();
target.LoadHaplotypes(haplotypes, true);
reference.CalculateFrequencies();
target.CalculateFrequencies();
target.CompareFrequencies(reference, markerIndex, markerList);
printf(" %d Target Haplotypes Loaded ...\n\n", target.count);
int startIndex = firstMarker.IsEmpty() ? 0 : referenceHash.Integer(firstMarker);
int stopIndex = lastMarker.IsEmpty() ? reference.markerCount - 1 : referenceHash.Integer(lastMarker);
if (startIndex < 0 || stopIndex < 0)
error("Clipping requested, but no position available for one of the endpoints");
printf("Setting up Markov Model...\n\n");
// Setup Markov Model
MarkovParameters mp;
mp.Allocate(reference.markerCount);
if (rounds > 0)
printf("Initializing Model Parameters (using %s and up to %d haplotypes)\n",
em ? "E-M" : "MCMC", states);
// Simple initial estimates of error and recombination rate
for (int i = 0; i < reference.markerCount; i++)
mp.E[i] = 0.01;
for (int i = 0; i < reference.markerCount - 1; i++)
mp.R[i] = 0.001;
if (mp.ReadErrorRates(errorRates))
printf(" Updated error rates using data in %s ...\n", (const char *) errorRates);
if (mp.ReadCrossoverRates(recombinationRates))
printf(" Updated recombination rates using %s ...\n", (const char *) recombinationRates);
// Parameter estimation loop
for (int round = 0; round < rounds; round++)
{
printf(" Round %d of Parameter Refinement ...\n", round + 1);
int iterations = states < reference.count ? states : reference.count;
MarkovModel original;
original.CopyParameters(mp);
#pragma omp parallel for
for (int i = 0; i < iterations; i++)
{
MarkovModel mm;
mm.Allocate(reference.markerCount, reference.count - 1);
mm.CopyParameters(original);
// Reference leave one out (loo) panel
char ** reference_loo = new char * [reference.count - 1];
for (int in = 0, out = 0; in < reference.count; in++)
if (in != i)
reference_loo[out++] = reference.haplotypes[in];
mm.WalkLeft(reference.haplotypes[i], reference_loo, reference.freq);
if (em)
mm.CountExpected(reference.haplotypes[i], reference_loo, reference.freq);
else
{
#pragma omp critical
{ mm.ProfileModel(reference.haplotypes[i], reference_loo, reference.freq); }
}
delete [] reference_loo;
#pragma omp critical
mp += mm;
}
if (round >= rounds / 2)
{
int iterations = states < target.count ? states : target.count;
#pragma omp parallel for
for (int i = 0; i < iterations; i++)
{
MarkovModel mm;
mm.Allocate(reference.markerCount, reference.count);
mm.CopyParameters(original);
// Padded version of target haplotype, including missing sites
char * padded = new char [reference.markerCount];
for (int k = 0; k < reference.markerCount; k++)
padded[k] = 0;
// Copy current haplotype into padded vector
for (int j = 0; j < target.markerCount; j++)
if (markerIndex[j] >= 0)
padded[markerIndex[j]] = target.haplotypes[i][j];
mm.WalkLeft(padded, reference.haplotypes, reference.freq);
if (em)
mm.CountExpected(padded, reference.haplotypes, reference.freq);
else
{
#pragma omp critical
{ mm.ProfileModel(padded, reference.haplotypes, reference.freq); }
}
delete [] padded;
#pragma omp critical
mp += mm;
}
}
mp.UpdateModel();
double crossovers = 0;
for (int i = 0; i < reference.markerCount - 1; i++)
crossovers += mp.R[i];
double errors = 0;
for (int i = 0; i < reference.markerCount; i++)
{
double heterozygosity = 1.0 - square(reference.freq[1][i])
- square(reference.freq[2][i])
- square(reference.freq[3][i])
- square(reference.freq[4][i]);
errors += mp.E[i] * heterozygosity;
}
errors /= reference.markerCount + 1e-30;
printf(" %.0f mosaic crossovers expected per haplotype\n", crossovers);
printf(" %.1f%% of crossovers are due to reference flips\n", mp.empiricalFlipRate * 100.);
printf(" %.3g errors in mosaic expected per marker\n", errors);
}
if (rounds > 0)
{
printf(" Saving estimated parameters for future use ...\n");
mp.WriteParameters(refMarkerList, prefix, gzip);
}
printf("\n");
// List the major allele at each location
reference.ListMajorAlleles();
printf("Generating Draft .info File ...\n\n");
// Output some basic information
IFILE info = ifopen(prefix + ".info.draft", "wt");
ifprintf(info, "SNP\tAl1\tAl2\tFreq1\tGenotyped\n");
for (int i = 0, j = 0; i <= stopIndex; i++)
if (i >= startIndex)
ifprintf(info, "%s\t%s\t%s\t%.4f\t%s\n",
(const char *) refMarkerList[i],
reference.MajorAlleleLabel(i), reference.MinorAlleleLabel(i),
reference.freq[reference.major[i]][i],
j < markerIndex.Length() && i == markerIndex[j] ? (j++, "Genotyped") : "-");
else
if (j < markerIndex.Length() && i == markerIndex[j])
j++;
ifclose(info);
printf("Imputing Genotypes ...\n");
IFILE dosages = ifopen(prefix + ".dose" + (gzip ? ".gz" : ""), "wt");
IFILE hapdose, haps;
if (phased)
{
hapdose = ifopen(prefix + ".hapDose" + (gzip ? ".gz" : ""), "wt");
haps = ifopen(prefix + ".haps" + (gzip ? ".gz" : ""), "wt");
}
ImputationStatistics stats(reference.markerCount);
// Impute each haplotype
#pragma omp parallel for
for (int i = 0; i < target.count; i++)
{
if (i != 0 && target.labels[i] == target.labels[i-1])
continue;
MarkovModel mm;
mm.Allocate(reference.markerCount, reference.count);
mm.ClearImputedDose();
mm.CopyParameters(mp);
// Padded version of target haplotype, including missing sites
char * padded = new char [reference.markerCount];
for (int j = 0; j < reference.markerCount; j++)
padded[j] = 0;
int k = i;
do {
printf(" Processing Haplotype %d of %d ...\n", k + 1, target.count);
// Copy current haplotype into padded vector
for (int j = 0; j < target.markerCount; j++)
if (markerIndex[j] >= 0)
padded[markerIndex[j]] = target.haplotypes[k][j];
mm.WalkLeft(padded, reference.haplotypes, reference.freq);
mm.Impute(reference.major, padded, reference.haplotypes, reference.freq);
#pragma omp critical
{ stats.Update(mm.imputedHap, mm.leaveOneOut, padded, reference.major); }
#pragma omp critical
if (phased)
{
ifprintf(hapdose, "%s\tHAPLO%d", (const char *) target.labels[i], k - i + 1);
ifprintf(haps, "%s\tHAPLO%d", (const char *) target.labels[i], k - i + 1);
for (int j = startIndex; j <= stopIndex; j++)
{
ifprintf(hapdose, "\t%.3f", mm.imputedHap[j]);
ifprintf(haps, "%s%c", j % 8 == 0 ? " " : "", mm.imputedAlleles[j]);
}
ifprintf(hapdose, "\n");
ifprintf(haps, "\n");
}
k++;
} while (k < target.count && target.labels[k] == target.labels[i]);
printf(" Outputting Individual %s ...\n", (const char *) target.labels[i]);
#pragma omp critical
{
ifprintf(dosages, "%s\tDOSE", (const char *) target.labels[i]);
for (int j = startIndex; j <= stopIndex; j++)
ifprintf(dosages, "\t%.3f", mm.imputedDose[j]);
ifprintf(dosages, "\n");
}
delete [] padded;
}
ifclose(dosages);
if (phased)
{
ifclose(hapdose);
ifclose(haps);
}
// Output some basic information
info = ifopen(prefix + ".info" + (gzip ? ".gz" : ""), "wt");
ifprintf(info, "SNP\tAl1\tAl2\tFreq1\tMAF\tAvgCall\tRsq\tGenotyped\tLooRsq\tEmpR\tEmpRsq\tDose1\tDose2\n");
// Padded version of target haplotype, including missing sites
char * padded = new char [reference.markerCount];
for (int k = 0; k < reference.markerCount; k++)
padded[k] = 0;
// Mark genotyped SNPs in padded vector
for (int j = 0; j < target.markerCount; j++)
if (markerIndex[j] >= 0)
padded[markerIndex[j]] = 1;
for (int i = startIndex; i <= stopIndex; i++)
{
ifprintf(info, "%s\t%s\t%s\t%.5f\t%.5f\t%.5f\t%.5f\t",
(const char *) refMarkerList[i],
reference.MajorAlleleLabel(i),
reference.MinorAlleleLabel(i),
stats.AlleleFrequency(i),
stats.AlleleFrequency(i) > 0.5 ? 1.0 - stats.AlleleFrequency(i) : stats.AlleleFrequency(i),
stats.AverageCallScore(i),
stats.Rsq(i));
if (padded[i])
ifprintf(info, "Genotyped\t%.5f\t%.5f\t%.5f\t%.5f\t%.5f\n",
stats.LooRsq(i), stats.EmpiricalR(i), stats.EmpiricalRsq(i),
stats.LooMajorDose(i), stats.LooMinorDose(i));
else
ifprintf(info, "-\t-\t-\t-\t-\t-\n");
}
ifclose(info);
delete [] padded;
time_t stop = time(NULL);
int seconds = stop - start;
printf("\nRun completed in %d hours, %d mins, %d seconds on %s\n\n",
seconds / 3600, (seconds % 3600) / 60, seconds % 60,
ctime(&stop));
}
bool Pedigree::TwinCheck()
{
bool fail = false;
IntArray mzTwins;
for (int f = 0; f < familyCount; f++)
{
mzTwins.Clear();
for (int i = families[f]->first, j; i <= families[f]->last; i++)
// Is this person an identical twin?
if (persons[i]->isMzTwin( *persons[i] ))
{
// Have we got another identical sib yet?
for ( j = 0; j < mzTwins.Length(); j++)
if ( persons[i]->isMzTwin( *persons[mzTwins[j]] ) )
break;
// If not, add to list of twins
if (j == mzTwins.Length())
{
mzTwins.Push(i);
continue;
}
// Check that their genotypes are compatible and
// merge new twin's genotypes into original twin...
Person * original = persons[mzTwins[j]];
Person * twin = persons[i];
for (int m = 0; m < Person::markerCount; m++)
{
if (!original->markers[m].isKnown())
original->markers[m] = twin->markers[m];
else
if (twin->markers[m].isKnown() &&
twin->markers[m] != original->markers[m])
printf("MZ Twins %s and %s in family %s have "
"different %s genotypes\n",
(const char *) original->pid,
(const char *) twin->pid,
(const char *) original->famid,
(const char *) Person::markerNames[m]),
fail = true;
if (twin->sex != original->sex)
printf("MZ Twins %s and %s in family %s have "
"different sexes\n",
(const char *) original->pid,
(const char *) twin->pid,
(const char *) original->famid),
fail = true;
}
}
if (mzTwins.Length() == 0) continue;
// In the second pass we copy merged twin genotypes
// from original twin to other twins
for (int i = families[f]->first, j; i <= families[f]->last; i++)
if (persons[i]->isMzTwin( *persons[i] ))
{
for ( j = 0; j < mzTwins.Length(); j++)
if ( persons[i]->isMzTwin( *persons[mzTwins[j]] ) )
break;
if (mzTwins[j] == i) continue;
Person * original = persons[mzTwins[j]];
Person * twin = persons[i];
for (int m = 0; m < Person::markerCount; m++)
twin->markers[m] = original->markers[m];
}
}
return fail;
}
