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Generic non-linear models of prognostic outcome. Paulo Lisboa , Terence Etchells, Ian Jarman Ana Sofia Fernandes Elia Biganzoli. Outline. Data from an observational longitudinal cohort study in oncology Risk stratification for time-to-event data
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Generic non-linear models of prognostic outcome Paulo Lisboa, Terence Etchells, Ian Jarman Ana Sofia Fernandes Elia Biganzoli
Outline • Data from an observational longitudinal cohort study in oncology • Risk stratification for time-to-event data • Integrated interface showing domain-specific visualization of the database • Multi-centre validation
Breast tumours - clinical indicators Recruitment criteria: TNM (<=2, <=1, 0), Path. size<= 5cm Modelling cohort recruited during (n=917) 1983-89 Validation cohort (n= 931) 1990-93
Cox regression Prognostic index βi X1 X2 … tk
Nottingham Prognostic Index (NPI) NPI= 0.2*Path. Size (cm)+ Histological Grade (1:3)+ N stage (1:3)
Partial Logistic Artificial Neural Network X1 X2 … tk 1 1 Prognostic index wij vjk
Partial Logistic Artificial Neural Network Attributes Time Value Event indicator X . . . . . . X 0.5 0 1 J X . . . . . . X 1.5 0 1 J X . . . . . . X 2.5 0 1 J X . . . . . . X 3.5 1 1 J Example:A patient who survives 3 years and dies during year 4
Bayesian regularisation framework 1 1 X1 X2 … tk
Automatic Relevance Determination (ARD) X1 X2 … tk 1 1 Path size Clinical stage nodes Histological type Nodes ratio Age ER status
Automatic Relevance Determination Bayesian regularization framework for ARD Setting the regularization parameters Model selection
Automatic Relevance Determination Bayesian regularization framework for ARD Setting the regularization parameters Model selection
The evidence approximation αm 1 1
Marginalisation a Σ 1 1
Cox regression, breast cancer mortality: Christie 1983-89 1 2 3 4 Cox regression prognostic indexes arising in a 60 months study of LRG
PLANN-ARD, breast cancer mortality: Christie 1983-89 1 2 3 4
Hazard function, breast cancer mortality: Christie 1983-89 Operable patients
1990-93 1983-89
Competing risks • Model time to first event • More than one risk – • e.g. intra-breast recurrence cf. distant metastasis • Case series from the Istituto dei Tumori, Milan (n=2,010) • (Veronesi et al. (1995) ) • Recruitment criterion QUART: conservative surgery
Competing risks • Classification into mutually exclusive and complete classes a1 y1=h1 + a2 y2 =h2 + a3 y3=1- h1 -h2 +
Cause-specific hazards DM IBTR Cumulative hazard Time
Conditional cause-specific hazard IBTR Distant metastasis Hazard rate 4.3 cm ← 0.2 cm Years Years 4.3 cm ← 0.2 cm Tumour size Tumour size
Conditional cause-specific hazard IBTR Distant metastasis Hazard rate Hazard rate 78 yrs ← 18 yrs 78 yrs ← 18 yrs Years Age Years Age Years Years 15 ← 0 15 ← 0 Nodes involved Nodes involved
Double blind evaluation Ocular melanoma
Double blind evaluation Ocular melanoma Cox regression PLSP PLANN-ARD
Individual Survival Distributions 88 82 1 2 3 … 60
Decision trees Rules PLANN-ARD
The Learned Intermediary Doctrine • The learned intermediary doctrine says that product manufacturers owe no duty to warn consumers about the risks of consuming their products because the manufacturers can rely on the prescribing physician to do so. Law of Torts
Rule extraction • Decompositional methods • Rules are derived for each hidden node • These rules are then composed together using the logic of the output node • Boolean logic derived in this way may contradict the real-valued network outputs x1 y x2 1 1
Rule extraction Axis parallel boxes to fit smooth decision surfaces
Multi-linear functions and scalar logic • Tsukimoto showed that the logic from a MLP with output • can be optimally resolved by approximating in [0,1] y as a function of the form • where or TSUKIMOTO, H., “Extracting rules from trained neural networks”, IEEE Transactions on Neural Networks, vol. 11, no. 2, pp. 377-389, March 2000. T.A. Etchells
Multi-linear functions and scalar logic • e.g. for a 2 input network • where the parameters are to be determined. • The parameters are evaluated by substituting the values 0 or 1 for each variable. T.A. Etchells
Rule extractionData in class are BLUE and data out of class are RED T.A. Etchells
The Decision Surface T.A. Etchells
Search in Orthogonal Directions T.A. Etchells
Search in Orthogonal Directions T.A. Etchells
Create Rule Box from the search T.A. Etchells
Sensitivity and Specificity T.A. Etchells