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Cited by 858Cancer, Hypoxia, and MetabolismCancer and biochemical researchMetabolism, Diabetes, and Cancer

Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?

Open access
DeBerardinis, Ralph J., Thompson, Craig B.·2012·Cell
DOI 10.1016/j.cell.2012.02.032PMC PMC3337773
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Abstract

An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states--often genetically programmed--that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This Review discusses the broad impact of metabolism in cellular function and how modern concepts of metabolism can inform our understanding of common diseases like cancer and also considers the prospects of developing new metabolic approaches to disease treatment.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that metabolism pervades every aspect of biology and that genetically defined metabolic outliers—inborn errors of metabolism and cancer—can reveal disease mechanisms and therapeutic opportunities. It highlights cancer metabolic reprogramming, including the Warburg effect and mutations in SDH, FH, IDH1/2, and PHGDH, and discusses prospects for metabolic imaging and in vivo flux studies.

Key findings

  • Metabolism is far broader than textbook biochemistry: KEGG annotates more than 8,700 reactions and 16,000 metabolites, and core metabolic pathways are integrated with signaling through PI3K/Akt/mTOR, AMPK, acetyl-CoA, sirtuins, and other mechanisms.
  • Inborn errors of metabolism (IEMs) are the largest category of heritable human diseases, with some 500 recognized IEMs; newborn screening programs now detect more than 20 individual disorders from a single blood sample and reveal marked phenotypic heterogeneity, including clinically silent cases.
  • Cancer is a paradigm of genetically defined metabolic abnormality: many tumors out-compete surrounding tissue for glucose (Warburg effect), and mutations in SDH and FH act as tumor suppressors, IDH1/2 mutations produce the oncometabolite 2-HG, and PHGDH amplification/overexpression can promote malignant phenotypes.
  • Metabolic imaging and flux analysis are promising frontiers: FDG-PET is established, newer PET agents target glutamine/glutamate, MRS can quantify metabolites such as glycine and 2-HG in gliomas, and hyperpolarized 13C can produce a transient sensitivity gain of 10,000-fold or more.

Methods

  • Narrative review synthesizing literature across biochemistry, genetics, inborn errors of metabolism, cancer metabolism, and metabolic imaging.
  • No primary experimental data, systematic search strategy, inclusion criteria, or meta-analysis are reported.
  • The paper discusses examples from human genetics, newborn screening, cancer genomics, metabolomics, and preclinical models to support its conceptual arguments.

Limitations

  • The paper states that metabolomics alone does not present a complete view of metabolism and can produce misleading results; elevated metabolite levels often reflect decreased rather than increased pathway flux, and it may be impossible to infer which pathway is affected from abnormal metabolite levels alone.
  • The paper notes that technical challenges remain for combined metabolomics–metabolic flux studies and that key mechanisms are unresolved, such as how G6Pase deficiency affects hepatocellular differentiation, whether PHGDH is a bona fide oncogene, and which nutrients produce 2-HG in IDH1/2-mutant tumors in vivo.
  • Evident from the text: as a review, it provides no primary data or systematic evidence synthesis, so its conclusions depend on the cited literature and selected examples.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2012.02.032

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Glucose and glutamine collaborate in the hexosamine pathway to modify nutrient transporters and growth factor receptors, enabling their expression on the cell membrane.

    “But they also collaborate in another biochemical pathway to produce hexosamines, which modify nutrient transporters and growth factor receptors, enabling their expression on the cell membrane (Figure 2).”
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  • Premisecitation

    Metabolite GWAS also found associations with drug toxicity, Crohn's disease and other conditions not conventionally thought to be related to intermediary metabolism.

    “However, there were also associations with drug toxicity, Crohn’s disease and other conditions not conventionally thought to be related to intermediary metabolism (Suhre et al., 2011).”
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    Much of the metabolic variation among individuals is genetically defined.

    “Much of the metabolic variation among individuals is genetically defined.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Generating sufficient quantities of a metabolite for protein modification requires access to nutrients in excess of the levels needed to run basic bioenergetic programs.

    “These modifications can signal states of nutrient abundance, because generating sufficient quantities of the requisite metabolite for protein modification requires access to nutrients in excess of the levels needed to run basic bioenergetic programs.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Other polymorphisms associated with metabolite levels had previously been shown to associate with cardiovascular disorders, gout and type-2 diabetes, all of which involve changes in core metabolic pathways.

    “Other polymorphisms had previously been shown to associate with cardiovascular disorders, gout and type-2 diabetes, all of which are known to involve changes in core metabolic pathways (Suhre et al., 2011).”
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    Premisecitation

    A rise in intracellular acetyl-CoA occurs in phase with induction of growth genes, and a bolus of extracellular nutrients convertible to acetyl-CoA causes yeast cells to short-circuit the metabolic cycle and enter directly into growth.

    “A rise in intracellular acetyl-CoA occurs in phase with the induction of growth genes, and a bolus of extracellular nutrients that can be readily converted to acetyl-CoA causes cells to short-circuit the metabolic cycle and enter directly into growth (Cai et al., 2011).”
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    Premisecitation

    There are now some 500 recognized IEMs, making this the largest category of heritable human diseases.

    “There are now some 500 recognized IEMs (Childs et al., 2001), making this the largest category of heritable human diseases.”
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    Premisecitation

    Altered cellular metabolism is a hallmark of cancer, contributing to malignant transformation and to the initiation, growth and maintenance of tumors.

    “Altered cellular metabolism is a hallmark of cancer, contributing to malignant transformation and to the initiation, growth and maintenance of tumors (Hanahan and Weinberg, 2011).”
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    Premisecitation

    The PI3K/Akt/mTOR pathway stimulates a rapid increase in essential nutrient uptake and the proper allocation of nutrients into catabolic and anabolic pathways to produce energy and macromolecules.

    “In particular, the PI3K/Akt/mTOR pathway stimulates both a rapid increase in essential nutrient uptake and the proper allocation of these nutrients into catabolic and anabolic pathways to produce energy and macromolecules, respectively (Gibbons et al., 2009).”
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    Premisecitation

    Acetyl-CoA groups used to modify histones are predominantly produced by acetyl-CoA synthetase in yeast and ATP-citrate lyase in mammalian cells, both of which enter the nucleus to produce a localized acetyl-CoA pool.

    “The acetyl-CoA groups used to modify histones are predominantly produced by acetyl-CoA synthetase in yeast and ATP-citrate lyase in mammalian cells, both of which enter the nucleus to produce a localized acetyl-CoA pool for this purpose (Figure 2).”
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    Premisecitation

    Synthesis of plasmalogens and oxidation of fatty acids 24-26 carbons in length occur in peroxisomes, as realized when abnormal levels of these metabolites were observed in patients with peroxisomal dysfunction.

    “Synthesis of plasmalogens and oxidation of fatty acids 24-26 carbons in length occur in the peroxisomes, but this was only realized when abnormal levels of these metabolites were observed in patients with peroxisomal dysfunction (Wanders and Waterham, 2006).”
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    Premisecitation

    The vast majority of IEMs result from recessively inherited loss-of-function mutations in enzymes and transporters, although several are caused by mutations that either stimulate basal enzymatic activity or evoke altogether new functions.

    “The vast majority of IEMs result from recessively inherited loss-of-function mutations in enzymes and transporters, although several are caused by mutations that either stimulate basal enzymatic activity or evoke altogether new functions (Kranendijk et al., 2010; Stanley et al., 1998).”
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    Interpretationcitation

    These studies prove that a wide range of human metabolic diversity is genetically programmed and emphasize intimate connections between metabolism and health.

    “These studies prove that a wide range of human metabolic diversity is genetically programmed, and they emphasize the intimate connections between metabolism and health.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Unless glucose is present in adequate amounts to supply flux through the hexosamine pathway, cells lose the ability to respond to growth factor signaling and no longer take up the full complement of nutrients required for growth.

    “Unless glucose is present in adequate amounts to supply flux through the hexosamine pathway, cells lose the ability to respond to growth factor signaling and no longer take up the full complement of nutrients required for growth (Wellen et al., 2010).”
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    Premisecitation

    AMPK inactivates energy-consuming growth-promoting pathways like protein and lipid synthesis and activates catabolism of fatty acids and other fuels, rebalancing energy supply with demand.

    “By phosphorylating a number of key targets, AMPK inactivates energy-consuming, growth-promoting pathways like protein and lipid synthesis, and activates catabolism of fatty acids and other fuels. This enables the cell to re-balance energy supply with demand.”
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    Premisecitation

    AMPK localizes to chromatin and phosphorylates histone H2B on serine 36, facilitating its effects on gene expression.

    “AMPK also coordinates the expression of stress response genes by localizing to chromatin and phosphorylating histone H2B on serine 36, and this activity facilitates AMPK’s effects on gene expression (Bungard et al., 2010).”
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    Premisecitation

    AMPK is a fuel sensor activated during compromised bioenergetic states such as acute nutrient deprivation and hypoxia.

    “This serine-threonine kinase is a “fuel sensor” activated during compromised bioenergetic states such as acute nutrient deprivation and hypoxia (Hardie, 2011).”
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    Premisecitation

    CPS is deacetylated by SIRT5 during fasting.

    “For example, the urea cycle enzyme carbamoyl phosphate synthetase (CPS) is deacetylated by the sirtuin SIRT5 during fasting (Nakagawa et al., 2009).”
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    Interpretationreasoning

    Metabolism impacts, or is impacted by, virtually every other cellular process, and no area of biological research is totally free from the influence of metabolism.

    “Rather, metabolism impacts, or is impacted by, virtually every other cellular process; there is no longer any space in biological research that is totally free from the influence of metabolism.”
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    Premisecitation

    Both succinate and fumarate aberrantly increase the function of hypoxia inducible factors (HIFs).

    “Furthermore, both succinate and fumarate aberrantly increase the function of hypoxia inducible factors (HIFs).”
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    Premisenone given

    G6Pase catalyzes the final common step in glycogenolysis and gluconeogenesis, and G6Pase deficiency results in extreme fasting intolerance and hypoglycemia.

    “G6Pase catalyzes the final common step in glycogenolysis and gluconeogenesis, and G6Pase deficiency results in extreme fasting intolerance and hypoglycemia.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Both succinate and fumarate interfere with processes potentially involved in tumor suppression, including c-Jun-mediated apoptosis in pheochromocytoma cells and AMPK signaling.

    “Both metabolites have been demonstrated to interfere with processes potentially involved in tumor suppression, including c-Jun-mediated apoptosis in pheochromocytoma cells (Lee et al., 2005) and AMPK signaling (Tong et al., 2011).”
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    Premisecitation

    Loss-of-function mutations have been identified in all four subunits of the SDH complex and in SDH5.

    “Loss-of-function mutations have been identified in all four subunits of the SDH complex (Baysal, 2008; Burnichon et al., 2010), and in SDH5, which encodes a protein involved in incorporation of SDH’s flavin adenine dinucleotide cofactor (Hao et al., 2009).”
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    Premisenone given

    G6Pase deficiency in Glycogen Storage Disease Type 1a is a risk factor for hepatocellular adenomas and HCC, but cirrhosis is not a prominent feature.

    “Glucose-6-phosphatase (G6Pase) deficiency in Glycogen Storage Disease Type 1a is a risk factor for hepatocellular adenomas and HCC, but cirrhosis is not a prominent feature.”
    Quote in the paperSubstantial claim

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    Premisenone given

    IDH1 and IDH2 mutations in cancer are somatically acquired, present on only one allele, and confined to the enzyme's active site.

    “IDH1 and IDH2 mutations in cancer are somatically acquired, present on only one allele, and confined to the enzyme’s active site.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    mTOR's influence on SREBP involves phosphorylation of Lipin-1; mTOR-dependent Lipin-1 phosphorylation causes it to be retained in the cytosol, whereas mTOR inhibition leads to dephosphorylation and nuclear translocation of Lipin-1, where it is involved with depletion of nuclear SREBP.

    “Recent work demonstrated that mTOR’s influence on SREBP involves phosphorylation of Lipin-1, a phosphatidic acid phosphatase. mTOR-dependent Lipin-1 phosphorylation causes it to be retained in the cytosol, whereas mTOR inhibition led to the dephosphorylation of Lipin-1 and its translocation to the nucleus, where it was involved with depletion of nuclear SREBP (Peterson et al., 2011).”
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    Interpretationreasoning

    Nrf2 induces expression of genes involved in defense against reactive oxygen species, perhaps enabling malignant FH-deficient cells to tolerate high levels of oxidants.

    “Nrf2 induces expression of a suite of genes involved in defense against reactive oxygen species, perhaps enabling malignant FH-deficient cells to tolerate high levels of exogenous or endogenous oxidants.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Both succinate and fumarate are competitive PHD inhibitors, and massive accumulation of these metabolites in cells lacking SDH or FH activity elicits a hypoxic response even under oxygen-replete conditions.

    “Both succinate and fumarate are competitive PHD inhibitors, and the massive accumulation of these metabolites in cells lacking SDH or FH activity elicit a hypoxic response even under oxygen-replete condition (Isaacs et al., 2005; Selak et al., 2005).”
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    Interpretationreasoning

    Reprogramming metabolism into a platform that promotes cell growth and proliferation is an essential component of growth-factor signaling pathways and of malignancy resulting from constitutive activation of these pathways.

    “Thus reprogramming metabolism into a platform that promotes cell growth and proliferation is an essential component of growth-factor signaling pathways and of malignancy resulting from constitutive activation of these pathways.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The pathway of heme synthesis from glutamine followed by degradation via HMOX1 is enhanced in FH-deficient cells, and silencing HMOX1 prevents these cells from forming colonies.

    “The pathway of heme synthesis from glutamine followed by degradation via HMOX1 is enhanced in FH-deficient cells, and silencing HMOX1 prevents these cells from forming colonies (Frezza et al., 2011b).”
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    Premisecitation

    Tumor tissue has additional metabolic characteristics, most consistently the tendency to metabolize glutamine and to synthesize fatty acids, both of which promote tumor growth in experimental models.

    “Other work has identified additional metabolic characteristics of tumor tissue, most consistently the tendency to metabolize glutamine and to synthesize fatty acids, both of which promote tumor growth in experimental models (DeBerardinis and Cheng, 2010; Swinnen et al., 2006).”
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    Premisecitation

    Both HIF-1α and HIF-2α are dispensable for the formation of hyperplastic renal cysts in mice lacking expression of FH in the kidney, suggesting additional consequences of these enzyme deficiencies.

    “However both HIF-1α and HIF-2α are dispensable for the formation of hyperplastic renal cysts in mice lacking expression of FH in the kidney (Adam et al., 2011), suggesting additional consequences of these enzyme deficiencies.”
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    Premisereasoning

    Cancer mutations are in general acquired somatically and associated with metabolic effects that appear to increase fitness and growth at the cellular level.

    “Cancer mutations are in general acquired somatically and associated with metabolic effects that appear to increase fitness and growth at the cellular level.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Many IEMs with increased cancer risk, particularly hepatocellular carcinoma, either involve accumulation of mutagens or cause cirrhosis, an independent risk factor for HCC.

    “Many of these diseases either involve the accumulation of mutagens or cause cirrhosis, an independent risk factor for HCC (Erez et al., 2011).”
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    • cites Erez et al., 2011

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    Interpretationreasoning

    In families with SDH- or FH-deficient tumors, affected individuals inherit one mutation and their tumors display loss of the wild-type allele; thus both SDH and FH are tumor suppressors.

    “In families with SDH- or FH-deficient tumors, affected individuals inherit one mutation and their tumors display loss of the wild-type allele. Thus, both SDH and FH are tumor suppressors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Magnetic resonance spectroscopy at 1.5-Tesla has been used for decades to produce semi-quantitative, non-invasive measurements of abundant metabolite pools in cancer.

    “Magnetic resonance spectroscopy (MRS) at 1.5-Tesla has been used for decades to produce semi-quantitative, non-invasive measurements of abundant metabolite pools in cancer (Glunde and Bhujwalla, 2011).”
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    Premisecitation

    2-HG is produced from NADPH-dependent reduction of α-ketoglutarate to 2-HG, a neomorphic enzyme activity that occurs very efficiently when both mutant and wild-type alleles are expressed together.

    “This metabolite is produced from the NADPH-dependent reduction of α-ketoglutarate to 2-HG (Fig. 3A,B), a neomorphic enzyme activity that occurs very efficiently when both mutant and wild-type alleles are expressed together (Pietrak et al., 2011).”
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    Interpretationreasoning

    Metabolomics methods do not present a complete view of metabolism and in some cases can produce misleading results.

    “While methods to catalog and quantify small molecules in biological fluids (metabolomics) are highly informative, they do not present a complete view of metabolism and in some cases can produce misleading results.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: An elevated level of a metabolite in newborn screening tests almost always reflects decreased rather than increased flux of the pathway.

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    Premisecitation

    The presence of IDH1/2 mutations in gliomas is associated with both lower histological grade and a slower rate of disease progression.

    “the presence of IDH1/2 mutations in gliomas is associated with both lower histological grade and a slower rate of disease progression”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Parsons et al., 2008 source

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    • cites Yan et al., 2009 source

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    Premisecitation

    Over-expressing PHGDH was sufficient to promote anchorage independence in breast epithelial cells and to disturb cell polarity, phenotypes taken to be consistent with malignancy.

    “over-expressing PHGDH was sufficient to promote anchorage independence in breast epithelial cells and to disturb cell polarity, phenotypes taken to be consistent with malignancy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Locasale et al., 2011 source

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    • Rests on an assumption: PHGDH is an enzyme required to produce the amino acids serine and glycine from glucose.
    • Rests on an assumption: Serine and glycine are crucial intermediates in biosynthetic processes including the production of nucleotides, proteins, glutathione, creatine, and methylated DNA.

  • May combine two claims.

    Premisecitation

    Similar approaches focusing on a handful of metabolites have already been used successfully in humans to measure gluconeogenesis and the urea cycle in vivo, and to compare metabolism between lung tumors and surrounding tissue.

    “Similar approaches focusing on a handful of metabolites have already been used successfully in humans to measure gluconeogenesis and the urea cycle in vivo, and to compare metabolism between lung tumors and surrounding tissue (Fan et al., 2009; Landau et al., 1996; Yudkoff et al., 2010).”
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    • cites Landau et al., 1996 source

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    • cites Yudkoff et al., 2010

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36 of 36

  • The paper relies on this without support.

    Children with (L)-2-hydroxyglutaric aciduria accumulate the (L)-isomer of 2-HG in all body fluids.

    “Children with (L)-2-hydroxyglutaric aciduria, an autosomal recessive condition caused by deficiency of (L)-2-HG dehydrogenase, which converts 2-HG to α-ketoglutarate, accumulate the (L)-isomer of 2-HG in all body fluids.”

  • The paper relies on this without support.

    The more than 50 mammalian dioxygenases that use α-ketoglutarate as a substrate regulate crucial processes including methylation of histones and DNA.

    “These enzymes regulate a number of crucial processes including methylation of histones and DNA.”

  • The paper relies on this without support.

    PHGDH is an enzyme required to produce the amino acids serine and glycine from glucose.

    “phosphoglycerate dehydrogenase (PHGDH), an enzyme required to produce the amino acids serine and glycine from glucose”

  • The paper relies on this without support.

    Serine and glycine are crucial intermediates in biosynthetic processes including the production of nucleotides, proteins, glutathione, creatine, and methylated DNA.

    “Serine and glycine are crucial intermediates in a variety of biosynthetic processes including the production of nucleotides, proteins, glutathione, creatine, and methylated DNA.”

  • The paper relies on this without support.

    An elevated level of a metabolite in newborn screening tests almost always reflects decreased rather than increased flux of the pathway.

    “An elevated level of a metabolite in these screening tests almost always reflects decreased rather than increased flux of the pathway”

  • The paper relies on this without support.

    SLC2A1 is a HIF-1 transcriptional target and encodes the predominant glucose transporter in cancer cells, GLUT1.

    “SLC2A1 is a HIF-1 transcriptional target and encodes the predominant glucose transporter in cancer cells, GLUT1.”

  • The paper relies on this without support.

    GLUT1 is the major transporter at the blood-brain barrier and is responsible for supplying glucose to the brain.

    “GLUT1 is also the major transporter at the blood-brain barrier and is responsible for supplying glucose to the brain.”

  • The paper relies on this without support.

    GLUT1 deficiency most commonly involves severe central nervous system manifestations including seizures, mental retardation and poor growth of the postnatal brain.

    “GLUT1 deficiency has a wide phenotypic spectrum but its most common form involves severe central nervous system manifestations including seizures, mental retardation and poor growth of the postnatal brain.”

  • The paper relies on this without support.

    Severe LDHA deficiency causes Glycogen Storage Disease Type XI, which causes exercise intolerance, cramps and occasional myoglobinuria in adolescents and adults, but is not associated with severe dysfunction of major homeostatic organs.

    “Severe LDHA deficiency is also a well-characterized human disease, Glycogen Storage Disease Type XI. This disorder causes exercise intolerance, cramps and occasional myoglobinuria in adolescents and adults, but is not associated with severe dysfunction of major homeostatic organs.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Steady-state metabolite levels provide no measurement of metabolite flux, that is, the speed or direction of metabolite flow through a given pathway.

    “One caution of measuring steady-state metabolite levels is that these data provide no measurement of metabolite flux, that is, the speed or direction of metabolite flow through a given pathway (115).”

    From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [115]

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Authors
DeBerardinis, R. J., & Thompson, C. B.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
  • DeBerardinis, Ralph J.
  • Thompson, Craig B.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2012-03
Volume
148
Issue
6
Pages
1132-1144
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2012.02.032
PMC
PMC3337773
OpenAlex
W2162790428
Cited by
858
References
100
Citations by year
2026: 45 · 2025: 49 · 2024: 71 · 2023: 82 · 2022: 65 · 2021: 89 · 2020: 73 · 2019: 63 · 2018: 60 · 2017: 40 · 2016: 42 · 2015: 59 · 2014: 61 · 2013: 40 · 2012: 19
FWCI
4.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA105463, R01CA157996)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
cellular metabolism, metabolic disorders, genetic metabolic disorders, cancer metabolism, metabolic therapy, tissue dysfunction, metabolic pathways
MeSH terms
Animals, Humans, Metabolic Diseases, Neoplasms, Metabolic Networks and Pathways

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Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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