Mean accuracy of imputation (r² of allelic dosage across all samples for a SNP) averaged across SNPs split by Minor Allele Frequency (MAF).

<p>MAF bins increase by factors of √10, to create four exponentially increasing bins.</p><p>N SNPs: number of SNPs in MAF bin.</p><p>1kG: 1000 Genomes used as reference panel.</p><p>1kG+LRP: 1000 Genomes plus local reference panel.</p><p>Increase r²: Average across all SNPs in MAF bin increase in r².</p><p>Std dev: The standard deviation (across SNPs) of the increase in r² at each SNP.</p><p>Inc. Sample: Increase in effective sample size for GWAS.</p><p>The standard errors of mean increases are less than 0.003. All improvements in r² are significantly different from zero and significantly different between MAF bands (P<0.001, two-sided t tests).</p

Illustration of the procedure to estimate imputation accuracy.

<p>We used a drop one-out crossvalidation approach. For the imputation step each subject was removed from the reference panel in turn, and this subject’s exome sequence SNPs were then imputed using either the 1000 Genomes reference panel alone or in conjunction with a second local reference panel. All subjects’ imputed allelic dosages were then compared with the exome sequence genotype data (“gold standard”).</p

Plot of mean improvement in imputation accuracy (r²) for SNPs with minor allele frequency (MAF) in the range 1–10% in our exome sequence data.

<p>Plot of mean improvement in imputation accuracy (r²) for SNPs with minor allele frequency (MAF) in the range 1–10% in our exome sequence data.</p

Frequency plot of imputation accuracy (r²) using 1000 Genomes data alone against 1000 Genomes plus a local reference panel for SNPs with Minor Allele Frequencies (MAF) of 1–3.2%.

<p>Frequency plot of imputation accuracy (r²) using 1000 Genomes data alone against 1000 Genomes plus a local reference panel for SNPs with Minor Allele Frequencies (MAF) of 1–3.2%.</p

Preparation of array data and local reference panel for imputation.

<p>The genotype data were quality controlled and phased. These data were then used in further downstream analysis.</p

Switch error (SE) rates for different methods applied to extended pedigrees.

<p>We evaluate SE for individuals who are members of a complex pedigree (pedigrees that are larger than a parent-child duo and father-mother-child trio). The first row is the number of individuals from each cohort in such pedigrees. The second row shows the yield of SLRP when applied to each cohort. Rows 3–6 show the SE for SHAPEIT2, SLRP, Beagle and HAPI-UR within SLRP detected IBD regions. Rows 7–9 show the SE for SHAPEIT2, Beagle and HAPI-UR outside SLRP detected IBD regions. Rows 10–12 show the overall SE for SHAPEIT2, Beagle and HAPI-UR. Rows 13–15 show the overall SE for SHAPEIT2, Beagle and HAPI-UR haplotypes after correction with the duoHMM method. Row 16 show the overall SE for Beagle applied to pedigrees partitioned into duos and trios where possible. Rows 17–18 show the switch error rate for the SHAPEIT2+duoHMM and Beagle Duo/Trio phasing <i>after</i> masking genotypes flagged as erroneous by the duoHMM.</p

Summary of IBD sharing in cohorts.

<p>Left: The proportion of heterozygote sites phased by SLRP for all individuals (pink) and when individuals with close relatives () are removed (blue). Right: The distributions of the average number of “surrogate” parents for each cohort when closely related pairs () are removed.</p

Summary of DuoHMM state transitions for each cohort.

<p>The mean number of switches occurring (excluding ) found by the Viterbi path through our four state HMM for SHAPEIT2 and Beagle maximum likelihood haplotypes for chromosome 10 for paternal (P) and maternal (M) duos. SHAPEIT2 has very few impossible transitions ( and ) and the number possible recombinations () are much closer to the genetic length of chromosome 10 than Beagle. The 2002 deCODE map gives the chromosome 10 genetic length as 1.34 and 2.18 Morgans for males and females respectively.</p

Switch error rates for samples containing nominally unrelated individuals.

<p>All individuals not explicitly related in the defined pedigrees were phased. We calculate overall SE rate (All), for chromosome 10 (this is not possible for SLRP) as well as SE rates within (IBD) and outside (no IBD) SLRP detected IBD regions. SHAPEIT2 consistently produces the most accurate haplotypes. Chip abbreviations: 370K - Illumina HumanHap 370CNV. 300K - Illumina HumanHap 300, 2.5S - Illumina Omni 2.5S.</p

Recombination detection accuracy in uninformative duos simulated from chromosome X data in the Val Borbera cohort.

<p>The green values are for a cohort with nominally unrelated individuals and the orange values are for a cohort that has been filtered such that no individuals are closely related (). Left: The ROC curves for recombination detection in uninformative duos for our duo HMM using the SHAPEIT2 haplotypes. Right: The average number of correct detections against the average posterior probability. Setting a high probability threshold ensures a very low false discovery rate.</p