// Evidence Grader
Claim grades, A through F
Every major genomics claim in this course gets a transparent grade — from clinically established interventions to outright misleading marketing. Use this dashboard to audit what's settled, what's preliminary, and what's hype.
A
Clinically established
B
Supported, context-specific
C
Promising, preliminary
D
Plausible, unproven
E
Popular, weak support
F
Misleading or false
A
Roughly 1–2% of the human genome encodes protein
Long established; figure stable across annotations.
Module 01 · The Human Genome at Scale →F
ENCODE's '80% functional' claim means most of the genome is biologically essential
ENCODE used a maximally permissive 'biochemical activity' definition. Comparative-genomics estimates put functionally constrained sequence at ~8–15%.
Module 01 · The Human Genome at Scale →A
T2T-CHM13 improves variant calling in centromeric and acrocentric regions
Demonstrated across multiple benchmarks (GIAB, T2T consortium 2022).
Module 01 · The Human Genome at Scale →A
Mitochondrial heteroplasmy fraction predicts clinical severity for many mtDNA disorders
Threshold effects well established for MELAS, MERRF, NARP, and Leigh syndrome.
Module 01 · The Human Genome at Scale →A
Long-read sequencing resolves structural variants missed by short-read WGS
Established across multiple benchmarks; HG002 truthset sensitivity gain is well documented.
Module 02 · Reading the Genome: Platforms & Modalities →A
Native methylation calling on PacBio and ONT is accurate enough to replace bisulfite sequencing
Concordance >95% with WGBS at >5x coverage; saves a sample and is non-destructive.
Module 02 · Reading the Genome: Platforms & Modalities →B
Whole-exome sequencing has higher diagnostic yield than gene panels for most rare-disease workups
True for broad/atypical phenotypes; panels still preferred for well-defined disease with clear-cut gene lists.
Module 02 · Reading the Genome: Platforms & Modalities →C
Clinical-grade nanopore sequencing is ready for primary diagnostic use today
Increasingly true for SVs and methylation; SNV calling is competitive but not yet a default reimbursable replacement.
Module 02 · Reading the Genome: Platforms & Modalities →A
The ACMG/AMP 2015 criteria are the standard for germline variant classification
Universally adopted; ClinGen continues to refine gene/disease-specific specifications.
Module 03 · Variant Interpretation: ACMG, VUS, and Penetrance →A
REVEL outperforms older missense predictors at clinically relevant thresholds
ClinGen Sequence Variant Interpretation working group recalibration confirms it on independent test sets.
Module 03 · Variant Interpretation: ACMG, VUS, and Penetrance →C
AlphaMissense should be used as primary clinical evidence today
Strong benchmark performance, but ClinGen has not yet defined formal evidence-strength tiers; treat as supporting.
Module 03 · Variant Interpretation: ACMG, VUS, and Penetrance →A
Population biobank-based penetrance estimates are systematically lower than family-based estimates
Documented across BRCA1/2, LDLR, MYH7, MYBPC3, LMNA, and ATTR.
Module 03 · Variant Interpretation: ACMG, VUS, and Penetrance →E
Direct-to-consumer 'health risk' reports based on a few SNPs accurately predict individual disease risk
23andMe-style reports explain a small fraction of variance; PRS-based reports are better but still calibration-poor outside the training ancestry.
Module 03 · Variant Interpretation: ACMG, VUS, and Penetrance →A
HLA-B*57:01 screening before abacavir prevents hypersensitivity reactions
PREDICT-1 (NEJM 2008); now standard of care.
Module 04 · Pharmacogenomics in Practice →A
DPYD genotyping before fluoropyrimidine chemotherapy reduces grade ≥3 toxicity
Henricks Lancet Oncol 2018; EMA mandate 2020.
Module 04 · Pharmacogenomics in Practice →A
Pre-emptive multi-gene PGx testing reduces clinically relevant adverse drug reactions
PREPARE trial, Lancet 2023, ~30% relative reduction.
Module 04 · Pharmacogenomics in Practice →B
CYP2D6 genotype-guided dosing improves outcomes for SSRIs
Improves tolerability and time-to-remission in some RCTs (GUIDED, IMPACT); effect modest and population-dependent.
Module 04 · Pharmacogenomics in Practice →F
MTHFR genotyping is clinically useful for thrombosis or psychiatric workups
ACMG explicitly recommends against; no clinical utility.
Module 04 · Pharmacogenomics in Practice →A
PARP inhibitors improve outcomes in BRCA1/2-mutant or HRD-positive ovarian cancer
SOLO-1, PAOLA-1, PRIMA — established maintenance setting.
Module 05 · Cancer Genomics: Germline, Somatic, and Liquid →A
ctDNA-positive MRD predicts recurrence in stage II/III colorectal cancer
GALAXY/CIRCULATE-Japan, BESPOKE, multiple cohorts; HR ~10–30 for relapse.
Module 05 · Cancer Genomics: Germline, Somatic, and Liquid →C
Adjuvant chemotherapy intensification based on ctDNA MRD improves overall survival
DFS signal in DYNAMIC; OS benefit not yet established. Active phase III work.
Module 05 · Cancer Genomics: Germline, Somatic, and Liquid →C
Multi-cancer early detection (MCED) tests like Galleri reduce cancer mortality in average-risk adults
Sensitivity for stage I disease modest (~17%); SYMPLIFY shows utility for symptomatic triage; mortality endpoint requires NHS-Galleri readout.
Module 05 · Cancer Genomics: Germline, Somatic, and Liquid →B
Tumor mutational burden (TMB) predicts checkpoint-inhibitor response across all solid tumors
Validated in NSCLC, melanoma, MSI-H/dMMR; pan-tumor cutoffs (≥10 mut/Mb) are imperfect.
Module 05 · Cancer Genomics: Germline, Somatic, and Liquid →A
A polygenic score for CAD identifies a top-percentile group with ~3× lifetime risk
Khera et al. Nat Genet 2018; replicated across UK Biobank, FinnGen, MVP.
Module 06 · Polygenic Risk & Early Warning →B
PRS adds incremental discrimination on top of pooled cohort equations / QRISK3
Modest C-statistic gain (~0.01–0.02) but meaningful net reclassification at intermediate-risk thresholds.
Module 06 · Polygenic Risk & Early Warning →F
European-trained PRS perform equally well in African-ancestry individuals
Documented R² loss of ~50% or more across most disease scores.
Module 06 · Polygenic Risk & Early Warning →B
PRS-guided breast-cancer screening start age improves cancer detection
BCSC + PRS modeling; pilot programs (CanRisk, MyPeBS) ongoing.
Module 06 · Polygenic Risk & Early Warning →E
Direct-to-consumer 'longevity PRS' tests give actionable individual guidance
Lifespan PRS R² is ~3–5%; individual guidance is overinterpretation.
Module 06 · Polygenic Risk & Early Warning →A
GrimAge predicts all-cause mortality better than chronological age and earlier clocks
Lu et al. Aging 2019; replicated across multiple cohorts.
Module 07 · The Epigenome and Methylation Clocks →A
EpiSign-style methylation profiling is a clinically actionable diagnostic for syndromic intellectual disability
>100 syndromes with validated episignatures; widely reimbursed in CA, EU.
Module 07 · The Epigenome and Methylation Clocks →B
Partial reprogramming (cyclic OSK) can reverse epigenetic age in human cells
Sarkar 2020, Lu 2020, Browder 2022 — strong cell/mouse evidence; no published human in-vivo trials yet.
Module 07 · The Epigenome and Methylation Clocks →C
Lowering your methylation-age via diet and exercise reduces personal mortality risk
Plausible from epidemiology; no RCT with a hard endpoint has demonstrated it.
Module 07 · The Epigenome and Methylation Clocks →D
Consumer methylation-age tests give individuals reliable biological-age estimates suitable for tracking interventions
Test-retest reliability and platform variability are substantial; useful for population research, weak for individual longitudinal claims.
Module 07 · The Epigenome and Methylation Clocks →A
Smoking produces large, reproducible methylation changes at AHRR and F2RL3
EWAS-replicated dozens of times; among the strongest environmental epigenetic signals known.
Module 08 · Lifestyle Inputs to the Epigenome →B
2-year caloric restriction (~12% deficit) slows pace-of-aging biomarkers
CALERIE secondary analysis (Waziry 2023); modest effect, primary endpoints were metabolic.
Module 08 · Lifestyle Inputs to the Epigenome →C
Mediterranean diet produces durable methylation-age reductions
Suggestive evidence (NU-AGE, PREDIMED subanalyses); effect sizes small, replication mixed.
Module 08 · Lifestyle Inputs to the Epigenome →E
Methylated B-vitamin supplementation reduces biological age in non-deficient adults
No RCT support; widespread wellness claim with no rigorous endpoint.
Module 08 · Lifestyle Inputs to the Epigenome →A
Regular aerobic + resistance exercise produces methylation changes at exercise-responsive loci in skeletal muscle
Reproducible across multiple training studies (e.g. Lindholm 2014, Robinson 2017).
Module 08 · Lifestyle Inputs to the Epigenome →A
Casgevy produces durable freedom from vaso-occlusive crises in severe sickle cell disease
CLIMB SCD-121 trial; sustained HbF elevation and crisis abolition through follow-up to date.
Module 09 · CRISPR Therapeutics: From Casgevy to In Vivo →A
NTLA-2001 produces durable, single-dose knockdown of serum TTR in ATTR amyloidosis
Phase 1 (NEJM 2021) and continued follow-up: ~90% knockdown sustained.
Module 09 · CRISPR Therapeutics: From Casgevy to In Vivo →B
Base editing achieves clinically meaningful PCSK9 lowering after a single in-vivo LNP infusion
VERVE-101 readout interrupted by a transient ALT signal; VERVE-102 with revised LNP underway.
Module 09 · CRISPR Therapeutics: From Casgevy to In Vivo →A
CRISPR editing routinely causes large deletions that go undetected by standard PCR/short-read screens
Kosicki 2018 and replications; long-read amplicon and single-cell methods now standard.
Module 09 · CRISPR Therapeutics: From Casgevy to In Vivo →F
Germline CRISPR editing of human embryos for medical indications is safe and ready for clinical use
He Jiankui case was scientifically and ethically condemned; no consensus body endorses germline editing for clinical use.
Module 09 · CRISPR Therapeutics: From Casgevy to In Vivo →A
Inclisiran (GalNAc-siRNA against PCSK9) achieves sustained LDL-C lowering with twice-yearly dosing
ORION-9/10/11 phase 3 trials; ~50% LDL-C reduction.
Module 10 · Beyond CRISPR: ASO, siRNA, mRNA, AAV, and Cell Therapy →A
Patisiran improves polyneuropathy and quality-of-life outcomes in hereditary ATTR amyloidosis
APOLLO trial, NEJM 2018.
Module 10 · Beyond CRISPR: ASO, siRNA, mRNA, AAV, and Cell Therapy →A
Onasemnogene abeparvovec (Zolgensma) preserves motor function in pre-symptomatic SMA when given before 6 weeks
SPR1NT trial; treatment timing is decisive.
Module 10 · Beyond CRISPR: ASO, siRNA, mRNA, AAV, and Cell Therapy →B
Personalized neoantigen mRNA vaccines reduce melanoma recurrence post-resection
KEYNOTE-942 phase 2 (mRNA-4157 + pembrolizumab) HR ~0.56; phase 3 ongoing.
Module 10 · Beyond CRISPR: ASO, siRNA, mRNA, AAV, and Cell Therapy →C
CD19 CAR-T induces durable remissions in refractory autoimmune disease (SLE, myositis, systemic sclerosis)
Schett group case series and small trials are striking; no controlled phase 3 yet.
Module 10 · Beyond CRISPR: ASO, siRNA, mRNA, AAV, and Cell Therapy →F
AAV gene therapy is generally re-dosable
Pre-existing and induced neutralizing antibodies preclude conventional re-dosing for current capsids; engineered evader capsids and IgG-cleaving enzymes are research-stage.
Module 10 · Beyond CRISPR: ASO, siRNA, mRNA, AAV, and Cell Therapy →A
CHIP independently increases coronary heart disease risk
Jaiswal NEJM 2017; replicated in UK Biobank, MGB, MVP.
Module 11 · Clonal Hematopoiesis & Aging Genomes →A
TET2-mutant CHIP drives an IL-1β/NLRP3-dependent atherosclerosis phenotype
Fuster Science 2017 (mouse) + CANTOS post-hoc in TET2-CHIP humans.
Module 11 · Clonal Hematopoiesis & Aging Genomes →C
Routine CHIP screening of asymptomatic adults improves outcomes
No RCT evidence; CHRS gives risk stratification but no validated intervention.
Module 11 · Clonal Hematopoiesis & Aging Genomes →B
PARP-inhibitor exposure increases AML/MDS risk in patients with pre-existing CHIP
Suggested by ovarian-cancer pharmacovigilance + mechanistic rationale; absolute risk increase modest.
Module 11 · Clonal Hematopoiesis & Aging Genomes →A
International scientific bodies oppose clinical heritable genome editing under current conditions
WHO, NASEM, Royal Society, Hinxton Group consensus.
Module 12 · Ethics, Equity, and the Germline Question →B
ACMG-recommended opportunistic secondary-finding return improves outcomes for some carriers
Plausible mechanism, supported by single-gene case series; controlled outcome data limited.
Module 12 · Ethics, Equity, and the Germline Question →D
Polygenic embryo screening (PGT-P) reliably and ethically improves child health outcomes
No long-term data; probabilistic re-ranking with limited absolute effect; unresolved ethics.
Module 12 · Ethics, Equity, and the Germline Question →F
GINA fully protects US patients against genomic discrimination
GINA covers health insurance and employment only; life, disability, and long-term-care insurers may use genetic information.
Module 12 · Ethics, Equity, and the Germline Question →