// 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
Filtered:
A
Roughly 1–2% of the human genome encodes protein
Long established; figure stable across annotations.
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 →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 →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 →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 →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 →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 →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 →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 →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 →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 →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 →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 →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 →