{
  "abstract": "Background: Published colorectal cancer (CRC) polygenic risk scores (PRS) may demonstrate similar population-level predictive performance but often assign substantially different risk classifications to the same individuals. Such discordance presents challenges for clinical implementation and return of results (RoR). Methods: We developed a stable PRS for CRC (stPRS-CRC) by integrating 28 published PRS using PRSmix in the All of Us (AoU) development cohort (n=321,703). Performance was evaluated in a held-out AoU validation cohort (n=80,423) and independently validated in the Genomic Health Initiative (GHI) (n=17,545). CRC associations were assessed using logistic regression, comparing individuals in the highest PRS decile with the remaining 90%. Individual-level concordance in high-risk classification was evaluated using mean Jaccard indices. Results: Published CRC PRS showed substantial discordance in individual-level high-risk classification despite generally consistent associations with CRC. stPRS-CRC integrated information from multiple published PRS and demonstrated CRC associations comparable to PGS003852, the strongest-performing individual PRS. The odds ratios for stPRS-CRC were 1.94 (95% CI, 1.79-2.11) in AoU development, 2.08 (1.76-2.45) in AoU validation, and 2.08 (1.55-2.79) in GHI. Mean Jaccard indices using stPRS-CRC versus PGS003852 as anchors, each compared with the same 27 published PRS, were 0.29 versus 0.20, 0.43 versus 0.25, and 0.27 versus 0.19, respectively (all P<0.001). Conclusions: Integrating multiple published CRC PRS significantly improved individual-level concordance in high-risk classification while maintaining population-level predictive performance. stPRS-CRC may provide a more consistent framework for clinical genetic risk assessment and ROR.",
  "abstract_shown": true,
  "affiliations": [
    "Endeavor Health"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "H. Tran"
    },
    {
      "name": "A. J. Mulford"
    },
    {
      "name": "J. Wei"
    },
    {
      "name": "Z. Shi"
    },
    {
      "name": "A. Ashworth"
    },
    {
      "name": "S. L. Zheng"
    },
    {
      "name": "B. T. Helfand"
    },
    {
      "name": "P. J. Hulick"
    },
    {
      "name": "A. DePersia"
    },
    {
      "name": "G. Suh"
    },
    {
      "name": "B. Jones"
    },
    {
      "name": "A. R. Sanders"
    },
    {
      "affs": [
        0
      ],
      "name": "J. Xu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/aejagfrs2kbaf.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.06.26367439",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.11.06.26367439v1.full",
  "id": "aejagfrs2kbaf",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.11.06.26367439v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "genetic and genomic medicine"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.11.06.26367439v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/aejagfrs2kbaf.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T00:22:41Z",
      "native_id": "10.64898/2026.11.06.26367439",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.11.06.26367439v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Improving Consistency in Colorectal Cancer Genetic Risk Assessment and Return of Results Through an Integrated Polygenic Risk Score",
  "title_text": "Improving Consistency in Colorectal Cancer Genetic Risk Assessment and Return of Results Through an Integrated Polygenic Risk Score",
  "type": "preprint",
  "updated_at": "2026-11-10T00:22:41Z",
  "url": "https://research.draconitic.com/paper/aejagfrs2kbaf",
  "venue": "medRxiv",
  "versions": []
}