r/BiomarkerScience

▲ 7 r/BiomarkerScience+2 crossposts

The same EKG you get at a routine checkup may hold a hidden warning sign for sudden cardiac death, and an AI can now read it. 86% of the high-risk people it found were missed by the test doctors rely on today

Sudden cardiac death is, in principle, preventable with an implantable defibrillator, but the hard part is knowing who needs one. The single biomarker in wide use is left ventricular ejection fraction (LVEF), basically how strongly the heart squeezes, measured by ultrasound. The problem is that LVEF misses most people who die suddenly, and at the same time over-flags others, since about two-thirds of defibrillators placed for low LVEF never end up delivering a life-saving shock. So the field has wanted a better predictor for a long time, and the ECG, which is cheap and everywhere, has been an obvious place to look.

The team trained a deep-learning model on every ECG from an entire Swedish region linked to death certificates, and they did something unusually disciplined: they locked away 40% of the data and did not touch it until after the paper was provisionally accepted, which is about the strongest guard against overfitting you can ask for. In that held-out set the model predicted sudden cardiac death within a year with an AUC of 0.872, well above standard cardiovascular risk scores (around 0.70). Their chosen high-risk group was the riskiest 2.2% of people, who had a 7.0% annual rate of sudden cardiac death, higher than the 4.6% rate in the group with reduced LVEF. The striking number is the overlap: 86% of the model's high-risk patients were not flagged by LVEF at all. Even among people with a normal LVEF, where today there is essentially no way to stratify risk, the model picked out a group at higher risk than the reduced-LVEF patients. And as suggestive (not definitive) evidence of real stakes, high-risk patients who happened to have a defibrillator already in place died about 54% less often than expected.

It held up outside Sweden too. With no retraining, the model hit an AUC of 0.822 for predicting the ventricular arrhythmias that cause sudden death in a US health system, and 0.767 for future arrhythmic cardiac arrests in a Taiwanese registry. They also ran a clever specificity check: the model did poorly (near chance, 0.58) at predicting non-arrhythmic arrests, which is what you want, since it suggests it is picking up arrhythmic death specifically rather than just "sick person." Then the genuinely novel part. Because a neural net cannot tell you what it sees, they paired it with a generative model that morphs a real low-risk ECG into a higher-risk version, letting them visualize the signal. Out came some known features (left axis deviation, poor R-wave progression) plus a previously undescribed one: a slurred tail on the QRS complex in lead aVL. Tracing that back to physiology, they propose diffuse myocardial fibrosis as the underlying culprit, supported by blinded heart-MRI review showing more diffuse scarring in high-risk patients. A telling detail: in those same patients' charts, no cardiologist had ever noted the fibrosis.

The limits are real and the authors are upfront about them. The defibrillator survival benefit is observational, drawn from patients already selected for devices under current practice, so it cannot prove a defibrillator would help these newly flagged patients. They explicitly call for a randomized trial, which is the right next step. The training label, death certificates, is imperfect for pinning down arrhythmic cause, though the multi-country arrhythmia validation cushions that. And this is a research model, not a deployed or cleared tool.

What you can follow

The conceptual shift worth tracking is from structural risk (how weak is the pump) to electrical risk read straight off the waveform, since these turn out to identify largely different people. The thing that would change practice is a randomized trial in the model's high-risk group, so watch for that. Two other threads are interesting: the generative "morphing" approach is a general recipe for turning an opaque model into a human-inspectable hypothesis, and the fibrosis story plus the aVL feature could feed back into ordinary ECG reading if they replicate. AI-ECG is a fast-moving area generally, so expect a wave of similar models, and apply the usual scrutiny about held-out validation and external cohorts.

Are there tests available today to measure this?

The input is about as available as medicine gets: a standard 12-lead ECG is cheap, fast, and probably already in your chart if you have seen a cardiologist. The catch is that this specific model is not a product you can request, not regulatory-cleared, and not running in clinics. Some AI-ECG tools are FDA-cleared for other tasks (detecting low ejection fraction or atrial fibrillation), but not this sudden-death biomarker. One nuance from the paper: single-lead versions of the model performed almost as well on discrimination, which is intriguing for the wearable era, but it would be a real stretch to read this as "your smartwatch can predict sudden cardiac death," and nobody should treat a consumer single-lead trace that way. If anyone here works in a system piloting AI-ECG risk tools, real deployment experience would be valuable, since this field is moving from papers to products quickly.

What you can track

This is a topic where the honest answer is that the action item is professional, not self-tracking. The modifiable, measurable drivers of cardiac risk are the familiar ones (blood pressure, ApoB or LDL, glucose, not smoking, cardiorespiratory fitness), and they are worth tracking on their own merits. But the specific signal here is not something to chase at home. The genuinely useful move is recognizing red flags that warrant a real cardiology workup: unexplained fainting, episodes of racing or irregular heartbeat, or a family history of sudden or unexplained death at a young age. Those are reasons to get evaluated, ECG included, rather than anything to monitor with a gadget.

Paper: https://doi.org/10.1038/s41586-026-10674-6

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u/DermSherpa — 6 days ago
▲ 8 r/BiomarkerScience+2 crossposts

Biological "age gap" has crept up generation by generation, and young adults whose biology runs older than their birthday had higher rates of early-onset cancer (154,169 in UK Biobank, echoed in a US cohort)

Early-onset cancer, the kind diagnosed before about 50 to 55, has been rising in younger generations for reasons that are not fully explained by the usual suspects. This study asked whether "biological age," the gap between how old your body looks on molecular and clinical measures versus your actual birthday, is part of the story. The appeal of that framing is that a single age-gap number rolls up the cumulative damage from many exposures at once, which is useful when no single risk factor explains the trend.

The team measured systemic biological age in 154,169 UK Biobank participants who were under 55 at enrollment, using PhenoAge (a clock built from nine routine blood values plus age), and cross-checked with two other clocks (the Klemera-Doubal clinical clock and a metabolomic clock from NMR data). Two things stood out. First, the age gap has drifted older across birth cohorts: people born 1965 to 1974 carried a meaningfully larger PhenoAge gap than those born 1950 to 1954, and in the US All of Us cohort the generational jump looked even steeper. Second, a larger age gap tracked with more early-onset cancer. Each standard-deviation increase in the PhenoAge gap was linked to roughly 8% higher risk of early-onset solid cancer overall, concentrated in lung, gastrointestinal (including colorectal), and uterine cancers. The association held after adjusting for smoking, BMI, lifestyle, telomere length, and genetic risk scores for both aging and cancer, which is the part that makes it more than a restatement of "unhealthy people get cancer." They then went one layer deeper with the proteomic organ-specific clocks and found specific pairings: an older immune system tracked with early-onset lung cancer, and older adipose tissue tracked with early-onset colorectal cancer.

The honest limits matter here. This is observational, so accelerated aging is associated with cancer but not proven to cause it, and residual confounding is always possible. The organ-specific part is the most tentative: it used a smaller subgroup, few cancer cases, and the organ clocks were originally built in an overlapping UK Biobank sample, which the authors flag as a circularity risk they reduced but could not fully remove. The US replication had only about 100 cancer cases over short follow-up. And these are relative risks layered on a still-uncommon outcome, so a larger age gap is a population signal, not a personal diagnosis.

What you can follow

The deeper question is whether the age gap is a cause you can act on or just a sensitive thermometer for accumulated exposure. Answering it needs within-person tracking over time rather than one snapshot, since the authors' own data showed a person's PhenoAge tertile was only moderately stable across about four years. Also worth watching: the generational drift itself, which points at shared exposures (earlier obesity and metabolic dysfunction, diet, sedentary time, environmental chemicals, circadian disruption) rather than genetics, and the organ-specific leads, since immune-to-lung and adipose-to-colorectal give mechanistic hooks that future work can test directly.

Are there tests available today to measure this?

This is the unusually accessible part. PhenoAge runs on nine standard analytes you can get from routine bloodwork (albumin, alkaline phosphatase, creatinine, C-reactive protein, glucose, mean cell volume, red cell distribution width, white blood cell count, and lymphocyte percentage) plus your age, so if you have a recent CBC, a metabolic panel, and a CRP, you already have the inputs, and free PhenoAge calculators exist. The Klemera-Doubal clock is similar. The metabolomic clock relies on Nightingale-style NMR panels, which a few consumer services now offer. The organ-specific proteomic clocks are still research-grade and run on the Olink platform, not something you can order off the shelf yet. If anyone has computed their own PhenoAge from standard labs or used a consumer metabolomic-age product, it would be useful to compare notes on how reproducible the numbers were between draws, since stability is the weak point.

What you can track

The neat thing about PhenoAge is that its inputs are themselves modifiable health markers, so the levers and the readout overlap. C-reactive protein reflects inflammation, fasting glucose reflects metabolic health, and the rest move with the usual factors: not smoking, body composition, activity, and alcohol. Track those directly, and if you compute a biological age, treat it as a trend line across several measurements rather than a single verdict. A one-off elevated age gap is a prompt to look at the underlying labs, not a reason to assume anything about cancer risk in particular.

Paper: https://doi.org/10.1038/s41591-026-04448-w

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u/DermSherpa — 9 days ago