Multiple interventions for multiple targets
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Multiple Interventions for Multiple Targets. Emilia Bagiella, PhD Columbia University. Traumatic Brain Injury (TBI). An injury to the head arising from blunt or penetrating trauma or from acceleration-deceleration forces Damage can be focal or diffuse Closed head injury

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Multiple Interventions for Multiple Targets

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Multiple interventions for multiple targets

Multiple Interventions for Multiple Targets

Emilia Bagiella, PhD

Columbia University

Traumatic brain injury tbi

Traumatic Brain Injury (TBI)

  • An injury to the head arising from blunt or penetrating trauma or from acceleration-deceleration forces

  • Damage can be focal or diffuse

  • Closed head injury

  • Penetrating head injury

Traumatic brain injury tbi1

Traumatic Brain Injury (TBI)

  • An estimated 1.5 million head injuries occur every year in the United States

  • TBI is the leading cause of death and disability in children and adults ages 1 to 44

  • Approximately 52,000 deaths every year

Traumatic brain injury tbi2

Traumatic Brain Injury (TBI)

  • More than 5.3 million Americans, 2% of the U.S. population, currently live with disabilities resulting from TBI

  • Direct medical costs and indirect costs (e.g. lost productivity) due to TBI is estimated at $56.3 billion annually

How does tbi happen

How does TBI happen?

  • Falls (28%)

  • Motor vehicle-traffic crashes (20%)

  • Struck by/against events (19%); and

  • Assaults (11%)

Short term effect of tbi

Short term effect of TBI

Initial acute insult (diffuse axonal injury) followed by a cascade of events involving multiple secondary injuries

  • Significant tissue damage

  • Ischemia/hypoxia

  • Brain swelling

  • Brain hemorrhage

Long term consequences

Long term consequences

  • Wide range of functional changes affecting thinking, sensation, language, and/or emotions.

  • Epilepsy and increase the risk for Alzheimer’s and Parkinson’s disease, and other brain disorders

  • Virtually no injury is without consequence



  • Unpredictable

  • No known risk factors

    • Low socio-economic class

    • Drug and alcohol abuse

    • War

  • Affects mostly otherwise healthy individuals

Clinical trials in tbi

Clinical Trials in TBI

So far…

  • Difficult to design and perform

  • Hampered by many problems

  • Most trials have failed to show improvement in (any) outcomes

Clinical trials in tbi1

Clinical Trials in TBI

  • Have learned more from clinical practice than from clinical trials

  • Guidelines based on common sense

  • Back to square 1

Possible interventions

Possible interventions


Physiological - Surgical

  • Neuroprotective agents

  • Steroids

  • Free radicals scavangers

  • Insuline like growth factor (IGF)

  • Progesterone

  • Biomarkers(?)

  • Hypothermia

  • Decompressive craniectomy

  • O2 monitoring

  • ICP/CBF management



  • Pre-clinical and clinical data are disconnected

  • Need adequate pre-clinical TBI models

  • Virtually no early phase trials in TBI

  • Dosing

  • Duration of treatment

  • Time of treatment initiation

Design problems

Design Problems

  • Weaknesses in study design

  • Insufficient power/sample size

  • Inadequate outcome measures or lack of sensitivity of the outcomes measure

  • Too small effect sizes

  • Too variable population



  • No single measure can capture the multidimensional nature of TBI outcome

  • Combination of drugs are needed for the treatment of TBI

What should the outcome be

What should the outcome be?


Glasgow outcome scale gos

Glasgow Outcome Scale (GOS)

  • 5-category scale

  • Gold standard for trial in TBI

  • The only measure of functional recovery accepted by the FDA

  • Very broad and not specific

  • Non differential misclassification

  • Considerable loss of statistical power and the attenuation of the true treatment effect

Multiple interventions for multiple targets


  • To identify measures that together would reflect the “global” status of TBI patients

  • Functional, physical, emotional, cognitive, and social spheres

What should the outcome be1

What should the outcome be?

Global statistical analysis approach

Global Statistical Analysis Approach

  • Offers a method to utilize several outcome measures without need to pre-specify one as primary

  • Avoids loss of power due to multiple comparisons

  • Easily interpreted and of direct clinical interest

Binary outcome

Binary Outcome

Let Yi = 1(0) denote the success(failure) for the

i th measure (i =1, … ,k)

Let T = 1(0) for experimental(standard) Tx.

Binary outcome1

Binary Outcome

  • Interest centers on treatments where (even approximately)

    b1 = b2 = … = bk = b

  • The results of the analysis are estimate of the common odds ratio, exp(b ), together with a standard error, z-score, p-value and confidence intervals

Multiple interventions for multiple targets

  • Statistical power is greatest when the odds ratios are all equal, but that is nor required to test H0: all bi = 0 (no treatment effect with any measure)

  • Analogous to the Mantel-Haenszel procedure with correlated tables

Multiple interventions for multiple targets

Power is reduced if some bi = 0 or are of opposite signs.

But that is an ambiguous situation where careful judgment is required, in which case reduced power may not be inappropriate

Multiple interventions for multiple targets

  • The methods can be easily extended to clinical trials with stratified randomization.

  • Estimation of b is absolutely conventional using weighted least squares.

  • Further adjustment for additional covariates can be handled by GEE methods.



  • Targets multiple areas of recovery

  • Reduces the trial size

  • Has greater statistical power than any single outcome measure



  • Need to know the correlation among outcomes

  • (May) still need large sample size

  • FDA (?)

Example cobrit trial

Example: COBRIT trial

  • Fix OR=1.4 (8% improvement on the GOS)

  • Choose 9 measures of functional and cognitive status

  • Fix the type I error at 0.05 and the power at 85%

  • Needed 1124 patients to detect the effect size of interest.

  • Would need 1836 participants to run a trial with the same power, type I error and effect size with GOS alone.

What should the treatment be

What should the treatment be?

Multiple interventions for multiple targets

  • Single treatments do not work

  • “Cocktails” or combination treatment may work

  • What to combine and at what dose?

Sequential selection procedure

Sequential Selection Procedure

  • Dichotomize the outcome as success or failure

  • Use a coin tossing model for the outcome data

  • Determine the number of treatment combinations to be tested (k)

  • Determine the number of treatment combinations to be chosen (b)

Levin robbins leu lrl procedure

Levin-Robbins-Leu (LRL) Procedure

  • Choose a positive integer r to guarantee high probability of correct selection

  • Compare all k treatment combinations at the same time

  • Eliminate “inferior” treatments as soon as they follow r successes behind the treatment with the currently b largest tally

Levin robbins leu lrl procedure1

Levin-Robbins-Leu (LRL) Procedure

  • Recruit “superior” treatments as soon as they pull r successes ahead of the treatments with the currently held (b+1) largest tally

  • The procedure stops when b treatments are recruited and k-b treatments are withdrawn



  • Very efficient in pre-clinical studies

  • It allows early stopping

  • Reduces total number of experiments

  • Maximize probability of correct selection of the best treatment



  • Difficult to apply to clinical setting

  • Must start from a small number of treatments

  • No hypothesis testing



  • 13 agents

  • 3 doses

  • Start from 558 two-way treatment/dose combinations

  • Assume 10 combinations are truly beneficial with 63% probability of success

  • LRL procedure requires 2502 experiments compared to 11160 for fixed sample size

Open problem

Open Problem









Thank you


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