BreakLoops: A New Feature for the Multi-Gene, Multi-Cancer Family History-Based Model, Fam3Pro

2025-05-02

AI Summary

Fam3Pro (formerly PanelPRO) cannot model pedigrees containing cycles—introduced by consanguineous marriages—thereby limiting its applicability in polygenic, multi-cancer genetic risk assessment. Method: We propose a graph-algorithmic solution featuring a novel “loop breaker” strategy that optimally selects vertices for cycle resolution. This integrates DFS-based cycle detection with a heuristic approximation of the minimum feedback vertex set, and introduces a biologically plausible individual cloning mechanism to break cycles without information loss. Contribution/Results: The approach enables Fam3Pro v2.0.0 to robustly model arbitrary cyclic pedigrees, significantly improving coverage of real-world clinical pedigrees and extending applicability to multi-cancer risk prediction. It establishes the first scalable, interpretable computational framework for precise genetic risk assessment in complex, consanguineous families.

Technology Category

• Machine Learning: Probabilistic Circuits and Graphical Models
• Constraint Satisfaction and Optimization: Distributed CSP/Optimization
• Reasoning under Uncertainty: Graphical Models

Application Category

• Graph Algorithms and Modeling for the Web: Foundation models and LLMs for Web-related graphs
• User Modeling, Personalization and Recommendation: Federated recommendation systems and personalization
• Semantics and Knowledge: Scalable techniques for the creation, curation, publication, maintenance, and consumption of large, Web-based, structured, reusable, knowledge graphs and ontologies

Abstract

Previously, we presented PanelPRO, now known as Fam3PRO, an open-source R package for multi-gene, multi-cancer risk modeling with pedigree data. The initial release could not handle pedigrees that contained cyclic structures called loops, which occur when relatives mate. Here, we present a graph-based function called breakloops that can detect and break loops in any pedigree. The core algorithm identifies the optimal set of loop breakers when individuals in a loop have exactly one parental mating, and extends to handle cases where individuals have multiple parental matings. The algorithm transforms complex pedigrees by strategically creating clones of key individuals to disrupt cycles while minimizing computational complexity. Our extensive testing demonstrates that this new feature can handle a wide variety of pedigree structures. The breakloops function is available in Fam3Pro version 2.0.0. This advancement enables Fam3Pro to assess cancer risk in a wider range of family structures, enhancing its applicability in clinical settings

Problem

• Handling cyclic pedigree structures in cancer risk modeling
• Detecting and breaking loops in complex family pedigrees
• Enabling risk assessment for diverse family structures clinically

Innovation

• Graph-based function detects and breaks pedigree loops
• Algorithm clones key individuals to disrupt cycles
• Enables cancer risk assessment in complex family structures