Datasets:

marin-dna
/

evals_eqtl

---
license: apache-2.0
tags:
  - biology
  - genomics
  - dna
size_categories:
  - 1K<n<10K
---

# evals_eqtl

Variant-effect-prediction benchmark of GTEx v8 fine-mapped eQTLs (49 tissues, pooled) vs tested-but-low-PIP variants, gene-matched 1:1 within consequence categories, MAF bins, and distance bins.

## Description

| | |
|---|---|
| Positives | GTEx v8 SuSiE fine-mapped variants with `max(PIP across tested tissues) > 0.9` |
| Negatives | `max(PIP) < 0.01` across all tested tissues; gene-matched 1:1 to positives |
| Source | [eQTL Catalogue r7](https://www.ebi.ac.uk/eqtl/), study `QTS000015` (GTEx v8), all 49 tissues × `ge` (gene-expression) quantification |
| Genome build | GRCh38 (Catalogue is hg38 native) |
| Variant type | SNVs only |
| Coordinates | 1-based (`pos` is 1-based; `ref` / `alt` are single bases) |

The negative pool is sourced from per-tissue **full** nominal sumstats (`*.all.tsv.gz`, ~3.5 GB per tissue), so it includes every variant tested in fine-mapping — including those that never reached a credible set. This is a structural improvement over earlier releases of this dataset (which sourced from a pre-filtered single-file release whose PIP floor at ~1e-4 capped the negative pool at ~1.3M variants); the current pool is ~10M tested variants.

## Splits

| Split | Variants (positives + matched negatives) | Chromosomes |
|---|---:|---|
| `train` | 4,612 (2,306 pos + 2,306 neg) | odd: 1, 3, …, X |
| `test`  | 3,854 (1,927 pos + 1,927 neg) | even: 2, 4, …, Y |
| **total** | **8,466 (4,233 pairs)** | |

## Columns

| Column | Type | Description |
|---|---|---|
| `chrom`, `pos`, `ref`, `alt` | str / int / str / str | Variant coordinates (1-based, GRCh38) |
| `label` | bool | `True` for high-PIP eQTL, `False` for tested-but-low-PIP matched negative |
| `subset` | str | Consequence-group label for stratified eval (`distal`, `tss_proximal`, `non_coding_transcript_exon_variant`, `3_prime_UTR_variant`, `5_prime_UTR_variant`, `missense_variant`, `synonymous_variant`, `splicing`) |
| `match_group` | int | Pos / neg pair ID (every group has 1 positive + 1 matched negative) |
| `pip` | float | Maximum PIP across the 49 tissues in which the variant was tested. For negatives this is `< 0.01` (often `0` — see Source) |
| `tissues` | str | Comma-separated list of tissues with PIP > 0.9 (empty for negatives) |
| `genes` | str | Comma-separated list of eGene Ensembl IDs the variant regulates with PIP > 0.9 (empty for negatives) |
| `biotype_classes` | str | Comma-separated `pc` / `nc` classes of the eGenes (e.g. `pc`, `nc`, `nc,pc`). Empty for negatives. Genes missing from Ensembl's biotype table default to `nc`. |
| `MAF` | float | Cohort-matched GTEx donor MAF (mean across the 49 per-tissue donor cohorts; the cohorts overlap heavily so per-tissue MAFs are very close) |
| `consequence`, `consequence_cre`, `consequence_final`, `consequence_group` | str | Ensembl VEP consequence + grouping used by the matcher |
| `distance_tss_pc`, `distance_tss_nc`, `distance_tss` | int | Distance (0-based, half-open) to nearest protein-coding / non-protein-coding TSS, plus their min |
| `tss_closest_pc_gene_id`, `tss_closest_nc_gene_id`, `tss_closest_gene_id` | str | Ensembl gene IDs at those distances |
| `distance_exon_pc`, `distance_exon_nc`, `distance_exon` | int | Same shape, for nearest exon |
| `exon_closest_pc_gene_id`, `exon_closest_nc_gene_id`, `exon_closest_gene_id` | str | Same shape |
| `distance_tss_pc_bin`, `distance_tss_nc_bin`, `distance_exon_pc_bin`, `MAF_bin` | str | Categorical bins used as exact-match keys during gene-matching |

## Per-subset retention

| Subset | n_pos in dataset_all | matched (kept) | retention |
|---|---:|---:|---:|
| `distal` | 5,333 | 3,067 | 57.5% |
| `tss_proximal` | 2,160 | 437 | 20.2% |
| `non_coding_transcript_exon_variant` | 1,290 | 318 | 24.7% |
| `5_prime_UTR_variant` | 544 | 86 | 15.8% |
| `3_prime_UTR_variant` | 535 | 223 | 41.7% |
| `splicing` | 333 | 9 | 2.7% |
| `missense_variant` | 269 | 46 | 17.1% |
| `synonymous_variant` | 230 | 47 | 20.4% |
| **total** | **10,694** | **4,233** | **39.6%** |

(Two tiny subsets — `mature_miRNA_variant` n=1, `stop_retained_variant` n=1 — fail to match and are dropped.)

Splicing has the worst retention (~3%) — splicing variants live next to a specific small set of exons, so the gene-id-based categorical match starves neg supply. The phenomenon is structural to the matching framework, not specific to eqtl.

## Matching design

Locked iter 33 from [issue #156](https://github.com/Open-Athena/bolinas-dna/issues/156), with one **round-2 tweak for eqtl** ([commit 1ad4fef7f7](https://github.com/Open-Athena/bolinas-dna/commit/1ad4fef7f7)) that closes a leak that only became detectable after switching to the richer Catalogue negative pool.

Matching is exact on every categorical key, then Euclidean-nearest on the (RobustScaler-scaled) continuous features as a within-group tie-breaker. Without replacement, k=1.

- **Continuous features**: `distance_tss_pc`, `distance_tss_nc`, `distance_exon_pc`, `distance_exon_nc`, `MAF`.
- **Categorical features**:
  - `chrom`, `consequence_final`
  - `tss_closest_pc_gene_id`, `tss_closest_nc_gene_id`, `exon_closest_pc_gene_id`, `exon_closest_nc_gene_id`
  - `distance_tss_pc_bin` (`tss_proximal` only; edges `[0, 50, 100, 200, 500, 1000]`)
  - `distance_tss_nc_bin` — **two-subset bin**:
    - `tss_proximal`: edges `[0, 50, 100, 200, 500, 1000]` (iter 33)
    - `non_coding_transcript_exon_variant`: edges `[0, 200, 1000, 5000]` (round-2 widen-and-extend; ncRNA-exon variants span a much broader dist-to-nc-TSS range than tss_proximal, q=0.05 ≈ 9 bp, q=0.95 ≈ 8.7 kb)
  - `distance_exon_pc_bin` (`splicing` only; edges `[0, 5, 20, 30]`)
  - `MAF_bin` — **per-subset tiered scheme with local-quantile bins for distal** (`MAF_TIERED_LOG8_DISTAL_ONLY`):
    - `distal`: **local equal-width log10(MAF) bins** computed per categorical match group, 8 buckets, joint pos+neg reference. Closes the asymptotic distal MAF residual leak that fixed global edges leave.
    - `tss_proximal`, `non_coding_transcript_exon_variant`: 20-bin (`MAF_BIN_EDGES_20`)
    - `3_prime_UTR_variant`, `5_prime_UTR_variant`, `missense_variant`: 10-bin (`MAF_BIN_EDGES_10`)
    - `synonymous_variant`, `splicing`, …: 5-bin (`MAF_BIN_EDGES_5`)

`tissues` / `genes` / `biotype_classes` are passthrough columns, **not** in the match key.

**Matched-feature diagnostic** (round 2-1): **one Bonferroni-significant leak closed** vs. the round-2 kickoff (ncRNA × distance_tss_nc, PA 0.401 → 0.483). Two small-effect residual leaks in `distal` (PA=0.470 on `distance_tss_pc`, PA=0.536 on `MAF`) left as below the "don't bother" effect-size threshold.

<details>
<summary>Full per-(subset, feature) PA / p-value table (round 2-1)</summary>

Format: PA / p. `**` = Bonferroni-significant at α = 0.05 / 40 = 1.25e-3 (8 subsets × 5 matched features). `*` = p < 0.05. PA close to 0.5 = well-matched.

| subset | n | distance_tss_pc | distance_tss_nc | distance_exon_pc | distance_exon_nc | MAF |
|---|---:|---|---|---|---|---|
| `3_prime_UTR_variant` | 223 | 0.502 / 1.0 | 0.457 / 0.23 | 0.487 / 0.24 | 0.439 / 0.03 \* | 0.547 / 0.18 |
| `5_prime_UTR_variant` | 86 | 0.360 / 0.013 \* | 0.395 / 0.066 | 0.494 / 1.0 | 0.442 / 0.25 | 0.535 / 0.59 |
| `distal` | 3,067 | **0.470 / 7.8e-4 \*\*** | 0.494 / 0.49 | 0.476 / 0.009 \* | 0.494 / 0.49 | **0.536 / 8.2e-5 \*\*** |
| `missense_variant` | 46 | 0.413 / 0.30 | 0.435 / 0.46 | 0.511 / 1.0 | 0.489 / 1.0 | 0.630 / 0.10 |
| `non_coding_transcript_exon_variant` | 318 | 0.544 / 0.13 | 0.483 / 0.57 | 0.487 / 0.69 | 0.502 / 1.0 | 0.553 / 0.064 |
| `splicing` | 9 | 0.556 / 1.0 | 0.444 / 1.0 | 0.667 / 0.51 | 0.611 / 0.73 | 0.333 / 0.51 |
| `synonymous_variant` | 47 | 0.404 / 0.24 | 0.340 / 0.040 \* | n/a | 0.489 / 1.0 | 0.574 / 0.38 |
| `tss_proximal` | 437 | 0.455 / 0.069 | 0.460 / 0.10 | 0.479 / 0.42 | 0.481 / 0.44 | 0.538 / 0.13 |

</details>

## Source

Per-tissue files from the [eQTL Catalogue r7 stable release](https://www.ebi.ac.uk/eqtl/) FTP at `ftp://ftp.ebi.ac.uk/pub/databases/spot/eQTL/`, study `QTS000015` (GTEx v8), all 49 GTEx tissue datasets × `ge` quantification. Two files per dataset:

- `*.credible_sets.tsv.gz` — SuSiE credible-set members + PIP.
- `*.all.tsv.gz` — full nominal sumstats (every tested variant × gene). Provides the "tested but never reached a credible set" negative pool.

Per-variant `pip` is `max` across the (variant, tissue, gene) rows that mention it. Variants present in `all.tsv.gz` but absent from every credible set are 0-filled (sentinel: "tested, no signal"). Per-variant MAF is the mean across the rows.

## Provenance

Built by the [`bolinas-dna`](https://github.com/Open-Athena/bolinas-dna) eval pipeline at commit [`1ad4fef7f7`](https://github.com/Open-Athena/bolinas-dna/tree/1ad4fef7f7/snakemake/evals). PR thread: [#167](https://github.com/Open-Athena/bolinas-dna/pull/167).

- Curation pipeline: [`snakemake/evals/`](https://github.com/Open-Athena/bolinas-dna/tree/1ad4fef7f7/snakemake/evals)
- Catalogue parser: [`src/bolinas/evals/catalogue_parser.py`](https://github.com/Open-Athena/bolinas-dna/blob/1ad4fef7f7/src/bolinas/evals/catalogue_parser.py)
- Labeling cascade: [`src/bolinas/evals/labeling.py`](https://github.com/Open-Athena/bolinas-dna/blob/1ad4fef7f7/src/bolinas/evals/labeling.py)
- Matching algorithm: [`src/bolinas/evals/matching.py`](https://github.com/Open-Athena/bolinas-dna/blob/1ad4fef7f7/src/bolinas/evals/matching.py)
- Design discussion: [issue #156](https://github.com/Open-Athena/bolinas-dna/issues/156) (iter 33 + round 2 ncRNA bin); eqtl-specific motivation: [issue #165](https://github.com/Open-Athena/bolinas-dna/issues/165)