Grade CModerate Confidence

Evidence Grade C

Observational data with consistent patterns

What Grade C Means

Grade C represents moderate confidence in a research finding. These claims are supported by observational data showing consistent patterns, or by studies with methodological limitations that prevent higher classification.

Observational studies suggest this pattern exists
The finding is consistent across multiple observations
Causation has not been established (correlation only)
More rigorous study designs are needed to confirm

Grade C findings are worth knowing about but require cautious interpretation.

Criteria for Grade C Classification

A finding receives Grade C status when it demonstrates:

Consistent Observational Patterns

Multiple observational studies or case series show the same trend, even without controlled intervention.

Biological Plausibility

The pattern makes sense given what we know about physiology, even if direct causal evidence is lacking.

Methodological Limitations

Studies may have small sample sizes, observational design only, potential confounders not fully controlled, or short duration.

Absence of Contradictory Evidence

No well-designed studies have contradicted the finding, even if confirmatory studies are limited.

The Correlation vs. Causation Problem

Grade C evidence often demonstrates correlation without proving causation.

Example: People with low TG/HDL ratios tend to be healthier. But does the favorable ratio cause better health, or do healthier behaviors produce both the favorable ratio and better health outcomes?

This distinction matters because:

• Improving the marker might improve health (causal)
• Improving the marker might not improve health if it's just a symptom (correlational)

For metabolic markers, we have reasonably strong mechanistic evidence supporting causal relationships, but Grade C findings require this caveat.

Why We Include Grade C Evidence

Despite lower confidence, Grade C evidence serves important purposes:

Emerging Areas of Research

New fields often lack the large RCTs needed for Grade A status. Grade C represents the frontier of knowledge.

Phenomena Difficult to Study

Some patterns can't be ethically or practically studied with randomized trials. Observational data may be the best available.

Pattern Recognition

Consistent observations can guide research priorities and help individuals make informed decisions.

Real-World Applicability

Observational studies often reflect real-world conditions better than controlled trials.

Examples of Grade C Evidence on Metabolicum

LMHR (Lean Mass Hyper-Responder) Phenotype

Some lean, metabolically healthy individuals on low-carbohydrate diets develop very high LDL (>200 mg/dL), very high HDL (>80 mg/dL), and very low triglycerides (<70 mg/dL).

Source: Feldman et al., 2022 (Curr Dev Nutr)

Why Grade C: Observational characterization, not intervention trial. Long-term cardiovascular outcomes unknown. No randomized evidence that this phenotype is safe or harmful.

Personal Fat Threshold Concept

Individuals have personal "fat thresholds" — the amount of fat they can carry before developing metabolic dysfunction — which varies dramatically between people.

Source: Clinical observations, Taylor & Sattar hypothesis

Why Grade C: Conceptual framework more than proven mechanism. Individual threshold prediction methods don't exist. Difficult to test prospectively.

How We Use Grade C Evidence

On Metabolicum, Grade C evidence appears in:

Educational content — Explaining emerging concepts and patterns
Context and discussion — Providing nuance beyond simple thresholds
Alternative interpretations — When multiple explanations exist
Areas of active research — Noting what science is currently investigating

We do NOT use Grade C evidence for:

• Primary calculator thresholds
• Definitive health recommendations
• Claims presented as established fact

The Path from C to Higher Grades

To Grade B:

A well-designed single study (RCT or large prospective cohort) confirms the pattern.

To Grade A:

Multiple independent confirmatory studies emerge with consistent results across populations.

We track promising Grade C findings and update grades as evidence evolves.

Red Flags That Keep Evidence at Grade C

Observational Design Only

Without intervention studies, we can't confirm causation.

Uncontrolled Confounders

When studies can't separate the effect of interest from correlated lifestyle factors.

Inconsistent Replication

If some studies show the pattern and others don't.

Surrogate Endpoints Only

When studies measure biomarkers rather than clinical outcomes.

Making Decisions with Grade C Evidence

Grade C findings can inform personal health decisions when:

1.Risk is low — The intervention being considered is safe
2.Grade A alternatives don't exist — No higher-quality evidence addresses your situation
3.You understand the uncertainty — Making a provisional decision, not permanent
4.You monitor outcomes — Track whether the approach is working for you
5.You remain open to revision — New evidence may change the picture

Grade C Citations on Metabolicum (1)

Feldman D, Bikman BT, Engel S, Wood RJ, Krebs JD, Norwitz NG (2022)

Lean mass hyper-responders: a new phenotype for low-carbohydrate diet adopters

Current Developments in Nutrition

Key finding: LMHR phenotype characterized by LDL >200, HDL >80, TG <70