Orchard

Orchard reconstructs cancer phylogenies from point mutations detected with bulk DNA sequencing using a stochastic combinatorial search approach that scales accurately to 1000 mutations.

Key Features:

• Scalable phylogeny reconstruction: Orchard accurately reconstructs cancer phylogenies using up to 1000 mutations, outperforming existing methods that become inaccurate beyond 30 mutations.
• Factorized posterior approximation: Orchard samples without replacement from a factorized approximation of the posterior distribution over phylogenies, where each factor corresponds to a conditional distribution for adding a new mutation to a partially built phylogeny.
• Sequential optimization: Orchard optimizes each factor sequentially, generating a sequence of incrementally larger phylogenies that culminate in a complete tree containing all mutations.

Scientific Applications:

• Cancer evolution analysis: Orchard reconstructs phylogenies depicting the evolutionary history of genetically heterogeneous subpopulations of cells from the same cancer, offering insights about cancer development and guiding treatment strategies.
• Somatic mutation pattern identification: The large and accurate phylogenies reconstructed by Orchard enable identification of patterns of somatic mutations and genetic variations among distinct cancer cell subpopulations.
• B-ALL phylogeny reconstruction: Orchard has been demonstrated on 14 B-progenitor acute lymphoblastic leukemias (B-ALLs) for reconstructing clinically relevant cancer phylogenies.

Methodology:

Orchard employs a stochastic combinatorial search that samples without replacement from a factorized approximation of the posterior distribution over phylogenies, with each factor representing a conditional distribution for adding a new mutation to a partially built phylogeny, optimized sequentially to build incrementally larger phylogenies.