Evidence Grade A
Replicated findings across multiple well-designed studies
What Grade A Means
Grade A represents our highest level of confidence in a research finding. These are claims supported by replicated findings across multiple well-designed studies, typically including randomized controlled trials (RCTs) or large prospective cohort studies that have been independently verified.
- Multiple research teams have tested this claim
- Results have been replicated in different populations
- Study designs minimize bias and confounding
- The scientific community broadly accepts these findings
Criteria for Grade A Classification
A finding receives Grade A status when it meets all of the following:
1. Replication Across Studies
The finding has been reproduced by independent research teams. A single study — no matter how well-designed — cannot achieve Grade A. We require at least 2-3 confirmatory studies from different institutions.
2. Robust Study Design
Supporting studies include randomized controlled trials (RCTs), large prospective cohort studies (n > 1,000), or systematic reviews/meta-analyses of quality studies.
3. Consistent Effect Direction
Results point in the same direction across studies. Minor variations in effect size are expected, but the fundamental finding remains consistent.
4. Biological Plausibility
The finding aligns with established physiological mechanisms. Surprising results require stronger replication evidence.
5. Clinical Validation
Where applicable, the finding correlates with clinical outcomes (disease incidence, mortality, symptom resolution) — not just biomarker changes.
What Grade A Does NOT Mean
Grade A does not mean "absolute truth." Even our highest-confidence findings carry uncertainty. Science is provisional by nature.
Grade A means:
- This is the best available evidence
- Multiple studies agree
- You can reasonably rely on this information
Grade A does NOT mean:
- This will never be revised
- This applies to every individual equally
- No exceptions exist
Examples of Grade A Evidence on Metabolicum
TG/HDL Ratio and Insulin Resistance
TG/HDL ratio ≥3.0 identifies insulin-resistant individuals with approximately 79% sensitivity.
Supporting Evidence:
- •McLaughlin et al., 2003 (Ann Intern Med) — Original validation in 258 subjects
- •McLaughlin et al., 2005 (Am J Cardiol) — Confirmed across different body weights
- •Gaziano et al., 1997 (Circulation) — Cardiovascular outcome correlation in 14,916 men
- •Salazar et al., 2013 — Superior to metabolic syndrome criteria
Why Grade A: Replicated across multiple populations, different research teams, consistent direction, validated against gold-standard insulin clamp measurements.
HOMA-IR Formula Validity
HOMA-IR correlates strongly (r ≈ 0.82) with the euglycemic clamp method for measuring insulin resistance.
Supporting Evidence:
- •Matthews et al., 1985 (Diabetologia) — Original formula derivation and validation
- •Wallace et al., 2004 (Diabetes Care) — Comprehensive review confirming appropriate use
- •Multiple subsequent validation studies across populations
Why Grade A: The formula has been validated against the gold standard across thousands of subjects over 40 years. It's the most widely used insulin resistance assessment in clinical research.
WHtR 0.5 Threshold
Waist-to-height ratio below 0.5 is associated with lower cardiometabolic risk across diverse populations.
Supporting Evidence:
- •Ashwell & Hsieh, 2005 — Established universal threshold rationale
- •Browning et al., 2010 (Nutr Res Rev) — Systematic review confirming 0.5 across 78 studies
- •Meta-analysis of 300,000+ participants
Why Grade A: Systematic review with massive sample size, consistent across ethnicities, ages, and sexes.
How We Use Grade A Evidence
On Metabolicum, Grade A evidence forms the foundation of our:
Calculator thresholds
Primary cutoffs come from Grade A sources
Core educational claims
Statements presented as established fact
Risk categorizations
How we label results (optimal, elevated, high)
When multiple Grade A sources suggest different thresholds, we present the range and explain the variation rather than arbitrarily choosing one value.
Limitations to Keep in Mind
Population Specificity
Most research is conducted in Western populations. Findings may not apply equally to all ethnicities. We note population limitations where known.
Individual Variation
Population-level findings describe averages. Your individual response may differ due to genetics, environment, and other factors.
Evolving Science
Grade A findings can be revised as new evidence emerges. We update our content when the science changes.
Context Matters
A Grade A finding about insulin resistance in overweight adults may not apply to lean individuals, athletes, or those with specific medical conditions.
Grade A Citations on Metabolicum (17)
Gaziano JM, Hennekens CH, O'Donnell CJ, Breslow JL, Buring JE (1997)
Fasting triglycerides, high-density lipoprotein, and risk of myocardial infarction
Circulation
Key finding: TG/HDL ratio was the strongest predictor of myocardial infarction among all lipid measures examined
McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G (2003)
Use of metabolic markers to identify overweight individuals who are insulin resistant
Annals of Internal Medicine
Key finding: TG/HDL ratio ≥3.0 identified insulin-resistant individuals with 79% sensitivity and 65% specificity
McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters D, Simon J, Krauss RM (2005)
Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease?
American Journal of Cardiology
Key finding: TG/HDL ratio identified insulin resistance regardless of body weight
Hanak V, Munoz J, Teague J, Stanley A Jr, Bittner V (2004)
Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B
American Journal of Cardiology
Key finding: TG/HDL ratio of 3.8 predicted LDL phenotype B (small, dense) with 79% sensitivity and 81% specificity
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985)
Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man
Diabetologia
Key finding: Established HOMA-IR formula and validated against euglycemic clamp
Wallace TM, Levy JC, Matthews DR (2004)
Use and abuse of HOMA modeling
Diabetes Care
Key finding: Comprehensive review of HOMA validation and appropriate use
Hallberg SJ, McKenzie AL, Williams PT, Bhanpuri NH, Peters AL, et al. (2018)
Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year
Diabetes Therapy
Key finding: TG/HDL ratio improved by 29%, HOMA-IR improved by 55%, HbA1c reduced from 7.6% to 6.3%
Athinarayanan SJ, Adams RN, Hallberg SJ, McKenzie AL, Bhanpuri NH, et al. (2019)
Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial
Frontiers in Endocrinology
Key finding: 2-year sustainability of metabolic improvements
Choi YJ, Jeon SM, Shin S (2020)
Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes: a meta-analysis of randomized controlled trials
Nutrients
Key finding: Significant TG reduction and HDL increase across 14 RCTs
Yuan X, Wang J, Yang S, Gao M, Cao L, Li X, Hong D, Tian S, Sun C (2020)
Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis
Nutrition & Diabetes
Key finding: TG decreased by 0.72 mmol/L, HDL increased by 0.14 mmol/L
Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S (1998)
The metabolically obese, normal-weight individual revisited
Diabetes
Key finding: Established MONW (metabolically obese normal weight) as clinical entity
Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, et al. (2008)
The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering
Archives of Internal Medicine
Key finding: 23.5% of normal-weight adults were metabolically abnormal
Ashwell M, Hsieh SD (2005)
Six reasons why the waist-to-height ratio is a rapid and effective global indicator for health risks of obesity
International Journal of Food Sciences and Nutrition
Key finding: WHtR <0.5 as universal threshold across populations
Browning LM, Hsieh SD, Ashwell M (2010)
A systematic review of waist-to-height ratio as a screening tool for the prediction of cardiovascular disease and diabetes
Nutrition Research Reviews
Key finding: Systematic review confirming 0.5 threshold across 78 studies
Begley CG, Ellis LM (2012)
Drug development: Raise standards for preclinical cancer research
Nature
Key finding: Only 11 of 53 (21%) landmark cancer studies could be replicated
Ioannidis JPA (2005)
Why most published research findings are false
PLoS Medicine
Key finding: Theoretical and empirical argument that majority of research findings are false
Open Science Collaboration (2015)
Estimating the reproducibility of psychological science
Science
Key finding: Only 36% of psychology studies replicated
See also
Evidence grades are informational and do not replace medical advice.