Introduction & covariates

Covariate Model Building

Pharmacometrics Research Group Department of Pharmaceutical Biosciences Uppsala University Sweden

Intro & Covariates

Building covariateparameter models Timevarying covariates

Exploratory analyses Building covariateparameter models

Special models & covariates

Study design & covariates

Missing covariates Covariate model use Model evaluation

Individual covariateparameter relations

Population analysis nonlinear mixed effects modeling

Observed plasma drug concentrations in children after a single dose
30

10

81 30

Dose
81 96

Concentration

54 44 31 11 28 54 31 98 15 12 15 23 76 57 60 52 12 23 46 89 97 5771 33 4 75 4 79 98 21 89 32 74100 59 33 76 63 6 48 61 9 62 46 26 28 92 26 100 38 91 74 6 32 95 476769 8 70 43 20 22 61 63 45 95 18 82 69 86 78 8 70 64 35 19 19 64 85 17 17 35 85 27 80 48 80 82 18 73 99 38 99 56 55 77 78 53 83 56 36 1314 88 41 49 27 49 55 77 29 53 83 93 73 93 87 1 94 36 90 41 1 94 88 90 16 58 40 5 5 91 39 66 29 66 87 40 92 25 37 25 37 42 39 42 11 44 96

V CL

71

97

68 62 45 58 10 51 79 75 3 65 2 84 24 7

21 51 59 67 9 3 47 60 2 52 10

24 68 84 22 43 20 65 72 34

72

13 8614

50

50

0 0 5 10 15

Time
3

Regression (population)
REAL WORLD MODEL WORLD Dose

V CL

+V ~ N (V , v 2 )
~ N (0, 2 )

CL ~ N (CL , CL 2 )

ESTIMATION

Why do we want to include covariates into the model?

Identify patient sub-groups at potential risk of toxicity/suboptimal effect Confirm absence of important influence from covariate Increase the predictive performance of the model Increase the understanding of a studied system Increase the mechanistic interpretability of the model Understand trial characteristics Hypothesis generation
5

Covariates
Demographics Gender, age, size (weight, height, BSA, BMI), race Lab values Serum creatinine, bilirubin, albumin, pheno/genotype Disease parameters Baseline, etiology, disease duration, general status Therapy related Comedication, pretreatment, dialysis
6

Covariates (contd)
Habits / Environmental factors Smoking, alcohol, food, diet, time of day or year Study related Center, investigator, visit

Covariate types
Continuous Age Bivariate (dichotomous) Sex Ordered categorical Smoking (none, occasional, daily) Non-ordered categorical Race (caucasian, black, asian)

Skewed distributions
Non-linear relationships with covariate, or Linear relationships with log(covariate)
ALT distribution
3000 2500 2000 1500 1000 500 1600 1400 1200 1000 800

log(ALT) distribution

600
400

200
0 2 16 30 44 58 72 86 100 114 128 142 156 170 184 198 212 226 240 254 268 281 295 309 323 337 351 365 0 0.7 1.4 2.0 2.7 3.3 4.0 4.7 5.3

10

Covariate correlations
1.8 1.6 1.4 1.2 1.2 1.4 1.6 1.8

SECR

1.2 1.0 0.8 0.6

0.6

0.8

1.0

1.2

100

120

120

100

WT
80

60 60 160 180 170 180 80

170 160

HT

160

150 140 50 60 60 150 160

140

50

AGE
40 30 30 40

11

Adults

Males

Females

Children

Males

Females

Nonsmokers

12

Nonsmokers

15

Smokers

18

Smokers

12

Covariate correlations
GENO: 2
40

GENO: 3

30

20

10

Percentage of total

GENO: 0
40

GENO: 1

30

20

10

0 20 25 30 35 40 45 20 25 30 35 40 45

AGE

13

Covariate correlations
Correlated covariates partially carry the same information To simultaneously have correlated covariates in the model will increase model instability and may result in counterintuitive models The relationship between a covariate and a parameter will be different if it is in a model alone or with a correlated covariate To determine which of correlated covariates carry the most predictive value is often hard Problems with correlated covariates increase with increasing correlation Correlation coefficient is often used to capture degree of correlation, but is (alone) not an ideal measure to decide on modeling strategy
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Other covariate classifications

Time-constant / time-varying (later lecture) Observed / missing (later lecture) Measured with or without error (later lecture) Directly observed or composed of other covariates Stratified or observational (later lecture) Prior belief in covariate-parameter relation
Certain of influence, likely, unlikely, almost certainly no influence (much more later)

Clinically available versus experimental Routine use or not for individualisation Of predictive value or not
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Covariate models - on which parameters

Structural parameters (almost the entire course) Interindividual variability Interoccasion variability Residual variability Covariate relationship (covariate interactions) On predictions directly1,2

1Bonate

P, Pharm Res. 22:541-9 (2005) 2Wilkins J & Looby M, PAGE (2010)

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Covariate-parameter relations under consideration

10

Number of parameters Number of parameters Number of parameters

Many

Increasing problems with model selection bias, model interpretability, model stability and/or parameter imprecision

False or irrelevant covariate relationships lead to:

Poorer precision in prediction Unnecessary information gathered Poor hypothesis generation Less trust in true covariate relationships

Few

1 10 Number of covariates Number of covariates 30+ Many Few Number of covariates

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Covariate model building a common way to do it

All covariate-parameter relationships of interest Scientific plausibility

Statistical significance

Clinical relevance

Final covariate-parameter relationships

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Par-Cov relations to consider for inclusion

Some of the principles used for selection
All possible relations Common, but may result in long model building process and many relations tested increases the risk for false Par-Cov relations All scientifically justifyable Makes sense, but may be cumbersome to select what is plausible and what is not All relations that are required for documentation May include relations that are not plausible, but where an absence of Par-Cov correlation needs to be documented for regulatory purposes All possible for the main parameter(s) of interest (e.g. CL), but only scientifically plausible for other (e.g. V, ka) parameters

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Starting model some alternatives I

No Par-Cov relations
Often used. Further discussed below

Major, known, covariates are incluced

Advantage: (i) shorter model building, (ii) graphical procedures for other covariates more informative, and (iii) unbiased estimate of major covariate relation(s)

Best-guess model
Advantage: unbiased estimates for all Par-Cov relations included in best guess model Like the approaches above it will involve further covariate model building (later lectures)

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Starting model some alternatives II

All relations of primary interest
Full model approach (later lecture) May include relation with expected lack of significance, but which may be of importance for clinical/regulatory confirmation of absence of influence Advantage: unbiased estimates of all relations of primary interest Generally include few relations in order to have a stable model Secondary hypothesis-generating model building step can be performed

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Selection criteria Scientific plausibility

Scientific plausibility Which Par-Cov relations? Sign and magnitude of Cov-Par relations
Should be viewed in combination with other relations

Problem in determining scientific basis:

Hard to think beforehand on all scientifically sound relations (Too) easy afterwards to find possible rationals for a found relationship

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Selection criteria Statistical criteria

Statistical criteria (examples)
Exploratory analysis is often used as a proxy for likelihood of statistical significance Difference in objective function value (main criteria, covered in later lecture) SE of parameter for Par-Cov relation Bootstrap confidence intervals for parameter Predictive performance in cross-validation (later lecture)

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Selection criteria Clinical importance I

Limits for what is clinically important changes in parameters can seldom be clearly defined because the relationship between a parameter value and clinically important changes in a clinically important endpoint can not be predicted (with sufficient precision). Therefore, interpretation of what is clinically important may differ between persons. An alternative, conservative, approach is to define a clinical insignificance criteria Clinically not significant changes may be related to available dosing strengths. This is maybe relevant for post-marketing situation, but is more difficult to justify in the drug development setting.

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Some measures for clinical significance

Influence at extreme percentiles of covariate distribution Difference between groups Decrease in unexplained variability Influence on some derived parameter (e.g. AUC, predicted effect, %responders)

25

Covariate models and model building strategies

Important to know covariate characteristics in order to decide about modelling strategy The most suitable covariate model will differ between different intended uses of the final model The most suitable model building strategy will depend on data, model, intended model use, and time and tools available A good working knowledge of several different techniques is therefore desireable

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Extra slides

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Example I: Covariate model from TDM data

Often relatively small data sets (<100 patients) Uncertainty regarding characteristics for observed patients compared to patient population Large heterogeneity in covariate distribution Often low quality in dosing/sampling history Aim can often be to create predictive model for initial dosing or dose adjustment

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Example II: Covariate model from Phase III study

Large study size (usually >300 patients) Relatively heterogenous covariate distribution Sometimes problems with low quality in dosing/sampling history Aim can be to confirm previous findings regarding covariate relations, investigate covariate relations not previously documented, create exposure-safety/efficacy relations

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Example III: Covariate model from Phase II study

Varying study size (30-300 patients) Often strict inclusion criteria resulting in exclusion of many patients from the patient population Usually rather high quality data Aim can often be to create model for aiding dosing strategy determination, characterize absence of influences and clinical trial simulations for phase III

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Example IV: Covariate model from combined Phase I studies

Intermediate study size (100-200 patients) Often only a few demographic covariates of interest (size, age, sex, genotype) High quality data Aim can often be to create model for characterising interactions between covariates and clinical trial simulations for phase II

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