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Bigdeli, A.

Publications and source records attributed to Bigdeli, A..

2 recordsLinked to original sources

Azurify integrates cancer genomics with machine learning to classify the clinical significance of somatic variants

Accurate classification of somatic variations from high-throughput sequencing data has become integral to diagnostics and prognostics across various cancers. However, the classification of these variations remains highly manual, inherently variable, and largely inaccessible outside specialized laboratories. Here, we introduce Azurify - a computational tool that integrates machine learning, public resources recommended by professional societies, and clinically annotated data to classify the pathogenicity of variations in precision cancer medicine. Trained on over 15,000 clinically classified variants from 8,202 patients across 138 cancer phenotypes, Azurify achieves 99.1% classification accuracy for concordant pathogenic variants in data from two external clinical laboratories. Additionally, Azurify reliably performs precise molecular profiling in leukemia cases. Azurifys unified, scalable, and modular framework can be easily deployed within bioinformatics pipelines and retrained as new data emerges. In addition to supporting clinical workflows, Azurify offers a high-throughput screening solution for research, enabling genomic studies to identify meaningful variant-disease associations with greater efficiency and consistency.

genomics↗

Classes of ITD predict outcomes in patients with AML treated with FLT3 inhibitors

Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML). ITD mutations of Fms-like tyrosine kinase 3 (FLT3) receptor increase kinase activity, and are associated with poor prognostic outcomes. Currently, several small-molecule FLT3 inhibitors (FLT3i) are in clinical trials for targeted therapy of high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3-ITD mutations in a patient might not guarantee effective clinical response to targeted inhibition of FLT3 kinase. Motivated by the heterogeneity of FLT3-ITD mutations, we sought to investigate the effects of FLT3-ITD structural features on response to treatment in AML patients. To this end, we developed HeatITup (HEAT diffusion for Internal Tandem dUPlication), an algorithm to efficiently and accurately identify ITDs and classify them based on their nucleotide composition into newly defined categories of \"typical\" or \"atypical\". Typical ITDs insert sequences are entirely endogenous to the FLT3 locus whereas atypical ITDs contain nucleotides exogenous to the wildtype FLT3. We applied HeatITup to our cohort of de novo and relapsed AML patients. Individuals with AML carrying typical ITDs benefited significantly more from FLT3i than patients with atypical ITDs, regardless of whether FLT3i was used after initial induction or at relapse. Furthermore, analysis of the TCGA AML cohort demonstrated improved survival for patients with typical ITDs treated with induction chemotherapy. These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing towards personalized treatment for AML patients.

cancer biology↗