The four late-onset sepsis models, compared across eight dimensions.

Why this page exists.

Episode 03 of Road to CEPAS 2026 is a close read of the four anchor papers in Branch A, continuous-physiology machine learning for late-onset sepsis (LOS) in preterm infants. The Substack post argues that the headline AUCs are similar but not the same, and that the two decisions which matter most, signal stack and alarm policy, are the two the literature documents least clearly.

This page is the working file behind that argument: the full eight-dimension comparison, read across Berg 2023 (WKZ Utrecht), Kausch 2023 (UVA and two partner NICUs), Yang 2024 (Eindhoven/Máxima) and Meeus 2024 (Antwerp/Innocens). Three supporting-cast papers from the Episode 02 map, Honoré, Leon, Rio, sit at the foot. Full citations and licensing are in the references.

The four papers at a glance.

Cohort design.

• Berg — Retrospective, single-centre, 2008–2019. Every consecutively admitted infant GA ≤32 wk regardless of admission reason: the broadest, least selected population of the four. Controls drawn from negative-culture and out-of-window patients, matched on GA and time-since-birth.
• Kausch — Retrospective, three NICUs, 2012–2021. Restricted to VLBW (<1500 g), a narrower, sicker slice. Strict definition: positive culture after day 3, ≥5 days antibiotics, ≥2 antibiotic-free days before.
• Yang — Retrospective, single-centre, 2016–2018. The smallest and most selected cohort: 51 LOS + 68 controls. Clean cases, clean controls, ideal for modelling, least representative of a real ward.
• Meeus — Retrospective, single-centre, 2012–2020. Outcome is LOS and NEC jointly, 206 combined episodes. Not a LOS-only paper.

Signal stack.

Really three decisions in one: which signals, sampled how fast, from which device.

• Berg — Two signals, 1/min: HR and SpO2 only. Deliberately excluded CRP and blood pressure (clinician-initiated, leakage risk) and temperature and RR (artefact-prone).
• Kausch — Two signals plus their cross-correlation, 0.5 Hz. Key finding: performance is essentially unchanged whether HR comes from ECG or pulse oximetry, the model can run on a standalone oximeter.
• Yang — Three signals, 1 Hz, 102 features. The sampling-rate ablation: raw waveform 0.886 → 1 Hz 0.875 → 1/min 0.825 → 1/h 0.687. Minute-by-minute is the deployable floor; hourly destroys the signal.
• Meeus — Seven signals, 1/min, the widest stack. But breadth does not produce a cleanly higher comparable AUC.

ML methodology.

• Berg — LR vs GAM vs XGBoost; all within 0.01 AUC, no significant difference by DeLong's test. Chose LR for interpretability.
• Kausch — LR (cubic splines) vs neural net vs XGBoost vs random forest; similar across all. Chose LR, "equal performance, better explainability."
• Yang — Seven methods including two deep-learning architectures. XGBoost won; deep learning underperformed.
• Meeus — XGBoost only, no bake-off. SHAP for explainability.

Validation rigour.

• Berg — 75/25 patient-grouped split, bootstrap CIs, longitudinal alarm simulation. Single-centre; no external validation.
• Kausch — The field's strongest: trained on one NICU, externally validated on two others. TRIPOD-reported, calibration assessed per site. External drop ≈0.03 AUC.
• Yang — 7-fold cross-validation, nested for hyperparameters. Single-centre; no external validation, named as the main limitation.
• Meeus — Cross-validation plus a temporal hold-out (year-2020 patients). Still single-centre; generalisability stated as the main limitation.

Performance.

Each number, with its conditions attached, that is the point.

• Berg 0.79 — cross-sectional AUC at t=0 (0.73 train / 0.79 test), whole-NICU, culture-positive LOS. Longitudinal: ≈58–67% recall under the multi-threshold policy; ≈47–60% of patients detected pre-clinically.
• Kausch ≈0.79 — prediction within 24 h, VLBW-only, external. Pulse-rate ≈ ECG. Risk rises significantly 23–24 h before blood culture.
• Yang 0.875 — measured 6 h before CRASH, on 119 hand-cleaned infants. Patient-wise sensitivity 96.1%, but specificity 19.1%.
• Meeus 0.93 — for LOS+NEC jointly, on cross-validated time windows (a metric Meeus flag as optimistic on imbalanced data). Sliding-window: 69% all / 81% severe; median time gain ≈10 h.

Alarm policy.

What converts an AUC into something a clinician actually experiences, chosen four different ways, rarely justified.

• Berg — Hourly scores; thresholds set to fixed unit-wide rates. 8-hour refractory period (a nursing shift); a muted alarm re-fires only if a higher threshold is crossed. Burden reported as alarms per patient-day.
• Kausch — An alert switches on at a threshold and stays on until 24 h with no further crossing. No refractory period, no escalation.
• Yang — Adopts Berg's framework wholesale, same 8-hour silencing, same multi-threshold escalation, and cites it.
• Meeus — Hourly probabilities aggregated into 24-hour buckets; reports alarm-days per week, echoing Berg's burden accounting without the refractory machinery.

Honest limitations.

• Berg — Imputed blood-culture timestamps; culture-positive-only labelling; blood-culture time as a suspicion proxy may overestimate lead time; may fire on non-sepsis deterioration.
• Kausch — Missing-data exclusions; culture-proven-only definition; co-morbidities alter features; a prospective multicentre study still needed.
• Yang — Selected, non-representative cohort; maturation difference between groups; small dataset; no external validation; deep learning underperformed.
• Meeus — LOS labelling is error-prone; retrospective-labelling risk; no generalisability data; AUROC optimistic on imbalanced data; metrics are backward-looking.

Unique contributions.

• Berg — Largest unselected single-centre cohort; the most extensive retrospective clinical-impact simulation in the LOS literature; the alarm-fatigue framework that became a field convention.
• Kausch — The only true multi-NICU external validation; the pulse-rate-equals-ECG finding; HR–SpO2 cross-correlation as a feature; a direct benchmark against the legacy HRC index.
• Yang — The sampling-rate ablation; the seven-method bake-off showing deep learning does not help; concrete evidence of Berg's alarm framework propagating.
• Meeus — Joint LOS+NEC prediction; the widest signal stack; the only commercial spinoff (Innocens BV); a pointed critique of AUROC on imbalanced data.

Supporting cast.

Three further Branch A groups mapped in Episode 02, included in the close read as context rather than as anchors.

• Honoré 2023, Karolinska / KTH. 325 infants, only 20 LOS cases; Naïve Bayes, chosen to avoid overfitting a tiny positive set; AUROC 0.82 up to 24 h before suspicion.
• Leon 2021, Rennes. 49 infants; HRV from ECG only, visibility-graph features; AUROC 0.877 in the 6 h before antibiotics. The methodologically distinctive single-signal end of the spectrum.
• Rio 2022, Lausanne. Not a model paper: an independent validation of the commercial HeRO/HRC index. Strongly gestational-age-dependent (sensitivity 76% at <28 wk vs 25% at >32 wk); optimal cutoff 2.76, not the FDA-cleared 2.0.