In this paper, we present a stochastic model for the dynamic fleet management problem with random travel times. Our approach decomposes the problem into time-staged subproblems by formulating it as a ...dynamic program and uses approximations of the value function. In order to deal with random travel times, the state variable of our dynamic program includes
all individual decisions over a relevant portion of the history. We show how to approximate the value function in a tractable manner under this new high-dimensional state variable.
Under our approximation scheme, the subproblem for each time period decomposes with respect to locations, making our model very appealing for large-scale applications. Numerical work shows that the proposed approach provides high-quality solutions and performs significantly better than standard benchmark methods.
•Multitude of DMD variants challenges the management and genetic counseling in dystrophinopathy.•Single exon deletion may accommodate pathogenic sequence variant in the probe binding ...site.•Co-occurrence of two mutations in the same allele may complicate phenotype associations.•Segregation assays may guide the critical evaluation of the variants’ pathogenicity.•Next generation sequencing technology allows the detection of mosaicism of the sequence variant.
We genetically evaluated 260 dystrophinopathy patients from Turkey. Karyotyping as an initial test in female patients, followed stepwise by multiplex ligation-dependent probe amplification and by targeted next-generation sequencing of DMD revealed definitive genetic diagnoses in 214 patients (82%), with gross deletions/duplications in 153 (59%), pathogenic sequence variants in 60 (23%), and X-autosome translocation in one. Seven of the gross and 27 of the sequence variants found novel. In silico prediction, co-segregation and transcript assays supported the pathogenic nature of the novel silent (p.Lys534=) and the splice site (c.4345–12C>G) alterations. From a total of 189 singleton cases, 154 (82%) had pathogenic alterations. From 138 of those who had maternal carrier testing, 68 out of 103 (66%) showed gross and 11 out of 35 (31%) showed small pathogenic variants. This suggests that the de novo occurrences in DMD appear approximately 2.1 times more frequently in meiotic unequal crossing-over than in uncorrected replication errors. Our study also disclosed three mothers as obligate gonadal mosaic carriers. Family-based investigation of dystrophinopathy patients is crucial for the ascertainment of novel or rare variants and also for counseling and follow-up care of the families.
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