PH525x series - Biomedical Data Science

Introduction

Acknowledgements
The authors would like to thank Alex Nones for proofreading the manuscript during its various
stages. Also, thanks to Karl Broman for contributing the “Plots to Avoid” section and to
Stephanie Hicks for designing some of the exercises.

This book was conceived during the teaching of several HarvardX courses, coordinated by
Heather Sternshein. We are also grateful to all the students whose questions and comments helped
us improve the book. The courses were partially funded by NIH grant R25GM114818. We are
very grateful to the National Institute of Health for its support.

A special thanks goes to all those that edited the book via GitHub pull requests: vjcitn, yeredh,
ste-fan, molx, kern3020, josemrecio, hcorrada, neerajt, massie, jmgore75, molecules, lzamparo,
eronisko, and obicke.

Cover image credit: this photograph is La Mina Falls, El Yunque National Forest, Puerto Rico,
taken by Ron Kroetz [Link] Attribution-
NoDerivs 2.0 Generic (CC BY-ND 2.0)

Introduction
The unprecedented advance in digital technology during the second half of the 20th century has
produced a measurement revolution that is transforming science. In the life sciences, data analysis
is now part of practically every research project. Genomics, in particular, is being driven by new
measurement technologies that permit us to observe certain molecular entities for the first time.
These observations are leading to discoveries analogous to identifying microorganisms and other
breakthroughs permitted by the invention of the microscope. Choice examples of these
technologies are microarrays and next generation sequencing.

Scientific fields that have traditionally relied upon simple data analysis techniques have been
turned on their heads by these technologies. In the past, for example, researchers would measure
the transcription levels of a single gene of interest. Today, it is possible to measure all 20,000+
human genes at once. Advances such as these have brought about a shift from hypothesis to
discovery-driven research. However, interpreting information extracted from these massive and
complex datasets requires sophisticated statistical skills as one can easily be fooled by patterns
arising by chance. This has greatly elevated the importance of statistics and data analysis in the
life sciences.

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 What Does This Book Cover?
This book will cover several of the statistical concepts and data analytic skills needed to succeed
in data-driven life science research. We go from relatively basic concepts related to computing p-
values to advanced topics related to analyzing high-throughput data.

We start with one of the most important topics in statistics and in the life sciences: statistical
inference. Inference is the use of probability to learn population characteristic from data. A
typical example is deciphering if two groups (for example, cases versus controls) are different on
average. Specific topics covered include the t-test, confidence intervals, association tests, Monte
Carlo methods, permutation tests and statistical power. We make use of approximations made
possible by mathematical theory, such as the Central Limit Theorem, as well as techniques made
possible by modern computing. We will learn how to compute p-values and confidence intervals
and implement basic data analyses. Throughout the book we will describe visualization
techniques in the statistical computer language R that are useful for exploring new data sets. For
example, we will use these to learn when to apply robust statistical techniques.

We will then move on to an introduction to linear models and matrix algebra. We will explain
why it is beneficial to use linear models to analyze differences across groups, and why matrices
are useful to represent and implement linear models. We continue with a review of matrix
algebra, including matrix notation and how to multiply matrices (both on paper and in R). We will
then apply what we covered on matrix algebra to linear models. We will learn how to fit linear
models in R, how to test the significance of differences, and how the standard errors for
differences are estimated. Furthermore, we will review some practical issues with fitting linear
models, including collinearity and confounding. Finally, we will learn how to fit complex models,
including interaction terms, how to contrast multiple terms in R, and the powerful technique
which the functions in R actually use to stably fit linear models: the QR decomposition.

In the third part of the book we cover topics related to high-dimensional data. Specifically, we
describe multiple testing, error rate controlling procedures, exploratory data analysis for high-
throughput data, p-value corrections and the false discovery rate. From here we move on to
covering statistical modeling. In particular, we will discuss parametric distributions, including
binomial and gamma distributions. Next, we will cover maximum likelihood estimation. Finally,
we will discuss hierarchical models and empirical Bayes techniques and how they are applied in
genomics.

We then cover the concepts of distance and dimension reduction. We will introduce the
mathematical definition of distance and use this to motivate the singular value decomposition
(SVD) for dimension reduction and multi-dimensional scaling. Once we learn this, we will be
ready to cover hierarchical and k-means clustering. We will follow this with a basic introduction
to machine learning.

We end by learning about batch effects and how component and factor analysis are used to deal
with this challenge. In particular, we will examine confounding, show examples of batch effects,

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 make the connection to factor analysis, and describe surrogate variable analysis.

How Is This Book Different?

While statistics textbooks focus on mathematics, this book focuses on using a computer to
perform data analysis. This book follows the approach of Stat Labs, by Deborah Nolan and Terry
Speed. Instead of explaining the mathematics and theory, and then showing examples, we start by
stating a practical data-related challenge. This book also includes the computer code that provides
a solution to the problem and helps illustrate the concepts behind the solution. By running the
code yourself, and seeing data generation and analysis happen live, you will get a better intuition
for the concepts, the mathematics, and the theory.

We focus on the practical challenges faced by data analysts in the life sciences and introduce
mathematics as a tool that can help us achieve scientific goals. Furthermore, throughout the book
we show the R code that performs this analysis and connect the lines of code to the statistical and
mathematical concepts we explain. All sections of this book are reproducible as they were made
using R markdown documents that include R code used to produce the figures, tables and results
shown in the book. In order to distinguish it, the code is shown in the following font:

x <- 2
y <- 3
print(x+y)

and the results in different colors, preceded by two hash characters (##):

## [1] 5

We will provide links that will give you access to the raw R markdown code so you can easily
follow along with the book by programming in R.

At the beginning of each chapter you will see the sentence:

The R markdown document for this section is available here.

The word “here” will be a hyperlink to the R markdown file. The best way to read this book is
with a computer in front of you, scrolling through that file, and running the R code that produces
the results included in the book section you are reading.

PH525x, Rafael Irizarry and Michael Love, MIT License

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