We ranked the valid trios for each quality parameter and designat

We ranked the valid trios for each quality parameter and designated as HQ only those trios in the lower 95th percentile for all three parameters. The effects of poor noise and signal parameters on the ability to distinguish copy-number states are demonstrated in Figure 2. For a given KS segment, states were only computed for probes that passed our filters. The first filter was the number of mappings of the probe sequence in the genome (hg18 build). We excluded

probes with more than two mappings, resulting in the exclusion of ∼3% of the probes. Further, we only considered probes with two mappings if the second mapping was to a site within the segment. This ensured that most probes behaved according to the five-state model. Our second filter was based on the frequency of polymorphism, or “population threshold.” If a probe was in a segment deemed amplified http://www.selleckchem.com/products/fg-4592.html or deleted in five or more parents, we excluded that probe from our analysis of the segment. This eliminated most regions where our reference genome was not in the standard copy-number state and guarded against cryptic de novo events, for which parents carry

both a duplication and a deletion of the same locus. To analyze trios for de novo mutations, we used KS segmentation of the child and generated three five-state models, one for each member of the trio. For each interval in the child’s segmentation, we determined the most likely copy-number state for each probe. If the majority of the child’s probes were most likely in the 0 or 1 state, check details much the segment was flagged as a potential deletion event. If they were most likely in the 3 or 4 state, the segment was flagged as a potential duplication. If the segment was flagged, we decided whether each probe was a “Mendel violator.” A probe is a deletion Mendel violator if the child probe is most likely in the 0 or 1 state and if both parents are most likely in the 2, 3, or 4 state. A probe is a duplication Mendel violator if the child probe is most likely in the 3 or 4 state and if both parents are most likely in the 0, 1, or 2 state. For each potential deletion (duplication) segment, we recorded the total number of probes and the number of deletion

(duplication) Mendel-violating probes. For each trio, we used the five-state model to simulate ratio data for all 125 trio states (0 to 4 for child, father, and mother.) Of the 125 states, 36 are “Mendel violator” states (child = 1, father = 2, mother = 2; child = 1, father = 2, mother = 3, etc.) and the remaining 89 trio states are “Mendel obedient” (child = 2, father = 2, mother = 2; child = 1, father = 1, mother = 2, etc.). For each trio state, we compute the probability that a probe drawn from that distribution is classified as a deletion (or duplication) Mendel violator. We apply that probability to parameterize a binomial distribution. This allows us to determine the likelihood that an N-probe segment in that trio state would generate M or more probes classified as Mendel violators.

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