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The slides of the lecture "Information-theoret ic analysis of -omics data," delivered 17 November 2008 in BIO 5106 (BIOL 5506) BIOINFORMATICS.

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An introduction

David R. Bickel

University of Ottawa

17 November 2008

**David Bickel (uOttawa) Information theory 17 November 2008 1 / 11
**

Today’s class

Di¤erential gene/protein/metabolite expression

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Today’s class

**Di¤erential gene/protein/metabolite expression
**

Which genes express di¤erently between treatment and control?

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Today’s class

**Di¤erential gene/protein/metabolite expression
**

Which genes express di¤erently between treatment and control?

Examples of "treatments"

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Today’s class

**Di¤erential gene/protein/metabolite expression
**

Which genes express di¤erently between treatment and control?

Examples of "treatments"

Medical: drug or chemotherapy applied to some patients

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Today’s class

**Di¤erential gene/protein/metabolite expression
**

Which genes express di¤erently between treatment and control?

Examples of "treatments"

Medical: drug or chemotherapy applied to some patients

Basic: hormone or other chemical added to some cell cultures

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Today’s class

**Di¤erential gene/protein/metabolite expression
**

Which genes express di¤erently between treatment and control?

Examples of "treatments"

Medical: drug or chemotherapy applied to some patients

Basic: hormone or other chemical added to some cell cultures

Other examples?

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Today’s class

**Di¤erential gene/protein/metabolite expression
**

Which genes express di¤erently between treatment and control?

Examples of "treatments"

Medical: drug or chemotherapy applied to some patients

Basic: hormone or other chemical added to some cell cultures

Other examples?

How much information or evidence is in the measurements

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Today’s class

**Di¤erential gene/protein/metabolite expression
**

Which genes express di¤erently between treatment and control?

Examples of "treatments"

Medical: drug or chemotherapy applied to some patients

Basic: hormone or other chemical added to some cell cultures

Other examples?

**How much information or evidence is in the measurements
**

for di¤erential expression?

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Today’s class

**Di¤erential gene/protein/metabolite expression
**

Which genes express di¤erently between treatment and control?

Examples of "treatments"

Medical: drug or chemotherapy applied to some patients

Basic: hormone or other chemical added to some cell cultures

Other examples?

**How much information or evidence is in the measurements
**

for di¤erential expression?

for equivalent expression?

**David Bickel (uOttawa) Information theory 17 November 2008 2 / 11
**

Pick the di¤erentially expressed genes

What is di¤erential gene/protein/metabolite expression?

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

An average expression ratio less than 1 indicates under-expression

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

An average expression ratio less than 1 indicates under-expression

An average expression ratio greater than 1 indicates over-expression

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

An average expression ratio less than 1 indicates under-expression

An average expression ratio greater than 1 indicates over-expression

"Average expression" is over the population, not just the observed data

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

An average expression ratio less than 1 indicates under-expression

An average expression ratio greater than 1 indicates over-expression

"Average expression" is over the population, not just the observed data

The histogram of a large expression data set resembles the true

distribution

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

An average expression ratio less than 1 indicates under-expression

An average expression ratio greater than 1 indicates over-expression

"Average expression" is over the population, not just the observed data

The histogram of a large expression data set resembles the true

distribution

Gene expression ratios measured by microarrays

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

An average expression ratio less than 1 indicates under-expression

An average expression ratio greater than 1 indicates over-expression

"Average expression" is over the population, not just the observed data

The histogram of a large expression data set resembles the true

distribution

**Gene expression ratios measured by microarrays
**

A sample from the treatment group and a sample from the control

group are hybridized to the same microarray slide

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

An average expression ratio less than 1 indicates under-expression

An average expression ratio greater than 1 indicates over-expression

"Average expression" is over the population, not just the observed data

The histogram of a large expression data set resembles the true

distribution

**Gene expression ratios measured by microarrays
**

A sample from the treatment group and a sample from the control

group are hybridized to the same microarray slide

Each gene’s expression ratio is a measurement of its expression in the

treatment group relative to its expression in the control group

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

Pick the di¤erentially expressed genes

**What is di¤erential gene/protein/metabolite expression?
**

An average expression ratio of 1 indicates equivalent expression

Two types of di¤erential expression

An average expression ratio less than 1 indicates under-expression

An average expression ratio greater than 1 indicates over-expression

"Average expression" is over the population, not just the observed data

The histogram of a large expression data set resembles the true

distribution

**Gene expression ratios measured by microarrays
**

A sample from the treatment group and a sample from the control

group are hybridized to the same microarray slide

Each gene’s expression ratio is a measurement of its expression in the

treatment group relative to its expression in the control group

Based on the expression data, which genes are di¤erentially expressed?

**David Bickel (uOttawa) Information theory 17 November 2008 3 / 11
**

data set #1 data set #2 data set #4 data set #6

data (n = 3)

data (n = 6)

model (n = 3)

model (n = 6)

evidence (n = 3)

evidence (n = 6)

For each data set, indicate whether the gene is equivalently expressed (E)

or di¤erentially expressed (D) according to the plot of the data, according

to the model, and according to the evidence for each number of

observations (3 or 6). Equivalent expression means the average expression

ratio is 1.

**David Bickel (uOttawa) Information theory 17 November 2008 4 / 11
**

Statistical models

p stands for the number of unknown parameters in a model

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

Unknown variability of expression

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

Unknown variability of expression

Expression ratio known to be 1

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

Unknown variability of expression

Expression ratio known to be 1

One unknown parameter (p = 1)

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

Unknown variability of expression

Expression ratio known to be 1

One unknown parameter (p = 1)

Di¤erential expression model

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

Unknown variability of expression

Expression ratio known to be 1

One unknown parameter (p = 1)

**Di¤erential expression model
**

Unknown variability of expression

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

Unknown variability of expression

Expression ratio known to be 1

One unknown parameter (p = 1)

**Di¤erential expression model
**

Unknown variability of expression

Unknown expression ratio

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

Unknown variability of expression

Expression ratio known to be 1

One unknown parameter (p = 1)

**Di¤erential expression model
**

Unknown variability of expression

Unknown expression ratio

Two unknown parameters (p = 2)

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Statistical models

**p stands for the number of unknown parameters in a model
**

Equivalent expression model

Unknown variability of expression

Expression ratio known to be 1

One unknown parameter (p = 1)

**Di¤erential expression model
**

Unknown variability of expression

Unknown expression ratio

Two unknown parameters (p = 2)

How do the model plots change your initial assessments?

**David Bickel (uOttawa) Information theory 17 November 2008 5 / 11
**

Balancing complexity and …t

**The di¤erential expression model (p = 2) is more complex than the
**

equivalent expression model (p = 1)

**David Bickel (uOttawa) Information theory 17 November 2008 6 / 11
**

Balancing complexity and …t

**The di¤erential expression model (p = 2) is more complex than the
**

equivalent expression model (p = 1)

More complex models tend to …t data better than simple models,

even if the simple models are better

**David Bickel (uOttawa) Information theory 17 November 2008 6 / 11
**

Balancing complexity and …t

**The di¤erential expression model (p = 2) is more complex than the
**

equivalent expression model (p = 1)

More complex models tend to …t data better than simple models,

even if the simple models are better

Overly complex models make poor generalizations

**David Bickel (uOttawa) Information theory 17 November 2008 6 / 11
**

Balancing complexity and …t

**The di¤erential expression model (p = 2) is more complex than the
**

equivalent expression model (p = 1)

More complex models tend to …t data better than simple models,

even if the simple models are better

Overly complex models make poor generalizations

A sample of patients may not represent the population

**David Bickel (uOttawa) Information theory 17 November 2008 6 / 11
**

Balancing complexity and …t

**The di¤erential expression model (p = 2) is more complex than the
**

equivalent expression model (p = 1)

More complex models tend to …t data better than simple models,

even if the simple models are better

Overly complex models make poor generalizations

A sample of patients may not represent the population

A single experiment may not re‡ect typical biological processes

**David Bickel (uOttawa) Information theory 17 November 2008 6 / 11
**

Balancing complexity and …t

**The di¤erential expression model (p = 2) is more complex than the
**

equivalent expression model (p = 1)

More complex models tend to …t data better than simple models,

even if the simple models are better

Overly complex models make poor generalizations

A sample of patients may not represent the population

A single experiment may not re‡ect typical biological processes

Fit

= Evidence

Complexity

**David Bickel (uOttawa) Information theory 17 November 2008 6 / 11
**

Balancing complexity and …t

**The di¤erential expression model (p = 2) is more complex than the
**

equivalent expression model (p = 1)

More complex models tend to …t data better than simple models,

even if the simple models are better

Overly complex models make poor generalizations

A sample of patients may not represent the population

A single experiment may not re‡ect typical biological processes

Fit

= Evidence

Complexity

How does balancing …t with complexity change your assessments?

**David Bickel (uOttawa) Information theory 17 November 2008 6 / 11
**

Quality of model …t to the data

n = sample size

**David Bickel (uOttawa) Information theory 17 November 2008 7 / 11
**

Quality of model …t to the data

n = sample size

number of measured expression ratios

**David Bickel (uOttawa) Information theory 17 November 2008 7 / 11
**

Quality of model …t to the data

n = sample size

number of measured expression ratios

MSE = mean of squared errors of the model

**David Bickel (uOttawa) Information theory 17 November 2008 7 / 11
**

Quality of model …t to the data

n = sample size

number of measured expression ratios

**MSE = mean of squared errors of the model
**

degree to which the model disagrees with the observed data (log scale)

**David Bickel (uOttawa) Information theory 17 November 2008 7 / 11
**

Quality of model …t to the data

n = sample size

number of measured expression ratios

**MSE = mean of squared errors of the model
**

degree to which the model disagrees with the observed data (log scale)

n

1

Fit = p

MSE

**David Bickel (uOttawa) Information theory 17 November 2008 7 / 11
**

Quality of model …t to the data

n = sample size

number of measured expression ratios

**MSE = mean of squared errors of the model
**

degree to which the model disagrees with the observed data (log scale)

n

1

Fit = p

MSE

degree to which the model …ts the observed data (assuming a normal

distribution)

**David Bickel (uOttawa) Information theory 17 November 2008 7 / 11
**

Model complexity

n = sample size

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

p = model dimension

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

p = model dimension

number of unknown parameters in the model

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

p = model dimension

number of unknown parameters in the model

p = 1 for the equivalent expression model

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

p = model dimension

number of unknown parameters in the model

p = 1 for the equivalent expression model

p = 2 for the di¤erential expression model

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

p = model dimension

number of unknown parameters in the model

p = 1 for the equivalent expression model

p = 2 for the di¤erential expression model

p (p + 1)

pc = p +

2 (n p + 1)

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

p = model dimension

number of unknown parameters in the model

p = 1 for the equivalent expression model

p = 2 for the di¤erential expression model

p (p + 1)

pc = p +

2 (n p + 1)

e¤ective number of parameters in the model (corrected for small n)

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

number of unknown parameters in the model

p = 1 for the equivalent expression model

p = 2 for the di¤erential expression model

p (p + 1)

pc = p +

2 (n p + 1)

e¤ective number of parameters in the model (corrected for small n)

Complexity = 2.718pc

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Model complexity

n = sample size

number of measured expression ratios

number of unknown parameters in the model

p = 1 for the equivalent expression model

p = 2 for the di¤erential expression model

p (p + 1)

pc = p +

2 (n p + 1)

e¤ective number of parameters in the model (corrected for small n)

Complexity = 2.718pc

Fit

= Evidence

Complexity

**David Bickel (uOttawa) Information theory 17 November 2008 8 / 11
**

Answers

How do our analyses compare to the truth?

**David Bickel (uOttawa) Information theory 17 November 2008 9 / 11
**

Answers

**How do our analyses compare to the truth?
**

If a statistical method says an equivalently expressed gene is

di¤erentially expressed, is the method useless?

**David Bickel (uOttawa) Information theory 17 November 2008 9 / 11
**

Answers

**How do our analyses compare to the truth?
**

If a statistical method says an equivalently expressed gene is

di¤erentially expressed, is the method useless?

If a statistical method says a di¤erentially expressed gene is

equivalently expressed, is the method useless?

**David Bickel (uOttawa) Information theory 17 November 2008 9 / 11
**

Answers

**How do our analyses compare to the truth?
**

If a statistical method says an equivalently expressed gene is

di¤erentially expressed, is the method useless?

If a statistical method says a di¤erentially expressed gene is

equivalently expressed, is the method useless?

The advantage of obtaining more data

**David Bickel (uOttawa) Information theory 17 November 2008 9 / 11
**

Answers

**How do our analyses compare to the truth?
**

If a statistical method says an equivalently expressed gene is

di¤erentially expressed, is the method useless?

If a statistical method says a di¤erentially expressed gene is

equivalently expressed, is the method useless?

The advantage of obtaining more data

The best possible assessment given the available data

**David Bickel (uOttawa) Information theory 17 November 2008 9 / 11
**

Answers

**How do our analyses compare to the truth?
**

If a statistical method says an equivalently expressed gene is

di¤erentially expressed, is the method useless?

If a statistical method says a di¤erentially expressed gene is

equivalently expressed, is the method useless?

The advantage of obtaining more data

**The best possible assessment given the available data
**

How con…dent should you be in your assessments?

**David Bickel (uOttawa) Information theory 17 November 2008 9 / 11
**

Answers

**How do our analyses compare to the truth?
**

If a statistical method says an equivalently expressed gene is

di¤erentially expressed, is the method useless?

If a statistical method says a di¤erentially expressed gene is

equivalently expressed, is the method useless?

The advantage of obtaining more data

**The best possible assessment given the available data
**

How con…dent should you be in your assessments?

Should you obtain more data before making an assessment?

**David Bickel (uOttawa) Information theory 17 November 2008 9 / 11
**

The expression data sets

data set #1 data set #2 data set #4 data set #6

ratio 1 2 1 1.4

expression equivalent di¤erential equivalent di¤erential

n = 10 0.44/1.38 0.14/0.09 0.14/0.17 0.19/0.37

n = 25 0.29/0.71 0.03/0.002 4.77/1.00 0.05/0.04

1 10 4

n = 100 36/69 16/32 0.03/0.01

2 10 7

Key

n is the number of observed expression ratios.

Evidence di¤erentially expressed

Each ratio is , the weight of evidence

Evidence equivalently expressed

favoring di¤erential expression over equivalent expression.

* misleading evidence for di¤erential expression

** misleading evidence for equivalent expression

David Bickel (uOttawa) Information theory 17 November 2008 10 / 11

Further study

**The method presented is based on the Akaike information criterion
**

(AIC) after correcting it for small numbers of measurements

**David Bickel (uOttawa) Information theory 17 November 2008 11 / 11
**

Further study

**The method presented is based on the Akaike information criterion
**

(AIC) after correcting it for small numbers of measurements

AICc = 2 ln (Evidence)

**David Bickel (uOttawa) Information theory 17 November 2008 11 / 11
**

Further study

**The method presented is based on the Akaike information criterion
**

(AIC) after correcting it for small numbers of measurements

AICc = 2 ln (Evidence)

Software packages with the AIC but without the correction may be

unreliable for small numbers of observations (n < 40)

**David Bickel (uOttawa) Information theory 17 November 2008 11 / 11
**

Further study

**The method presented is based on the Akaike information criterion
**

(AIC) after correcting it for small numbers of measurements

AICc = 2 ln (Evidence)

Software packages with the AIC but without the correction may be

unreliable for small numbers of observations (n < 40)

Kenneth Burnham and David Anderson, Model Selection and

Multi-Model Inference

**David Bickel (uOttawa) Information theory 17 November 2008 11 / 11
**

Further study

**The method presented is based on the Akaike information criterion
**

(AIC) after correcting it for small numbers of measurements

AICc = 2 ln (Evidence)

Software packages with the AIC but without the correction may be

unreliable for small numbers of observations (n < 40)

Kenneth Burnham and David Anderson, Model Selection and

Multi-Model Inference

These slides and …gures will be on the lab website

**David Bickel (uOttawa) Information theory 17 November 2008 11 / 11
**

Further study

**The method presented is based on the Akaike information criterion
**

(AIC) after correcting it for small numbers of measurements

AICc = 2 ln (Evidence)

Software packages with the AIC but without the correction may be

unreliable for small numbers of observations (n < 40)

Kenneth Burnham and David Anderson, Model Selection and

Multi-Model Inference

**These slides and …gures will be on the lab website
**

www.statomics.com

David Bickel (uOttawa) Information theory 17 November 2008 11 / 11

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