feeding-rcts-lipids-healthy

Orientation — feeding-rcts-lipids-healthy (searcher 4)

Slice: controlled-feeding / metabolic-ward studies and egg-feeding RCTs in general or healthy adults measuring the average response of blood lipids (LDL-C, ApoB, HDL-C, LDL:HDL or TC:HDL ratio, lipoprotein particle size/number) to dietary cholesterol / egg intake. Endpoint = surrogate throughout. This is the core mean dose-response of the lipid pathway — the mechanistic backbone slices 1/2’s cohort associations are usually assumed to run through.

Sources by topic (best-first within each)

Foundational metabolic-ward dose-response (the Keys/Hegsted/Mattson tradition — establishes that cholesterol raises cholesterol, with a concave/diminishing-returns shape)

1. Keys, Anderson & Grande 1965 Metabolism — foundational metabolic-ward dietary-cholesterol dose-response equation — the founding √-dose equation, multi-institution pooled data.
2. McNamara et al. 1987 JCI — heterogeneity of cholesterol homeostasis and compensatory absorption-synthesis — direct mechanism (absorption/synthesis compensation) behind the diminishing returns; 301 citations, heavily used.
3. Mattson, Erickson & Kligman 1972 AJCN — Procter & Gamble metabolic-ward dietary-cholesterol dose-response — clean formula-diet slope estimate; non-egg-industry COI (P&G).
4. Quintao, Grundy & Ahrens 1971 JLR — dietary cholesterol and regulation of total body cholesterol pool — earliest whole-body-pool evidence for the same homeostatic buffering; citation count unavailable.

Controlled egg/cholesterol-dose feeding trials with a clear LDL/ApoB rise (anti-egg / mechanism-confirming) 5. Sacks 1984 Lancet — egg feeding raises LDL and ApoB in free-living lacto-vegetarians — the most load-bearing “one egg/day raises LDL+ApoB” primary; near-free-living design (weaker control than a metabolic ward, stronger ecological validity). 6. Ginsberg 1994 Arterioscler Thromb — dose-response of dietary cholesterol-egg feeding on lipoproteins in healthy young men — controlled dose-response, but effect conditional on background fat quality (P:S ratio). 7. Ginsberg 1995 ATVB — dietary cholesterol-egg dose-response raises both LDL and HDL in healthy young women — companion trial in women; parallel LDL+HDL rise, so LDL:HDL ratio moves less than LDL alone.

Whole-egg RCTs showing HDL-up / LDL-neutral or particle-quality-improving responses (pro-egg / null; mostly Fernandez-lab, egg-industry-funded) 8. DiMarco et al. 2017 Lipids — dose-escalation egg RCT- HDL up, LDL unchanged, TMAO unchanged in healthy adults — dose-escalation (0-3 eggs/day) in one trial, cleanest dose-response on the pro-egg side; TMAO arm cross-relevant to slice 7. 9. Mutungi et al. 2008 J Nutr — egg-derived cholesterol raises HDL in carbohydrate-restricted overweight men — disclosed Egg Nutrition Center funding; HDL up, LDL:HDL maintained. 10. Greene et al. 2006 Nutrition & Metabolism — egg feeding shifts LDL-HDL particle characteristics and raises plasma carotenoids in an elderly population — the only source in this slice using NMR particle size/number (not just LDL-C mass) as the surrogate; disclosed AEB/ENC funding; elderly population.

Null / comparator-dependent trials (egg vs. active comparator, not vs. neutral control) 11. Kim & Campbell 2018 Nutrients — dietary cholesterol from whole eggs is poorly absorbed, no acute rise in plasma cholesterol — acute kinetic mechanism (poor absorption) behind the null; not a chronic trial. 12. Vorster et al. 1992 AJCN — egg intake does not change plasma lipoprotein or coagulation profiles (South African trial) — independent non-US, non-Fernandez-lab population; adds a second CVD-relevant surrogate (coagulation factors). 13. Njike et al. 2010 Nutrition Journal — daily egg consumption in hyperlipidemic adults, lipids and endothelial function — CDC-funded (no egg-industry COI); shows the comparator (egg substitute vs. whole egg vs. sausage-cheese) drives the sign. 14. Katz et al. 2005 Int J Cardiol — egg vs. oatmeal crossover trial- endothelial function and lipids unaffected by eggs — CDC-funded; oatmeal (not egg) produced the LDL-lowering effect — same substitution-dependence lesson as #13, independent trial/cohort.

search_scope

Started from the five named discovery hubs (Clarke 1997 BMJ metabolic-ward meta-analysis; Weggemans 2001 AJCN dietary-cholesterol meta-analysis; Berger 2015 AJCN systematic review; the Vincent 2019 AJCN meta-regression; Rouhani 2018 JACN egg-and-lipids meta-analysis) to map the debate and harvest reference lists. Cross-checked/verified each candidate primary’s metadata (authors, venue, year, DOI) via PubMed, Crossref API, and the Semantic Scholar Graph API (for citation counts, as of 2026-07-23). Targeted searches per named anchor in the brief (Sacks 1984, Ginsberg 1994/1995, Mutungi 2008, DiMarco 2017, Blesso 2013, Njike 2010, Kim & Campbell 2018) plus generic queries for the “Keys/Hegsted/Weggemans metabolic-ward tradition” to surface Keys 1965, Mattson 1972, McNamara 1987, and Quintao 1971. Did not exhaustively snowball citation chains beyond what the hubs and named anchors covered, given the read/write budget — see gaps below.

exclusions

1. Blesso 2013 (“Whole egg consumption improves lipoprotein profiles… in individuals with metabolic syndrome,” Metabolism) — named as an anchor in the brief but its population is metabolic-syndrome-defined; per the 4/6 boundary rule this belongs to slice 6 (egg RCTs in diabetic/prediabetic/metabolic-syndrome populations). Not minted; recorded here so slice 6 can pick it up and so nobody double-mints it.
2. Clarke 1997 BMJ, Weggemans 2001 AJCN, Berger 2015 AJCN, Vincent 2019 AJCN (meta-regression), Rouhani 2018 JACN — all discovery-hub meta-analyses/systematic reviews per the brief; mined for reference lists and background dose-response numbers, never minted as their own source.
3. Flynn et al. 1979 AJCN (“Effect of dietary egg on human serum cholesterol and triglycerides,” 116 men, no significant cholesterol rise) — a genuine, independent null-effect classic, but redundant with the null signal already carried by Vorster 1992 and Katz 2005; dropped for budget, not for quality — a legitimate top-up candidate if slice 4’s pool needs another null anchor.
4. McNamara 2000 JACN / McNamara 2015 Nutrients (“The Fifty Year Rehabilitation of the Egg”) — narrative reviews/commentary by the same author as the 1987 JCI primary, not primaries themselves; not minted.
5. A companion Greene et al. 2005 J Nutr paper (“Maintenance of the LDL cholesterol:HDL cholesterol ratio… elderly population given a dietary cholesterol challenge”) that I recall from background knowledge as likely reporting on the same or an overlapping elderly cohort as the Greene 2006 Nutrition & Metabolism paper I did mint (S-79) — I could not verify this one’s metadata directly (no clean web confirmation this session), so I neither minted it nor can confidently flag duplicate_of/shared data_basis. Flagging here as a probable-overlap risk for step 2 to check if it surfaces from another slice.
6. Herron/Fernandez hyper-/hypo-responder classification papers, ApoE-genotype studies — explicitly out of scope for this slice (slice 5’s territory); noted but not investigated in depth.
7. DiMarco 2017’s TMAO finding — the same paper (S-71) also reports plasma TMAO was unchanged; minted here because HDL/LDL is its headline framing, but flagged so slice 7 can mine the TMAO result via found_via rather than re-minting the paper.

Slice shape and gaps

14 sources written (budget: 14), covering four sub-lines: (a) the foundational Keys/Hegsted-tradition metabolic-ward equations and their homeostatic-compensation mechanism (4 sources, 1965-1987), (b) controlled cholesterol/egg dose-response trials showing a clear mean LDL(+ApoB) rise (3 sources, the strongest anti-egg mechanism anchors), (c) modern whole-egg RCTs showing HDL-up/LDL-neutral or improved-particle-quality responses, mostly from the egg-industry-funded Fernandez lab (3 sources), and (d) null/comparator-dependent trials in hyperlipidemic or healthy adults, none egg-industry-funded (4 sources). Independence: 14 genuinely distinct trials/datasets (I did not include an additional Fernandez-lab hyper-responder paper or a second Ginsberg-adjacent re-analysis to avoid pool collapse), spanning 5 distinct research groups (Rockefeller/Ahrens; Columbia/Ginsberg; P&G/Mattson; UConn/Fernandez; Yale-Griffin/Katz-Njike) plus one Minnesota (Keys) and one South African (Vorster) trial. Balance: 3 clear anti-egg, 3 clear pro-egg, 4 null/comparator-dependent, 4 foundational/mechanistic (cut both ways — they establish both “cholesterol raises cholesterol” and “with diminishing returns”). Motivatedness flagged for 3 (Mutungi 2008, Greene 2006 — both confirmed ENC/AEB-funded; Mattson 1972 — P&G, opposite-direction COI) plus 2 flagged as likely-but-unconfirmed (DiMarco 2017, Kim & Campbell 2018 — both from labs that have taken ENC funding on other papers, but I could not confirm the specific funding statement for these papers behind paywalls).

Gaps: I did not verify citation counts for Quintao 1971 (Semantic Scholar has no record under that DOI) or confirm the funding disclosure text for DiMarco 2017 / Kim & Campbell 2018 (both paywalled); step 2 should treat those two motivatedness flags as provisional. I also did not go looking for a non-US, non-Fernandez-lab whole-egg RCT with a clear HDL-up result (all the pro-egg whole-egg RCTs I found trace to the same UConn group) — if step 2 wants an independent pro-egg trial outside that lab, that is a real hole in the pool, not something I checked and ruled out. I did not deeply chase Beynen/Katan-style Dutch metabolic-ward trials beyond what Clarke/Weggemans cite, so there may be additional 1980s European feeding trials still unmined.