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preeclampsia

README.md

Preeclampsia QSP Model

Disease Compartments Scenarios References

Overview

Preeclampsia (PE) is a pregnancy complication affecting 2–8% of pregnancies worldwide, defined by new-onset hypertension (SBP ≥140 or DBP ≥90 mmHg) after 20 weeks gestation combined with proteinuria (≥300 mg/24h) and/or end-organ damage. It is a leading cause of maternal and perinatal morbidity and mortality globally.

This QSP model integrates:

  • Placental dysfunction and inadequate spiral artery remodeling
  • Angiogenic imbalance: sFlt-1↑, PlGF↓, sEng↑
  • Endothelial dysfunction: NO↓, ET-1↑, ROS↑
  • Multiorgan involvement: cardiovascular, renal, coagulation, neurological, hepatic
  • Drug PK/PD: Aspirin (prophylaxis), Labetalol, Nifedipine, MgSO4

Mechanistic Map

Preeclampsia QSP Map

Figure: Mechanistic map of preeclampsia pathophysiology and pharmacology. Click image to open interactive SVG. Generated with Graphviz (neato layout).

15 subgraph clusters covering: Maternal Risk Factors · Placental Dysfunction · Angiogenic Imbalance · Endothelial Dysfunction · Cardiovascular/BP · Renal · Coagulation/HELLP · Neurological · Hepatic · Complement · Fetal · Aspirin PK/PD · Labetalol PK/PD · Nifedipine PK/PD · Magnesium Sulfate PK/PD · Clinical Endpoints

Model Structure

ODE Compartments (20 total)

# Compartment Description
1 DEPOT_ASP Aspirin gut absorption depot
2 ASPIRIN Aspirin central plasma (mg)
3 SALICYLATE Salicylate (hydrolysis product)
4 COX1_INH COX-1 inhibition state (0–1, irreversible)
5 DEPOT_LAB Labetalol gut depot
6 LABETALOL Labetalol central plasma
7 DEPOT_NIF Nifedipine gut depot
8 NIFEDIPINE Nifedipine central plasma
9 MG_PLASMA Magnesium plasma pool (mmol)
10 SFLT1 sFlt-1 plasma (pg/mL)
11 PLGF PlGF plasma (pg/mL)
12 SENG Soluble endoglin (ng/mL)
13 NO_EA Nitric oxide bioavailability (relative)
14 ET1 Endothelin-1 (pg/mL)
15 ROS Reactive oxygen species index
16 SBP Systolic blood pressure (mmHg)
17 DBP Diastolic blood pressure (mmHg)
18 GFR_C Glomerular filtration rate (mL/min/1.73m²)
19 PROTEINURIA Proteinuria (mg/24h)
20 PLATELET Platelet count (×10³/µL)
+2 LDH_MK, SEIZURE_RISK HELLP/neurological markers

Treatment Scenarios (6)

Scenario Treatment Rationale
1 No treatment Natural PE progression
2 Aspirin 75 mg/day (12 wk→) ASPRE trial: 62% reduction in early PE
3 Labetalol 200 mg BID (24 wk→) CHIPS trial: α1+β blocker for BP control
4 Nifedipine 30 mg MR/day (24 wk→) L-type Ca²⁺ blocker, CHIPS trial
5 MgSO4 4 g load + 1 g/h (30 wk→) Magpie trial: 58% ↓ eclampsia
6 Combination (Aspirin + Labetalol + MgSO4) Optimal multidrug approach

Key Clinical Thresholds

Biomarker Normal PE Threshold Severe PE
SBP (mmHg) <140 ≥140 ≥160
DBP (mmHg) <90 ≥90 ≥110
sFlt-1/PlGF ratio <38 38–85 >85
Proteinuria (mg/24h) <300 ≥300 ≥5000
Platelets (×10³/µL) >150 100–150 <100 (HELLP)
LDH (IU/L) <600 600–800 >800 (HELLP)
Mg²⁺ plasma (mmol/L) 0.7–1.0 1.7–3.5 (therapeutic) >3.5 (toxic)

Files

File Description
pe_qsp_model.dot Graphviz source (15 clusters, 150+ nodes)
pe_qsp_model.svg Scalable vector mechanistic map
pe_qsp_model.png PNG thumbnail (150 dpi)
pe_mrgsolve_model.R mrgsolve ODE model + 6 scenario simulations
pe_shiny_app.R 8-tab Shiny interactive dashboard
pe_references.md 60 curated references (PubMed links)
README.md This file

Quick Start

# Render mechanistic map
neato -Tsvg pe_qsp_model.dot -o pe_qsp_model.svg
neato -Tpng -Gdpi=150 pe_qsp_model.dot -o pe_qsp_model.png
# Run mrgsolve simulation
install.packages(c("mrgsolve","dplyr","ggplot2","tidyr","patchwork"))
source("pe_mrgsolve_model.R")

# Launch Shiny dashboard
install.packages(c("shiny","shinydashboard","DT","gridExtra"))
shiny::runApp("pe_shiny_app.R")

Shiny Dashboard Tabs

  1. Patient Profile — Parameters, clinical status at GA 36wk, threshold table
  2. Drug PK — Aspirin, Labetalol, Nifedipine, MgSO4 plasma concentrations over gestation
  3. Angiogenic Balance — sFlt-1, PlGF, sEng, sFlt-1/PlGF ratio trajectories
  4. Cardio-Renal — BP (SBP/DBP), endothelial markers, GFR, proteinuria
  5. HELLP & Neuro — Platelet count, LDH, seizure risk, Mg safety window
  6. Scenario Comparison — All 6 treatment arms side-by-side
  7. Biomarker Panel — Heatmap + data table across gestation
  8. About — Model description, calibration sources, thresholds

Key Calibration Sources

Trial Finding Model Parameter
ASPRE (Rolnik 2017, Lancet) Aspirin 62% ↓ early PE F_Asp, kBP_Asp
Maynard 2003 (J Clin Invest) sFlt-1 overexpression → PE phenotype kprod_sFlt1, k_sFlt1_rise
Verlohren 2010 (AJOG) sFlt-1/PlGF ratio cutoff 38 Threshold encoding
CHIPS 2015 (NEJM) Labetalol/Nifedipine BP control Emax_Lab, Emax_Nif
Magpie 2002 (Lancet) MgSO4 58% ↓ eclampsia Emax_NMDA, seizure ODE

Pathophysiology Summary

Placental Hypoxia / Insufficient Trophoblast Invasion
       ↓
HIF-1α → ↑sFlt-1 secretion ──→ Sequestration of VEGF & PlGF
       ↓                              ↓
   ↑sEng ──────────────────→  ↓ VEGFR2 signaling
                                      ↓
              Endothelial Dysfunction (↓NO, ↑ET-1, ↑ROS)
                          ↓
         ┌─────────────────┴──────────────────┐
         ↓                                     ↓
    ↑SVR → Hypertension              Glomerular endotheliosis
    ↑TXA2 → Platelet aggregation     → Podocyte injury
         ↓                                     ↓
    HELLP Syndrome                        Proteinuria
    Eclampsia (if MgSO4 ↓)           ↓GFR → ↑Creatinine

Generated by Claude Code Routine (CCR) — QSP Disease Model Library | 2026-06-25