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What Metabolic Profiling & Metabolomics got wrong, from 29 theses
Summary written by a model from the records below: Metabolic profiling and metabolomics investigations frequently encounter methodological roadblocks that compromise biomarker discovery, statistical modeling, and analytical quantification. Studies report high rates of model overfitting, loss of statistical significance after rigorous correction, confounding by non-target clinical variables, and failures of putative biomarkers to replicate across cohorts. These records come from graduate theses, 2021 to 2025, each labeled with its degree where the repository states it, and each links to its thesis. They were extracted by language models reading the full text, so treat each as a lead to read, not a verdict.
Plus 10 problems the authors left open, listed at the end.
Failure modes, by theses reporting them
Select a mode to jump to its records.
Supervised multivariate models suffer from overfitting and fail cross validation
Supervised classification techniques like partial least squares discriminant analysis showed apparent fit but failed permutation testing, resulting in non-significant or negative cross-validation scores. These models were unable to reliably separate disease states, treatment groups, surgical cohorts, or progression stages.
Tried and failed
multivariate statistical classification using targeted metabolomics applied to dietary pattern differentiation in biofluids. Outcome: no signal. Reason: metabolite profiles exhibited insufficient discriminatory variance across dietary groups resulting in negative Q2 values
Investigating the role of different dietary patterns on gut metabolites · Imperial · PhD
Tried and failed
OPLS-DA on untargeted metabolomic profiles applied to distinguishing clinical disease subgroups. Outcome: no signal. Reason: metabolic profiles had insufficient separation between patient subgroups to build statistically significant discriminant models
Diet-microbiome-metabolomic interactions in inflammatory bowel disease and comparing patients with and without a colon · Imperial · PhD
Tried and failed
O-PLS-DA classification of metabolomic profiling data applied to differentiating disease state from controls. Outcome: no signal. Reason: metabolic features failed to show significant predictive discrimination between groups in cross-validation permutation testing
Metabolic profiling of traumatic brain injury, associated outcomes and treatment in rodents · Imperial · PhD
Tried and failed
1H NMR metabolomic profiling with multivariate analysis applied to longitudinal urinary biomarkers for physiological state. Outcome: no signal. Reason: Unsupervised and supervised multivariate models showed no predictive metabolic shift (CV-ANOVA p>0.05, Q2Y<0)
Immunology of choriodecidua and onset of labour · Imperial · PhD
Tried and failed
supervised multivariate discriminant analysis of metabolite profiles applied to treatment group classification. Outcome: overfit. Reason: model showed high fit (R2Y) but lacked predictive significance (Q2 p>0.05) and group separation
A novel quantification method of lysophosphatidic acid and the role of autotaxin/Lysophosphatidic acid axis in acute-on-chronic liver failure · Imperial · PhD
Tried and failed
supervised multivariate discriminant analysis on untargeted metabolomics applied to longitudinal serum metabolomic profiles. Outcome: no signal. Reason: metabolic variance between surgery and control cohorts was indistinguishable across multiple gestational timepoints
Pregnancy following bariatric surgery: maternal considerations · Imperial · Doctorate
Tried and failed
supervised multivariate classification on metabolomic spectral profiles applied to intergenerational metabolic fermentation response profiles. Outcome: no signal. Reason: models failed to discriminate metabolic differences between mother and offspring cohorts
Investigation of the effects of dietary fibres on gut microbiota, metabolism and glycaemic control across generations · Imperial · PhD
Tried and failed
untargeted NMR metabolomic profiling and classification applied to cord blood serum from postoperative cohorts. Outcome: no signal. Reason: models showed negative Q2 indicating severe overfitting and absence of discriminative metabolic differences between groups
Pregnancy following bariatric surgery: maternal considerations · Imperial · Doctorate
Candidate metabolic biomarkers lose statistical significance after multiple testing correction or univariate filtering
Individual metabolites identified during exploratory profiling failed to reach significance once adjustments for multiple comparisons and clinical covariates were applied. Furthermore, standalone pathway metabolites lacked sufficient discriminatory power to stratify clinical severity, predict intervention response, or differentiate genetic groups.
Tried and failed
mass-spectrometry metabolomic profiling with multiple testing correction applied to cancer risk biomarker discovery. Outcome: no signal. Reason: No individual metabolites remained statistically significant after adjusting for multiple hypothesis testing.
Exploring Pre- and Postmenopausal Breast Cancer Risk Factors through Metabolomics and Risk Prediction Modeling · Harvard · PhD
Tried and failed
untargeted metabolomic profiling and statistical testing applied to distinguishing genetic clones from non-clones. Outcome: no signal. Reason: Rank-sum test yielded no statistically differentiating metabolites between clonal and non-clonal samples.
Metabolomic characterization of coral species susceptible to stony coral tissue loss disease · Georgia Tech · PhD
Tried and failed
targeted liquid chromatography mass spectrometry metabolomics applied to stratifying disease severity stages. Outcome: no signal. Reason: metabolic profiles showed no statistically significant differences across disease progression stages
Upper gastrointestinal disease in familial adenomatous polyposis · Imperial · PhD
Tried and failed
untargeted metabolomic profiling via mass spectrometry applied to disease staging and demographic stratification. Outcome: no signal. Reason: no statistically significant metabolite differences detected across disease stages or patient demographics
Upper gastrointestinal disease in familial adenomatous polyposis · Imperial · PhD
Tried and failed
multivariable biomarker association testing with multiple testing correction applied to circulating metabolite and inflammatory marker associations. Outcome: no signal. Reason: association lost statistical significance after adjusting for confounding metabolic covariates and multiple testing correction
Application of novel technologies to cardiovascular prevention · Harvard · PhD
Tried and failed
Baseline metabolomic profiling for outcome classification applied to surgical diabetes resolution prediction. Outcome: no signal. Reason: No statistically significant differences in baseline metabolite levels between resolution and non-resolution groups
Metabolic insights into bariatric surgical diabetes resolution · Imperial · PhD
Tried and failed
univariate biomarker classification applied to necrotizing enterocolitis diagnosis. Outcome: no signal. Reason: individual pathway metabolites lacked sufficient discriminatory power as standalone diagnostic markers
Mapping the metabolome in the developing gut · Imperial · PhD
Computational annotation, scoring, and feature matching algorithms produce false discoveries or poor discrimination
In silico annotation tools generated structural false positives, while scoring metrics such as retention time and mass error demonstrated near-random ranking accuracy. In addition, isotopic distribution models and feature-matching constraints failed when biological assumptions were violated or dataset features did not overlap.
Tried and failed
binomial distribution modeling of metabolic isotopic labeling applied to partially labeled peptide mass spectra. Outcome: did not generalise. Reason: tracer incorporation is correlated across metabolic pathways rather than being statistically independent and uniformly scrambled
The development and application of mass-spectrometry-based tools to monitor proteome remodeling in microbes · MIT · PhD
Tried and failed
deep learning based molecular fingerprints applied to metabolite structural similarity and phenotype prediction. Outcome: worse than baseline. Reason: Learned and hybrid representations underperformed simple predefined substructure fingerprints for structural grouping.
Computational prediction of health status from the human gut microbiome and metabolome · MIT · PhD
Considered and rejected
Considered and rejected: Rejected standard balanced Gromov-Wasserstein for LC-MS feature matching because exact marginal constraints force all metabolites to match, failing when datasets have non-overlapping features.
Inference from Limited Observations in Statistical, Dynamical, and Functional Problems · MIT · PhD
Considered and rejected
Considered and rejected: Rejected using experimental MS Z-score, RT score, and PPM score to rank putative metabolites due to near-random discriminatory power (AUCs ~0.55-0.59).
Detection and analysis of binding sites and protein-ligand interactions · Boston University · PhD
Tried and failed
metabolite set enrichment analysis on ranked metabolites applied to disease progression regression model features. Outcome: no signal. Reason: VIP-ranked metabolites yielded no statistically significant biological pathways
Machine Learning Approaches for Characterizing ALS Disease Progression · MIT · PhD
Tried and failed
in silico mass spectrometry metabolite annotation applied to bacterial natural product identification. Reason: generated a false positive structural identification disproven upon manual evaluation
Metabolomic characterization of coral species susceptible to stony coral tissue loss disease · Georgia Tech · PhD
Analytical detection limits, low ion intensity, and preparation complexity hinder metabolite measurement
Low-abundance metabolites frequently fell below the quantification limits of platforms like nuclear magnetic resonance and gas chromatography mass spectrometry, generating high proportions of missing values. Target compounds also remained undetected due to complex derivatization requirements or insufficient ion intensities in crude extracts.
Tried and failed
cross-platform metabolite quantification comparison applied to low-abundance urinary metabolites. Outcome: data insufficient. Reason: metabolites fell below NMR quantification limits, yielding too few valid measurements for cross-platform correlation
Lost to a baseline
Metabolomics analysis excluded 11 of 58 identified metabolites because they had 57-92% missing values, violating the 80% rule
Validation and use of novel techniques to study the impacts of large-scale environmental changes on the health of wild waterfowl · Saskatchewan · PhD
Lost to a baseline
Single-quadrupole GCMS SIM methods failed to quantify low-abundance steroids and their metabolites in mouse serum due to extraction and derivatization complexity.
Gut bacterial metabolism of corticoids and other host-produced steroids · Harvard · PhD
Tried and failed
untargeted LC-MS metabolomics profiling applied to plant secondary metabolite detection. Outcome: no signal. Reason: failed to detect target specialized metabolites previously documented in literature for multiple taxa
Exploring quinolizidine alkaloids : built-in pesticide for the Genisteae tribe (Fabaceae) · UT Austin · PhD
Considered and rejected
Considered and rejected: SIRIUS in silico metabolite annotation was rejected for remaining nodes in the B. dendrobatidis network due to insignificant ion intensities in the crude extract.
Chemical Investigation of Chytrid Fungi and Amphibian Skin Microbiome Bacteria · Tübingen · PhD
Discovered metabolic signatures fail to generalize across cohorts or translate across biological settings
Biomarkers discovered in controlled experimental trials or in vitro cultures failed to replicate in free-living human populations and primary tissues. Furthermore, adding candidate metabolic panels to established clinical prediction algorithms failed to improve predictive accuracy over standard baseline scores.
Tried and failed
Multivariate metabolic profiling for biomarker identification applied to personalized dietary intake assessment. Outcome: did not generalise. Reason: Identified biomarkers lacked specificity across diverse demographics, leading to contradictory and uninterpretable dietary feedback
Developing a Personalised Nutrition toolkit for the nutritional management of individuals at risk of cardiovascular disease · Imperial · Master's
Tried and failed
metabolomic profiling via GC-MS applied to primary tumour tissue validation. Outcome: did not generalise. Reason: metabolic trends observed in in vitro cell lines were opposite or absent in primary tumours
Metabolomic characterisation of malignant pleural mesothelioma cell lines and tumours · Imperial · PhD
Tried and failed
supervised multivariate regression on metabolic profiles applied to dietary assessment in free-living individuals. Outcome: did not generalise. Reason: controlled trial biomarkers had poor agreement and systematic bias when applied to free-living populations
Applying metabolic profiling as an objective dietary assessment method for personalised nutrition · Imperial · PhD
Lost to a baseline
Adding metabolites via Elastic-Net or BorutaSHAP failed to outperform standard recalibrated QRISK3 in C-index (0.759 vs 0.750 in women; 0.710 vs 0.706 in men) or categorical NRI.
Metabolomics and coronary heart disease risk in UK Biobank · Oxford · PhD
Target metabolic differences are obscured by dominant clinical confounders and non-specific physiological variance
Multivariate metabolic profiles were often dominated by background variables such as medication metabolites, primary disease states, or end-stage structural damage. Consequently, unsupervised clustering and classification methods separated samples along confounding axes rather than the intended clinical phenotypes.
Tried and failed
multivariate statistical analysis of NMR metabolomic profiles applied to stratifying patients by body mass index. Outcome: no signal. Reason: metabolic variance was dominated by primary disease state rather than obesity
Metabonomic profiling in inflammatory bowel disease: application to real-life population of patients · Imperial · Doctorate
Tried and failed
unsupervised principal component analysis on metabolomic profiles applied to disease case-control stratification. Outcome: no signal. Reason: metabolic variance lacked distinct unsupervised clustering corresponding to clinical disease or outcome groups
Mapping the metabolome in the developing gut · Imperial · PhD
Considered and rejected
Considered and rejected: Rejected sampling urine metabolites from diagnosed CKDnt cases because resulting metabolite profiles reflect non-specific structural end-stage damage rather than early causal etiology.
Role of endogenous and exogenous factors in chronic disease development and progression · Boston University · PhD
Tried and failed
multivariate classification of NMR metabolic profiles applied to ulcerative colitis biomarker discovery. Outcome: no signal. Reason: separation was driven by medication metabolites rather than underlying disease pathophysiology
Metabonomic profiling in inflammatory bowel disease: application to real-life population of patients · Imperial · Doctorate
Left open by the authors
Problems the authors named and did not get to.
Left open
Validate associations between intra-individual metabolite variability and clinical risk profiles using longitudinal metabolomics data from cohorts with metabolic diseases. Blocker: Access to longitudinal, repeated-measurement clinical metabolomics datasets with disease outcome annotations.
Exploring intra-individual metabolite variation in metabolomic data · University College Dublin · PhD
Left open
Compute Spearman correlations between microbiome taxonomic abundances and urinary metabolite levels and generate heatmap correlograms. Blocker: Requires the private patient 16S sequencing and 1H-NMR metabolomics datasets generated in the thesis
Metabonomic profiling in inflammatory bowel disease: application to real-life population of patients · Imperial · Doctorate
Left open
Integrate microbial composition data with participant metabolite profiles to identify bacterial strains associated with specific metabolite surges. Blocker: Requires private paired microbial sequencing and participant-specific metabolomic data from the thesis study.
Investigating the role of the gut metabolome in appetite regulation and obesity · Imperial · PhD
Left open
Replicate and validate the 204-metabolite ultra-processed food signature in independent cohorts using alternative metabolomics platforms. Blocker: Requires access to controlled/restricted independent cohort metabolomics and dietary datasets.
Left open
Determine whether lysosome-related organelle-dependent modular metabolite biosynthesis is conserved in mammalian systems. Blocker: Requires wet-lab experimental biology and mammalian cell/tissue metabolomic profiling
COMBINATORIAL ASSEMBLY OF MODULAR METABOLITES VIA CARBOXYLESTERASES IN NEMATODES · Cornell · PhD
Left open
Identify and characterise unknown LC-MS metabolomic features (e.g., m/z 162.0533, 198.0386, 166.0131) elevated during Drosophila bacterial infection. Blocker: Requires original raw MS/MS spectra, physical reference standards, or wet-lab validation to confirm metabolite identities
A genetic and metabolomic analysis of the Drosophila melanogaster innate immune response · Imperial · PhD
Left open
Identify the specific metabolomic features driving Telmisartan's divergent metabolic separation over the 0-8 h time course dataset. Blocker: Requires private experimental mass spectrometry metabolomics time-course data from the thesis author's lab.
Development of Metabolomics Approaches to Decipher Chemical Interactions in Microbial Communities · Tübingen · PhD
Left open
Conduct metabolomic studies to evaluate whether taurine metabolites provide a better therapeutic effect than taurine itself in taiep rats. Blocker: Requires wet lab facilities, biological samples, and metabolomic profiling instruments (e.g., mass spectrometry).
Efecto de la administración de taurina sobre citoesqueleto, mielina, actividad motriz y neurogénesis en la rata taiep · BUAP · PhD
Left open
Perform fecal metabolomic profiling to correlate excreted microbial metabolites with circulating and tissue metabolic outcomes in the mouse cohort. Blocker: Requires wet-lab metabolomics instrumentation and physical fecal samples from the animal cohort
Understanding the Interactions Between Maternal PBDE Exposure and the Functional Gut Microbiome in Developing Mouse Offspring · University of Washington · PhD
Left open
Perform metabolomic and metatranscriptomic profiling to identify and quantify novel secondary metabolite/PKS products linked to gene expression in Gambierdiscus microbiomes. Blocker: Requires wet-lab experiments for metabolomics and metatranscriptomic sequencing of Gambierdiscus microbiomes.
Novel microbes and viruses with roles in biogeochemical cycling and eukaryogenesis in marine systems · UT Austin · PhD
Who has worked on this
Authors of the public theses cited on this page, most-cited first.
- Sam Tristan Richmond Powles · Imperial · Doctorate · 2021
Metabonomic profiling in inflammatory bowel disease: application to real-life population of patients - Jessica M. Deutsch · Georgia Tech · PhD · 2024
Metabolomic characterization of coral species susceptible to stony coral tissue loss disease - Isabel Martin · Imperial · PhD · 2024
Upper gastrointestinal disease in familial adenomatous polyposis - Maria Sani · Imperial · PhD · 2023
Mapping the metabolome in the developing gut - Chidimma Kanu · Imperial · Doctorate · 2021
Pregnancy following bariatric surgery: maternal considerations - Abzer Kelminal Pakkir Mohamed Shah · Tübingen · PhD · 2026
Development of Metabolomics Approaches to Decipher Chemical Interactions in Microbial Communities - Jerusa Brignardello · Imperial · PhD · 2025
Investigating the role of different dietary patterns on gut metabolites - Shubbham Gupta · University College Dublin · PhD · 2025
Exploring intra-individual metabolite variation in metabolomic data - Sarah Kim · University of Washington · PhD · 2025
Understanding the Interactions Between Maternal PBDE Exposure and the Functional Gut Microbiome in Developing Mouse Offspring - Kenny Mendoza-Herrera · Harvard · PhD · 2024
Association Between Ultra-Processed Food Intake and Metabolic Profile and Risk of Type 2 Diabetes and Cardiovascular Disease in U.S.-Residing Cohorts of Hispanic/Latino and White Adults - Bertina Telusma · MIT · PhD · 2024
The development and application of mass-spectrometry-based tools to monitor proteome remodeling in microbes - Monica-Maria Hill · Imperial · PhD · 2024
Investigation of the effects of dietary fibres on gut microbiota, metabolism and glycaemic control across generations
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