Bordeaux Serpents

SurvivalLadder is an open-source screening tool — ten Galaxy tools, a Snakemake pipeline, and a Shiny app, all calling one identical R analysis core — that tests a user-defined geneset, a directional _UP/_DOWN signature, or a single gene against clinical outcome across 33 TCGA projects and 21 published immunotherapy cohorts, or against any expression matrix the user supplies. Each signature is scored per sample (ssGSEA, GSVA, PLAGE, z-score or raw expression) and taken through confounder-adjusted regression: a Cox model for the five survival endpoints (OS, PFI, DSS, DFI, and PFS in the immunotherapy trials), and a logistic model reporting odds ratios for RECIST response. It then closes the loop, running differential expression between the two arms the survival model itself separated and screening the resulting signature against cell-line drug sensitivity. What makes it useful for real research questions is not a longer feature list than the established portals — cBioPortal and TIMER3 are strong, and TIMER3 in particular already scores signatures, adjusts for tumour purity, and fits Cox models. It is the shape of the answer. The portals return one query, one split, one model, one number, and give the researcher no way to see how much of that number was manufactured by those choices. SurvivalLadder refuses to collapse either axis: a score is cut at a ladder of percentiles rather than one arbitrary median or quartile, so an effect is read as a trend across the tails and a result that exists only at one lucky split is exposed as such; and each effect is refitted up a ladder of nested adjustment models — unadjusted, plus tumour purity, plus proliferation, plus both — reported side by side, so that the movement between the rungs is the finding. This is what a single adjusted hazard ratio structurally cannot show: that two confounders may act on the same signature in opposite directions, one masking the effect while the other inflates it, a structure any one adjusted number silently averages away. Around this sit three further things the portals do not attempt — screening many signatures in one run with multiple-testing correction across them, where a portal answers one query at a time and corrects for nothing; treating cell proliferation as an adjustable confounder, which neither competitor offers; and keeping prognosis and benefit-from-treatment strictly apart, since a signature can be strongly prognostic and useless for predicting who responds. And because every run emits a reproducibility manifest — pinned package versions, the random seed, and a SHA-256 of every input file — a result can be re-derived years later, which is precisely what a portal whose methods live in a backend that can change without notice cannot promise. The tool runs locally today, from a clean checkout, which is what makes it defensible. The next step is to make it broadly usable: publishing the ten wrappers to the Galaxy ToolShed and registering the Shiny app as a Galaxy Interactive Tool, so that a researcher with no command line gets the same point-and-click access the existing portals offer — but backed by versioned, inspectable, reproducible code rather than a hidden backend. The ambition is not to replace the portals, but to give the field an exploratory screen whose answers survive being asked twice.