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+---
+name: end-to-end-study
+description: Data-first reproducible research workflow. Given a topic (or none), find the best underutilised public dataset, identify the low-hanging-fruit claim inside it, target the highest-acceptance-probability journal, fetch that journal's author instructions, design method under standard-of-rigor checklist, analyse, write reviewer-and-reader-oriented LaTeX + BibTeX manuscript matching the target-journal style, and ship to a private GitHub repo with CI-built tagged releases bundling PDF + .tex. Use when the user says "end-to-end paper", "take topic to publication", "find a paper in this dataset", "what's publishable here", or asks for a full research pipeline from idea to a tagged release. Good fit for computational-biology, bioinformatics, and clinical-genomics studies on public datasets (TCGA, BeatAML, GEO, GDC, UCSC Xena, cBioPortal).
+---
+
+# end-to-end-study
+
+Chain: **best data for novelty** -> **low-hanging fruit** -> **most-likely paper (venue + story)** -> **author instructions** -> **method under rigor checklist** -> **reader/reviewer-oriented writing** -> **reviewer cycle** -> **private repo + tagged release**.
+
+Seven phases. Each phase links to a dedicated reference file.
+
+## Phase 0 - Orientation (30 s)
+
+Confirm with the user: domain (oncology? immunology? neurology?), topic vagueness (is a topic given, or should the skill scan datasets first?), claim type preference (method / translational finding / benchmark). Decline phases outside scope (wet-lab validation, actual journal submission).
+
+## Phase 1 - Best data for novelty (data-first scan)
+
+Novelty usually lives in **under-mined assets of recently released large cohorts**, not in re-analyses of classic datasets. Scan for (1) recent large-cohort releases with a secondary modality that has not been systematically exploited, (2) paired-modality data where one modality is under-used, (3) public drug-response or perturbation screens paired with rich clinical metadata.
+
+See [references/data-first-novelty.md](references/data-first-novelty.md) for the scan heuristics, a catalog of currently-underutilised public datasets, and worked example (BeatAML ex-vivo drug-sensitivity table in Tyner 2018 supplementary).
+
+**Exit criterion**: a primary dataset is named, its under-mined asset is identified, and a short list of 2-3 candidate claims is drafted.
+
+## Phase 2 - Low-hanging fruit selection
+
+Within the chosen dataset, pick the claim with the best effort-to-impact ratio. See [references/low-hanging-fruit.md](references/low-hanging-fruit.md) for the selection matrix (combination-gap claim vs scale-gap vs rigor-gap vs orthogonal-outcome claim), with expected-IF mapping for each type.
+
+Use WebSearch + bioRxiv / PubMed MCP to verify the chosen claim is actually un-done. Heuristics for keyword laddering and gap verification are in [references/novelty-search.md](references/novelty-search.md).
+
+**Exit criterion**: one sentence of the form "No prior work does X in Y; this paper shows Z (effect-size guess)", validated against literature.
+
+## Phase 3 - Target journal + author instructions
+
+Pick the journal where this specific claim has the highest acceptance probability, not the highest IF in absolute terms. See [references/journal-targets.md](references/journal-targets.md) for the tiered catalog with acceptance-probability heuristics. Then immediately **fetch the target journal's author instructions** with WebFetch and distil them into the project-local `manuscript/JOURNAL.md`.
+
+See [references/author-instructions.md](references/author-instructions.md) for the extraction checklist (word limits, figure count, reference style, reporting-guideline requirements, data-availability policy, preprint policy) and canonical author-instructions URLs for Nature Commun, Leukemia, Genome Medicine, Cell Reports Medicine, Blood Cancer Journal, Briefings in Bioinformatics.
+
+Copy the LaTeX skeleton from `assets/latex/` and edit the bibliography style, section order, and figure-count cap to match the target journal.
+
+**Exit criterion**: journal named, author-instructions distilled into `manuscript/JOURNAL.md`, LaTeX template adjusted, tex compiles with placeholder title.
+
+## Phase 4 - Project setup + preregistration + method design
+
+Scaffold with `scripts/init_project.py <project-dir>` (creates `data/raw`, `data/processed`, `data/results`, `analysis/`, `manuscript/`, `figures/`, `docs/`, `.github/workflows/`, `.gitignore`, `LICENSE`, `README.md`, `pyproject.toml`, and a `docs/prereg.md` stub). The script refuses to overwrite existing critical files without `--force` (which takes timestamped backups). Install Python dependencies with `uv add`.
+
+**Commit `docs/prereg.md` before touching any outcome-related analysis.** The preregistration commit is the single most important integrity artefact; skipping it turns any later outcome pivot into HARKing. See [references/preregistration-and-integrity.md](references/preregistration-and-integrity.md) for the required contents and the rules that make the orthogonal-outcome pivot legitimate.
+
+Design the method **before** looking at results. See [references/method-design.md](references/method-design.md) for the rigor checklist (leakage-free feature selection, stability / parameter sweep, permutation null, proportional-hazards tests, nested C-index, calibration + DCA / NRI if clinical, bootstrap CIs, multiple-testing correction). The target journal's author instructions drive the checklist priority - clinical journals weight calibration + DCA; methods journals weight stability + null models.
+
+Common open-dataset URLs and download recipes live in [references/open-datasets.md](references/open-datasets.md); access codes (Open / Gated / Mixed) in [references/data-first-novelty.md](references/data-first-novelty.md) tell you which raw artefacts can be redistributed in the final release.
+
+**Exit criterion**: `docs/prereg.md` committed, data downloaded, analysis scripts stubbed, `uv run python analysis/01_prepare_data.py` succeeds.
+
+## Phase 5 - Analysis, figures, manuscript with journal-matched writing
+
+Iterate analysis -> figures -> LaTeX. Structural conventions in [references/manuscript-structure.md](references/manuscript-structure.md).
+
+Writing style is journal-specific. See [references/reader-reviewer-writing.md](references/reader-reviewer-writing.md) for the explicit reader and reviewer profiles of Nature Commun, Leukemia, Genome Medicine, BCJ, Cell Reports Medicine, Briefings in Bioinformatics, and the abstract-headline + discussion-caveat patterns that work at each. A Leukemia reader expects the clinical hook in the first sentence; a Briefings reader expects the methods gap; a Nature Commun reader expects the broad-interest statement followed by the quantitative headline.
+
+Compile with `cd manuscript && make`.
+
+**Exit criterion**: full PDF compiles; abstract-headline, discussion-caveats, and data/code availability sections match the style targeted at `manuscript/JOURNAL.md`.
+
+## Phase 6 - Reviewer cycle
+
+Dispatch four adversarial reviewers in parallel (methods, clinical, biostatistics, target-journal editor). Iterate until unanimous accept. Pattern and prompt templates in [references/reviewer-cycle.md](references/reviewer-cycle.md). The target-journal editor reviewer is instantiated with that journal's historical concerns - loaded from the author-instructions file produced in Phase 3.
+
+## Phase 7 - Repo and tagged release
+
+Create private GitHub repo, wire CI, push tag, release PDF + .tex + source bundle. Exact commands + CI workflow template in [references/release-workflow.md](references/release-workflow.md). CI template at `assets/github/release.yml`; LaTeX helpers at `assets/latex/Makefile` + `latexmkrc`. Use `scripts/new_release.sh` for a preflight-checked release (rejects dirty git tree, missing `gh` auth, stale placeholder DOIs, absent figures).
+
+Release naming: `v<MAJOR>.<MINOR>.<PATCH>` where MAJOR bumps reflect scientific pivots, MINOR bumps reflect reviewer-round revisions, PATCH bumps reflect typos and terminology.
+
+## Phase 8 - Submission support (optional but expected at IF 10+)
+
+The skill's release workflow ends at a tagged preprint-ready PDF. Actual submission happens off-skill, but the supporting artefacts are templated here:
+
+- Preprint posting (bioRxiv / medRxiv / arXiv) + Zenodo DOI minting: [references/preprint-and-dois.md](references/preprint-and-dois.md). Ship the preprint before the journal submission so the cover letter can cite it.
+- Cover letter + point-by-point rebuttal templates: [references/cover-letter-and-rebuttal.md](references/cover-letter-and-rebuttal.md). Rebuttals are the highest-leverage artefact in a revision cycle.
+- Submission-portal quirks (Editorial Manager, ScholarOne, Snapsubmit, figure-format, ORCID, supplementary material): [references/submission-portals.md](references/submission-portals.md).
+- CRediT authorship, ethics and competing-interests language: [references/credit-and-ethics.md](references/credit-and-ethics.md). Do the CRediT assignment with all authors during Phase 4 or 5; negotiating at the last minute causes submission delays.
+
+## Scripts
+
+- `scripts/init_project.py <project-dir>` - scaffold directory tree, copy LaTeX + GH Actions templates, write `.gitignore`, `LICENSE`, `README.md`, `pyproject.toml`. Run once at start of Phase 4.
+- `scripts/new_release.sh <project-dir> <version> "<title>" "<notes>"` - build PDF, stage artefacts into `/tmp`, create tagged `gh release` with PDF + .tex + source bundle. Run at Phase 7 and after every review round.
+
+## Non-goals
+
+- Wet-lab experiments, patient-level trial design, regulatory submission.
+- Actual journal submission (the skill ends at a release-tagged preprint-ready PDF matched to one target journal's style).
+- Author-name or ORCID fill-in (always prompt the user).
+
+## Pitfalls the skill's references protect against
+
+- Topic-first workflow that picks a fashionable method and shops for data -> Phase 1 is data-first precisely to avoid this.
+- Novelty hallucinated from training data -> `novelty-search.md` verifies against current literature.
+- Picking the highest-IF journal before checking acceptance probability -> `journal-targets.md` scores fit, not just IF.
+- Writing manuscript before reading author instructions -> Phase 3 fetches and distils them up front.
+- Gene-panel leakage across cohorts -> `method-design.md`.
+- Claims that collapse under a proper clinical baseline -> `reviewer-cycle.md` catches it before submission.
+- Release without GPG-signed tag fails on first push -> `release-workflow.md` uses `gh release create` (remote tag) to sidestep local signing.
@@ -0,0 +1,34 @@
+# Python
+.venv/
+__pycache__/
+*.pyc
+*.pyo
+.python-version
+
+# LaTeX build artefacts
+manuscript/*.aux
+manuscript/*.bbl
+manuscript/*.blg
+manuscript/*.fdb_latexmk
+manuscript/*.fls
+manuscript/*.log
+manuscript/*.out
+manuscript/*.synctex.gz
+manuscript/*.toc
+
+# Raw data (regenerable from documented URLs)
+data/raw/*
+!data/raw/.gitkeep
+
+# Processed artefacts (regenerable)
+data/processed/*.tsv
+data/processed/*.txt
+data/processed/*.csv
+data/results/*.npz
+
+# Large supplementary files
+*.xlsx
+!assets/**/*.xlsx
+
+# macOS
+.DS_Store
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+name: build-and-release
+
+on:
+  push:
+    tags:
+      - "v*"
+  workflow_dispatch: {}
+
+permissions:
+  contents: write
+
+jobs:
+  build:
+    runs-on: ubuntu-latest
+    outputs:
+      has_figures: ${{ steps.check_figures.outputs.has_figures }}
+    steps:
+      - name: Checkout
+        uses: actions/checkout@v4
+
+      - name: Build LaTeX
+        uses: xu-cheng/latex-action@v3
+        with:
+          root_file: main.tex
+          working_directory: manuscript
+          latexmk_use_xelatex: false
+          args: -pdf -interaction=nonstopmode -file-line-error
+
+      - name: Verify PDF produced
+        run: |
+          test -s manuscript/main.pdf || { echo "main.pdf missing or empty"; exit 1; }
+
+      - name: Lint placeholder DOIs
+        run: |
+          if grep -q "10.0000/placeholder" manuscript/references.bib; then
+            echo "references.bib still contains 10.0000/placeholder entries"
+            exit 1
+          fi
+
+      - name: Check for figures
+        id: check_figures
+        run: |
+          shopt -s nullglob
+          FIGS=(manuscript/Fig*.pdf)
+          if [ ${#FIGS[@]} -gt 0 ]; then
+            echo "has_figures=true" >> "$GITHUB_OUTPUT"
+          else
+            echo "has_figures=false" >> "$GITHUB_OUTPUT"
+          fi
+
+      - name: Stage release artefacts
+        run: |
+          SLUG="${GITHUB_REPOSITORY#*/}"
+          mkdir -p release
+          cp manuscript/main.pdf "release/${SLUG}.pdf"
+          cp manuscript/main.tex "release/${SLUG}.tex"
+          cp manuscript/references.bib release/
+          if [ -d figures ]; then cp -r figures release/figures; fi
+          tar_extra=()
+          if compgen -G "manuscript/Fig*.pdf" >/dev/null; then
+            tar_extra+=(manuscript/Fig*.pdf)
+          fi
+          if [ -f docs/prereg.md ]; then
+            tar_extra+=(docs/prereg.md)
+          fi
+          tar -czf release/source-bundle.tar.gz \
+            manuscript/main.tex manuscript/references.bib \
+            manuscript/Makefile manuscript/latexmkrc \
+            analysis README.md LICENSE .github/workflows/release.yml \
+            "${tar_extra[@]}"
+          ls -la release/
+
+      - name: Upload PDF as workflow artefact
+        uses: actions/upload-artifact@v4
+        with:
+          name: manuscript-pdf
+          path: release/*.pdf
+
+      - name: Attach artefacts to the tagged release
+        if: success() && startsWith(github.ref, 'refs/tags/v')
+        uses: softprops/action-gh-release@v2
+        with:
+          files: |
+            release/*.pdf
+            release/*.tex
+            release/references.bib
+            release/source-bundle.tar.gz
+          fail_on_unmatched_files: true
+          # Do NOT auto-generate release notes: user-supplied notes via
+          # `gh release create --notes` are the single source of truth.
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+PDF := main.pdf
+TEX := main.tex
+BIB := references.bib
+FIGS := $(wildcard Fig*.pdf)
+
+.PHONY: all clean full
+
+all: $(PDF)
+
+$(PDF): $(TEX) $(BIB) $(FIGS)
+	latexmk -pdf $(TEX)
+
+full:
+	latexmk -C
+	pdflatex -interaction=nonstopmode $(TEX)
+	bibtex main
+	pdflatex -interaction=nonstopmode $(TEX)
+	pdflatex -interaction=nonstopmode $(TEX)
+
+clean:
+	latexmk -C
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+$pdf_mode = 1;
+$bibtex_use = 2;
+$pdflatex = 'pdflatex -interaction=nonstopmode -file-line-error %O %S';
+@default_files = ('main.tex');