Research report
A research report is the sourced material a domain
dossier is synthesized from — generated on a plan and a cadence, one topic per file.
A report carries no confidence tags. Its bracketed markers say who might have
an incentive to shade a line; none of them says anyone checked it. To reach a score, a line has
to be drafted onto a candidate as unverified and pass the Verifier or the
Corroborator, like everything else.
Section user-groups · Version 2026-09-26 · Cadence annual · Evidence class mixed · Sources 13 · Supersedes none
Domain: ctdna-mrd-assay-validation · Scope: Per the manifest scope note (idea-003 claims 30, 59, 61). eCFR text of 21 CFR (Title 21 of the Code of Federal Regulations) 610.40 and 630.3 via the regulation connector and the eCFR versioner API; PubMed via the literature connector at abstract depth for native cfDNA (cell-free DNA) concentration and clonal-hematopoiesis (CH) variant background in healthy people; supplier web pages for US normal human plasma, limited to what each supplier publishes. Excludes supplier quotes not published online, fda.gov guidance documents, paywalled full text, and supplier pages that render only in a browser (BioIVT, Golden West plasma listings).
Sourcing: The testing obligation rests on two eCFR sections; supplier facts rest on five manufacturer pages, only one of which posts prices; the cfDNA and CH background rests on six PubMed abstracts, none of which studied a commercial plasma pool.
21 CFR 610.40 requires an establishment collecting blood or blood components "for use in manufacturing a product, including donations intended as a component of, or used to manufacture, a medical device" to test each donation for HIV, HBV and HCV, and names HTLV, syphilis, West Nile virus and Chagas disease as the next tier [1][2]. The same section exempts device-component donations from HTLV testing only, unless the final device contains viable leukocytes, and exempts research samples not used in manufacturing a product [1]. In healthy people, most somatic variants found in plasma cfDNA are consistent with clonal hematopoiesis, driven mainly by DNMT3A and TET2 [8][9]. No supplier page read for this report states a cfDNA concentration, a CH screen, or collection in a cfDNA-stabilising tube for its catalogue plasma.
_Baseline (v1). No prior version; this establishes the starting point for future diffs._
[1] 21 CFR 610.40 Test requirements — eCFR, Office of the Federal Register (issue 2026-09-22; accessed 2026-09-26). 21 CFR 610.40 — https://www.ecfr.gov/current/title-21/section-610.40 [federal-registry] [2] 21 CFR 630.3 Definitions — eCFR, Office of the Federal Register (issue 2026-09-22; accessed 2026-09-26). 21 CFR 630.3 — https://www.ecfr.gov/current/title-21/section-630.3 [federal-registry] [3] Pooled Human Plasma (Blood Derived) — Innovative Research (published 2020-02-28 per the storefront product record; accessed 2026-09-26). catalog no. IPLAWBK2E1000ML — https://www.innov-research.com/products/pooled-human-plasma-blood-derived [manufacturer] [4] Pooled Human Plasma Apheresis Derived — Innovative Research (publication date not shown on the page; accessed 2026-09-26). catalog no. IPLAK2E1000ML — https://www.innov-research.com/products/pooled-human-plasma [manufacturer] [5] Human Serum, Human Plasma — SeraCare, LGC Diagnostics & Genomics (undated; accessed 2026-09-26). [no-identifier] an undated corporate product-family page with no catalogue number shown and no registrar behind it — https://www.seracare.com/Plasma---Serum-Diluents---Derivatives-Human-Plasma---Serum/ [manufacturer] [6] Grifols Bio Supplies home page — Grifols Bio Supplies Inc. (undated; accessed 2026-09-26). [no-identifier] an undated corporate landing page that no registrar numbers — https://www.biosuppliesproducts.com/en/home [manufacturer] [7] Where to Look for cfDNA: Implications for Liquid Biopsy Approaches — Discovery Life Sciences (published 2026-06-29; accessed 2026-09-26). [no-identifier] a corporate blog post that no registrar numbers — https://dls.com/blog/where-to-look-for-cfdna-implications-for-liquid-biopsy-approaches/ [manufacturer] [8] High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants — Nature Medicine (published 2019-12, day not given in the PubMed record; accessed 2026-09-26). PMID (PubMed identifier) 31768066 — https://pubmed.ncbi.nlm.nih.gov/31768066/ [peer-reviewed] [9] Biological background of the genomic variations of cf-DNA in healthy individuals — Annals of Oncology (published 2019-03-01; accessed 2026-09-26). PMID 30475948 — https://pubmed.ncbi.nlm.nih.gov/30475948/ [peer-reviewed] [10] Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults — Nature Communications (published 2016-08-22; accessed 2026-09-26). PMID 27546487 — https://pubmed.ncbi.nlm.nih.gov/27546487/ [peer-reviewed] [11] Clonal hematopoiesis landscape in frequent blood donors — Blood (published 2025-05-22; accessed 2026-09-26). PMID 40067117 — https://pubmed.ncbi.nlm.nih.gov/40067117/ [peer-reviewed] [12] Analysis of a cell-free DNA-based cancer screening cohort links fragmentomic profiles, nuclease levels, and plasma DNA concentrations — Genome Research (published 2025-01-22; accessed 2026-09-26). PMID 39603706 — https://pubmed.ncbi.nlm.nih.gov/39603706/ [peer-reviewed] [13] The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer — Cancer Discovery (published 2023-10-05; accessed 2026-09-26). PMID 37565753 — https://pubmed.ncbi.nlm.nih.gov/37565753/ [peer-reviewed]
Well established: Only one line rests on two sources: that the device-component exemption covers HTLV [1][2]. It is the same regulator in two sections, so it is not two independent sources in the full sense. The CH-dominance line in section 1 draws on two unaffiliated cohorts [8][9].
Thin: Every supplier line is [single-source · manufacturer] and reports that supplier's own page only [3]–[7]. The concentration range [12] and the leukocyte fraction [13] are each [single-source]. The literature was read at abstract depth only. Methods, VAF thresholds and per-gene frequencies in [8]–[11] were not read, so no per-variant CH frequency at a stated VAF is reported here.
Rescoped from class 3: None in this report. Claim 59 (single-supplier concentration) is not a question about what a person would do. It was treated as a question about what suppliers publish, and no supplier-share data were found.
Out of scope: BioIVT pages (bioivt.com/human-plasma, /normal-human-plasma) returned HTTP 200, but the body was script-rendered with no readable text. They were not retrieved, and a search-result summary of BioIVT's donor panel was not used. Golden West Diagnostics' human-donor listing showed no plasma products when fetched. The Fisher Scientific plasma category returned HTTP 503. Also out of scope: quotes that must be requested (every supplier except Innovative Research), fda.gov guidance on pooled NAT, and full text of Federal Register 2015-12228.
Not searched vs. not found: Not found: any supplier page stating cfDNA concentration, CH or somatic-variant screening, a donor count per standard pool, or catalogue plasma collected in Streck Cell-Free DNA BCT. Not found: any PubMed study of CH background in a commercial pooled plasma lot. Not searched: per-donation infectious-disease testing prices (claim 61's cost element), non-US suppliers, and MT Group, iSpecimen and Sanguine beyond a search-result mention.
[inference] The (c)(3) samples exemption excludes material used "in the manufacture of a product" [1]. Plasma sold for research use may therefore not carry the testing status that a reference material sold as a product would need. Whether a ctDNA (circulating tumour DNA) reference material is a "medical device" under (c)(2) is a regulatory reading that no source here settles.
[inference] If cfDNA in a pool comes mostly from leukocytes [13] and most healthy adults carry CH clones detectable below 0.02 VAF [10], each donor's clones will be diluted by pooling but not removed. The resulting background at 0.001–0.01% VAF has not been measured in any source found.
[inference] Per-litre list price for K2 EDTA at Innovative Research is about $1,394 blood-derived versus $726 apheresis [3][4]. The cheaper product was collected in citrate, which matters for native cfDNA [4].
| Proposition | Evidence class | Resolvable identifier | Dossier section |
|---|---|---|---|
| 21 CFR 610.40(c)(2)(i) exempts donations used solely as a component of a medical device from HTLV testing unless the final device contains viable leukocytes | 1 registry | 21 CFR 610.40 | care-pathway |
| 21 CFR 610.40(c)(3) exempts research-use plasma samples only where not intended for manufacture of a product | 1 registry | 21 CFR 610.40 | care-pathway |
| 21 CFR 630.3(h)(1) lists HIV, HBV, HCV, HTLV, syphilis, West Nile virus, Chagas, CJD, vCJD and malaria as relevant transfusion-transmitted infections | 1 registry | 21 CFR 630.3 | care-pathway |
| In 862 healthy individuals, plasma cfDNA concentration ranged 1.61–41.01 ng/mL | 2 published | PMID 39603706 | technology |
| 60% (155/259) of cancer-free individuals had at least one nonsynonymous cfDNA mutation, mostly shared with blood cells | 2 published | PMID 30475948 | clinical-evidence |
| 81.6% of cfDNA mutations in 47 non-cancer controls had features consistent with clonal hematopoiesis | 2 published | PMID 31768066 | clinical-evidence |
| Error-corrected sequencing to 0.0003 VAF found clonal hematopoiesis in 95% of healthy 50–60-year-olds studied | 2 published | PMID 27546487 | clinical-evidence |
| Leukocytes contributed about 76% of cfDNA across 242 individuals with and without cancer | 2 published | PMID 37565753 | technology |
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