Hypothesis

We hypothesize that integrating longitudinal multi‑omics (genomics, proteomics, metabolomics) with an AI‑driven adaptive therapy algorithm yields a clinically meaningful improvement in progression‑free survival and quality‑adjusted life years compared with standard‑of‑care guided by single‑omics (ctDNA) monitoring, provided the incremental cost per patient remains below $150,000.

Mechanistic rationale

Single‑omics ctDNA captures genomic alterations but misses non‑genomic resistance mechanisms such as kinase‑signaling rewiring, metabolic plasticity, and post‑translational modifications that emerge under treatment pressuremulti‑omics integration study. Multi‑omics liquid biopsies detect these layers, enabling the identification of actionable bypass nodes (e.g., MAPK re‑activation via proteomic phosphorylation, NADPH‑dependent redox shifts via metabolomics)proteogenomic liquid biopsies study. An AI model trained on paired multi‑omics time series can predict the emergent signaling state and suggest rational drug combinations before clinical progressionMolecular Twin platform study. Early intervention at the molecular‑ecosystem level therefore prevents the outgrowth of resistant clones, translating into longer PFS and better QALY.

Testable predictions

• In a prospective randomized trial, patients receiving multi‑omics‑guided adaptive therapy will have a median PFS increase of ≥3 months over the ctDNA‑only arm.
• The same cohort will show a ≥0.08 gain in QALYs at 24 months.
• The incremental cost‑effectiveness ratio (ICER) will be ≤$100,000 per QALY gained; if the ICER exceeds $150,000, the hypothesis is falsified.
• Exploratory: Proteogenomic signatures of pathway re‑activation will diminish ≥50 % after the first adaptive switch in the multi‑omics arm but remain unchanged in the control arm.

Falsifiability criteria

The hypothesis is falsified if any of the following occur:

1. No statistically significant difference in PFS or QALY between arms (p > 0.05).
2. The ICER exceeds $150,000 per QALY gained.
3. Multi‑omics profiling fails to detect actionable non‑genomic changes in ≥80 % of cases where ctDNA shows stability but radiographic progression occurs.

By tying measurable clinical endpoints to a mechanistic chain—multi‑omics detection → AI prediction → pre‑emptive combination therapy → clonal suppression—this hypothesis moves beyond association to a causal, cost‑aware claim that can be tested in a single, well‑designed trial.