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%  EXAMPLE OF USING CUMULATIVE OVERLAYS 
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 \documentclass{seminar}
 \usepackage{psfig,shadow,epsf,sem-a4,fancybox,pstricks,amsthm,amssymb,amsmath}
 \usepackage{graphicx,psfrag,pst-node,subfigure}
 \usepackage{fancyheadings}
 \usepackage{curves}
 \usepackage{semlayer,semcolor}
 \slideframe{none}
 \input{seminar.bug}

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%  The following are some newcommands I have defined for making
%  boxes for headings, colors, etc.
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%  Makes a box around stuff
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\def\boxit#1{\vbox{\hrule\hbox{\vrule\kern3pt
          \vbox{\kern5pt#1\kern5pt}\kern3pt\vrule}\hrule}}
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\newcommand{\myheading}[1]{\begin{center}\shabox{ \slbf{#1}} \end{center}}
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% Command so bullets aren't colored
\newcommand{\citem}{\item $\mbox{}$}

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\newgray{vlgray}{0.9}
\newrgbcolor{lblue}{0.8 0.92 0.95}
\newrgbcolor{lred}{1 0.8 0.8}
\newrgbcolor{lyellow}{1 1 0.6}
\newrgbcolor{orange}{1 0.7 0.2}
\newrgbcolor{lgreen}{0.87 0.95 0.8}
%\newrgbcolor{dgreen}{0.37 0.43 0.37}
\newrgbcolor{dgreen}{0.36 0.75 0.41}
\newrgbcolor{violet}{0.6 0.0 0.4}

\newcommand{\SlideColours}[3][black]{
%#1 = frame line color (optional, default=black),
%#2 = foreground color, #3 = background color
\slideframe[\psset{linecolor=#1,fillcolor=#3,fillstyle=solid}]{scplain}
\color{#2}}

%example: \SlideColours[red]{black}{Pink} %[] for frames is optional

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\setlength{\slideheight}{6.6in}
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%  CODE TO MAKE ANIMATION EFFECTS (BRING UP BULLETS ONE AT A TIME, ETC)

\makeatletter
\def\pst@initoverlay#1{%
\pst@Verb{%
/BeginOL {dup (all) eq exch TheOL le or {IfVisible not {Visible
/IfVisible true def} if} {IfVisible {Invisible /IfVisible false def} if}
ifelse} def
\tx@InitOL /TheOL (#1) def}}
\makeatother

%  turn overlays on or off -- turn off to print handouts!

\overlaystrue
%\overlaysfalse

\begin{document}

%  with linux uncomment this

%\renewcommand{\slideleftmargin}{1.4in}

%  if you want yellow on black background

%\yellow
%\SlideColours{white}{black}

%  makes everything except headings sans serif

\sf
\newcommand{\slf}{\sf \em}
\newcommand{\slbf}{\sf \textbf}

\pagestyle{fancy}
\setlength{\headrulewidth}{0.15pt}
\setlength{\footrulewidth}{.15pt}
\rhead{\includegraphics[height=0.3cm]{newlogo.ps}}
\lhead{{\scriptsize \sl What is Biostatistics?}}
\lfoot{\scriptsize \sl }
\cfoot{  }
\rfoot{\scriptsize \rm \theslide}

\begin{slide}
\begin{center}
\begin{large}
\myheading{{\blue WHAT IS BIOMEDICAL STATISTICS?}}
({\Large {\red \it OR, WHAT IS BIOSTATISTICS}\,?}) \\
\end{large}

\vspace*{0.35in}

{\bf \large Marie Davidian} \\*[0.1in]

\includegraphics[height=0.8cm]{deptlogo.ps}

{\tt davidian@stat.ncsu.edu} 
\end{center}

\centering {\tt http://www.stat.ncsu.edu/$\sim$davidian} 

\end{slide}

\begin{slide}
\begin{center}
\myheading{{\blue Outline}}
\end{center}

\begin{enumerate}
\ritem Biomedical and public health research
\ritem Why is studying humans is so complicated?
\ritem Example 1: Comparing treatments based on a time-to-event
\ritem Example 2: Longitudinal studies with repeated measures
\ritem Example 3: Should this study be stopped? 
\ritem Example 4: Pharmacokinetics
\ritem Biostatistical research
\ritem Where do biostatisticians work?
\ritem Training to be a biostatistician
\end{enumerate}
\end{slide}

%  Stuff between \begin{overlay}{n} and \end{overlay} shows on the slide
%in the order n=0,1,2,...

\begin{slide}
\begin{overlay}{0}
\begin{center}
\myheading{{\blue 1. Biomedical and public health research}}
\end{center}

\vspace*{0.3in}

\slbf{\red Research related to the betterment of human health:}
\end{overlay}
\begin{overlay}{1}
\begin{itemize}
\ritem An enormous enterprise in the US, involving {\blue \em
billions} of dollars

\ritem Funded mostly by the {\blue \em federal government} and the
{\blue \em pharmaceutical industry}
\end{itemize}
\end{overlay}
\end{slide}

\begin{slide}
\slbf{\red Broad goal:} To acquire new knowledge to help prevent,
detect, diagnose, and treat {\blue \em disease}
\begin{itemize}
\ritem Cancer, heart disease, diabetes, HIV/AIDS, mental illness to
the common cold, flu, athlete's foot!

\ritem Develop new drugs and other therapies to {\blue \em treat} disease

\ritem Uncover factors and behaviors that are associated with
{\blue \em developing} disease and thus how to {\blue \em prevent} disease

\ritem Understand the {\blue \em manifestation} and {\blue \em course}
of disease

\ritem Develop new devices and procedures for {\blue \em detecting} and
{\blue \em monitoring} disease
\end{itemize}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red National Institutes of Health (NIH):} The government
agency responsible for coordinating most health-related research
funded by the US Government
\begin{itemize}
\ritem Budget of over \$23 {\blue \em billion} in 2002

\ritem Mainly for {\blue \em grants} to researchers in universities,
research institutes, hospitals to carry out studies addressing these
issues

\ritem Research on {\blue \em all aspects}\,: prevention, detection,
diagnosis, and treatment
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red Pharmaceutical and biotechnology industries:}
\begin{itemize}
\ritem Focused mostly on {\blue \em developing new therapies} for
prevention and treatment

\ritem {\blue \em Huge} investment in money, effort, and people
\end{itemize}
\end{overlay}
\end{slide}

\begin{slide}
\slbf{\red Scope of research:}
\begin{itemize}
\ritem {\blue \em Laboratory}\,: identifying compounds, understanding
workings of cells, etc.

\ritem {\blue \em Animal studies}\,: use animals as {\blue \em models}
for humans 

\item {\yellow$\mbox{}$} {\blue \em Human studies}\,: {\blue \em
experimental} or {\blue \em observational}
\end{itemize}
\end{slide}

\begin{slide}
\slbf{\red Experimental biomedical studies:} {\blue \em Clinical
trials}
\begin{itemize}
\ritem Evaluation of treatments in a {\blue \em controlled} setting

\ritem Is a new headache medication safe?  Does a new anti-fungal
medication cure athlete's foot?  Does a new drug for treating
HIV-infected patients work better than an older one?  Does hormonal
therapy reduce the risk of breast cancer? \ldots

\ritem Studies in which the participants receive treatments according
to a {\blue \em controlled plan}
\end{itemize}
\end{slide}

\begin{slide}
\slbf{\red In the news recently:} The {\blue \em Women's Health  
Initiative} (WHI)
\begin{itemize}
\ritem A 15-year research program funded by the {\blue \em National
Heart, Lung, and Blood Institute} (NHLBI)

\ritem {\blue \em Estrogen+Progestin study}\,: A {\blue \em clinical
trial} to test the risks and benefits of using this therapy versus not

\ritem 16,608 women ages 50 to 79 years were {\blue \em  randomly assigned} to 
take E+P or a {\blue \em placebo} and monitored periodically for
disease

\ritem {\blue \em Analysis}\,: Compare rates of disease in the 2 groups

\ritem {\blue \em Stopped} due to an increased risk of {\blue \em
invasive breast cancer} for E+P
\end{itemize}

\end{slide}

\begin{slide}
\slbf{\red Public health research:} {\blue \em Epidemiology}
\begin{itemize}
\ritem Study of the {\blue \em causes and origins} of disease

\ritem Second-hand smoke and lung cancer, Air pollution and respiratory
illness, Diet and heart disease, \ldots

\ritem {\blue \em Common approach}\,: Identify a group of people and 
{\blue \em observe} their disease status and other factors

\ritem Look for {\blue \em associations} between factors and disease
that may reflect {\blue \em risk} 

\ritem {\blue \em Often}\,: Follow {\blue \em over time}
\end{itemize}
\end{slide}

\begin{slide}
\slbf{\red Often in the news:} The {\blue \em Framingham Heart Study}
\begin{itemize}
\ritem Started in 1948, funded by NHLBI

\ritem {\blue \em Cohort} of 5,209 men and women ages 30--62 in
Framingham MA recruited and given extensive {\blue \em physical
exams}, {\blue \em lifestyle interviews}

\ritem Return every 2 years for {\blue \em medical history}, {\blue
\em physical exam}, and {\blue \em lab tests}

\ritem In 1971, the study enrolled a {\blue \em 2nd-generation cohort}\,:
5,124 of the original participants' adult children and spouses

\ritem {\blue \em Objective}\,: Understand {\blue \em causes} and
{\blue \em risk factors} associated with {\blue \em cardiovascular disease}
(CVD)

\ritem Identification of major CVD risk factors, including high blood
pressure, high blood cholesterol, smoking, inactivity, \ldots

\ritem Currently recruiting a {\blue \em 3rd-generation cohort} of 3,500
grandchildren to facilitate study of {\blue \em genetic factors}

\ritem Evaluation of new {\blue \em diagnostic technologies} like
echocardiography
\end{itemize}
\end{slide}

\begin{slide}
\vspace*{0.3in}
\begin{overlay}{0}
\slbf{\red Little-known fact I:} {\blue \em Statisticians} have played
and continue to play a {\blue \em key role} in almost all of this!
\end{overlay}
\begin{overlay}{1}
\begin{itemize}
\ritem {\blue \em Design} of studies

\ritem {\blue \em Analysis} of data

\ritem Basis for {\blue \em regulatory} requirements of the {\blue \em US FDA}
\end{itemize}
\end{overlay}


\vspace*{0.1in}

\begin{overlay}{2}
\slbf{\red Little-known fact II:} Interpreting the results of such
studies requires {\blue \em specialized statistical methods}
\begin{itemize}
\ritem \ldots because of the special {\blue \em challenges} involved
in studying humans!
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{2}
\slbf{\red Biomedical statistics or biostatistics:} {\blue \em The
field of application of statistics to address problems in biomedical
and public health research}
\end{overlay}
\end{slide}

\begin{slide}
\begin{center}
\myheading{{\blue 2. Why is studying humans is so complicated?}}
\end{center}

\slbf{\red The ``ideal'' agricultural experiment:} Compare {\blue \em
yields} of wheat plants for 2 different {\blue \em fertilizers}
\begin{itemize}
\ritem Plant wheat plants in {\blue \em plots} in a field

\ritem Assign plots to receive Fertilizer A or B {\blue \em at random}

\ritem Apply assigned fertilizers to plots

\ritem Measure {\blue \em wheat yield} for each plot at the end of the
growing season

\ritem Compare {\blue \em mean wheat yield} for A vs. B by a {\blue
\em t-test}
\end{itemize}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red Features:} 
\begin{itemize}
\ritem Plants actually {\blue \em show up} to be planted in the plots

\ritem The experimenter can ensure that the fertilizer {\blue \em
actually applied} to a plot is the {\blue \em assigned} fertilizer
recorded for that plot

\ritem The plants {\blue \em stick around} through the whole study
and are there to be {\blue \em measured} at the end 
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red Result:} {\blue \em Data} intended to be collected
\begin{itemize}
\ritem Are {\blue \em all} available

\ritem And thus may be {\blue \em analyzed} according to plan
\end{itemize}
\end{overlay}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red The ``ideal'' human study:} Compare {\blue \em reduction in blood 
pressure} for two different {\blue \em anti-hypertensive drugs}
\end{overlay}
\begin{itemize}
\begin{overlay}{1}
\ritem Subjects are {\blue \em recruited} to take part in the study
and asked to show up for {\blue \em baseline} blood pressure reading,
recording of {\blue \em demographic information}, and a {\blue \em
month's supply} of assigned pills with dosing instructions
\end{overlay}

\begin{overlay}{2}
\ritem {\blue \em All} recruited subjects show up for {\blue \em
baseline} reading, {\blue \em provide all requested information},
and {\blue \em take home} supply of pills
\end{overlay}

\begin{overlay}{3}
\ritem {\blue \em All} subjects take their assigned pills {\blue \em 
exactly according to the instructions}
\end{overlay}

\begin{overlay}{4}
\ritem {\blue \em All} subjects return as directed for {\blue \em
monthly} visits to the clinic to {\blue \em receive more pills} and
have {\blue \em blood pressure reading} until the end of the study
\end{overlay}
\end{itemize}

\begin{overlay}{5}
\vspace*{0.1in}
\slbf{\red What's wrong with this picture?}
\end{overlay}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red Problem:} Humans are {\blue \em notorious} for {\blue \em
not doing as they are told}\,!
\end{overlay}
\begin{itemize}
\begin{overlay}{1}
\ritem A subject may agree to participate and then {\blue \em change his 
mind}
\end{overlay}

\begin{overlay}{2}
\ritem A subject may show up for the initial visit but then {\blue \em
change her mind} 
\end{overlay}

\begin{overlay}{3}
\ritem A subject may show up for the initial visit but {\blue \em
refuse to provide} needed information or provide {\blue \em incorrect}
information
\end{overlay}

\begin{overlay}{4}
\ritem A subject may not take the pills as {\blue \em directed} (or 
{\blue \em not all}\,)
\end{overlay}

\begin{overlay}{5}
\ritem A subject may {\blue \em miss} some monthly visits (e.g. vacation)
\end{overlay}

\begin{overlay}{6}
\ritem A subject's physician may recommend she {\blue \em discontinue}
participation in the study
\end{overlay}

\begin{overlay}{7}
\ritem A subject may {\blue \em move away} or be hit by a {\blue \em bus}
\end{overlay}

\begin{overlay}{8}
\ritem A subject may  {\blue \em die} of a hypertension-related ailment
\end{overlay}
\end{itemize}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red Result:} {\blue \em Data} intended to be collected
on humans routinely
\begin{itemize}
\ritem May be {\blue \em missing} or {\blue \em incomplete}

\ritem May be {\blue \em error-prone}

\ritem May not reflect {\blue \em what was intended} because
subjects may not {\blue \em comply} with their treatment
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red Implications:}
\begin{itemize}
\ritem It is {\blue \em unlikely} that the data may be analyzed
according to the initial plan

\ritem {\blue \em Specialized} analysis methods are required to 
take into account these ``{\blue \em human}\,'' problems

\ritem In fact, {\blue \em designs} for studies that {\blue \em
anticipate} these problems are needed
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{2}
\slbf{\red Biostatistics}\ldots
\end{overlay}
\end{slide}


\begin{slide}
\begin{center}
\myheading{{\blue 3.  Comparing treatments based on a time-to-event}}
\end{center}
\slbf{\red Evaluation and comparison of treatments in clinical trials:} 
\begin{itemize}
\ritem {\blue \em Randomization} of a fixed number subjects to treatments

\ritem For each subject, observe a {\blue \em response}

\ritem Evaluate or compare on the basis of some summary of the
response, like the {\blue \em mean}

\ritem The response is called the {\blue \em primary endpoint}
\end{itemize}
\end{slide}

\begin{slide}
\slbf{\red For chronic diseases:} Cancer, HIV, diabetes,\ldots
\begin{itemize}
\ritem The {\blue \em primary endpoint} on which evaluation is
based is a {\blue \em time until an event occurs}

\ritem ``{\blue \em Survival}\,''

\ritem Time from {\blue \em initiation of treatment to death} for 
lung cancer patients

\ritem Time from {\blue \em initiation of treatment until an
AIDS-defining event} for HIV-infected patients

\ritem Time from {\blue \em initiation of treatment until myocardial
infarction or death} for patients with CVD

\ritem {\blue \em Objectives}\,: {\blue \em Summarize} and {\blue \em
compare} the {\blue \em distributions} of times-to-event for each treatment
\end{itemize}
\end{slide}

\begin{slide}
\slbf{\red Further complication:} 
\begin{itemize}
\ritem The study occurs over a {\blue \em finite period of time}
(e.g. 3--5 years)

\ritem Logistically, subjects in a clinical trial cannot be recruited
{\blue \em all at once}

\ritem Instead, subjects are recruited as they become {\blue \em available}

\ritem Some subjects enter the study {\blue \em early}

\ritem Others enter when the study is nearing an {\blue \em end}

\ritem ``{\blue \em Staggered entry}\,''
\end{itemize}
\end{slide}

\begin{slide}
\setlength{\unitlength}{1in}
\begin{picture}(5,2)

\begin{overlay}{0}
\put(0.3,0.25){\makebox(0,0){\red Study}}
\put(0.3,0.15){\makebox(0,0){\red starts}}
\put(1.8,0.25){\makebox(0,0){\red Study}}
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\put(0.3,0.5){\line(0,1){1.5}}
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\put(1.25,1.0){\circle*{0.05}}
\put(1.25,1.0){\line(1,0){0.45}}
\put(1.7,1.0){\blue \circle{0.05}}

\put(0.5,1.75){\circle*{0.05}}
\put(0.5,1.75){\line(1,0){0.65}}
\put(1.15,1.75){\makebox(0,0){\red x}}

\put(1.0,1.25){\circle*{0.05}}
\put(1.0,1.25){\line(1,0){0.25}}
\put(1.25,1.25){\makebox(0,0){\red x}}

\put(0.75,1.5){\circle*{0.05}}
\put(0.75,1.5){\line(1,0){1.35}}
\put(2.10,1.5){\makebox(0,0){\red x}}

\end{overlay}

\begin{overlay}{1}

\put(2.5,1.75){\circle*{0.05}}
\put(2.5,1.75){\line(1,0){0.65}}
\put(3.15,1.75){\makebox(0,0){\red x}}


\put(2.5,1.5){\circle*{0.05}}
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\put(2.5,1.25){\circle*{0.05}}
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\put(2.75,1.25){\makebox(0,0){\red x}}

\put(2.5,0.25){\makebox(0,0){\red Time 0}}

\put(2.5,0.5){\line(1,0){1.5}}
\put(2.5,0.5){\line(0,1){1.5}}

\put(2.5,1.0){\circle*{0.05}}
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\put(2.95,1.0){\blue \circle{0.05}}

\end{overlay}
\end{picture}
\begin{overlay}{0}
\hspace*{0.5in} {\blue \em Calendar Time}
\end{overlay} \begin{overlay}{1} \hspace{1.25in} {\blue \em Patient Time}
\end{overlay}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red Result:} {\blue \em Censoring}
\begin{itemize}
\ritem For some subjects, regardless of {\blue \em time of entry}, we
do not observe the endpoint due to {\blue \em competing causes}, e.g.
hit by a bus

\ritem For some subjects entering the study {\blue \em late}, the
study may {\blue \em end} before the endpoint happens

\ritem The endpoint is {\blue \em censored} for these subjects
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red Analysis:}
\begin{itemize}
\ritem {\blue \em Ignoring} the censored data (throw those subjects out)
leads to {\blue \em inaccurate} picture of survival 

\ritem {\blue \em Needed}\,: Methods for {\blue \em fair} summary
and comparison that take {\blue \em censoring} into account

\ritem {\blue \em Survival Analysis}
\end{itemize}
\end{overlay}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\begin{center}
\myheading{{\blue 4.  Longitudinal studies with repeated measures}}
\end{center}
\slbf{\red Often}\,: Questions of interest have to do with
how something {\blue \em changes over time}
\begin{itemize}
\ritem Diet medications and weight loss

\ritem Cholesterol-lowering drugs

\ritem Anti-hypertensive medications

\ritem HIV viral load following antiretroviral therapy

\ritem Prostate-specific antigen for monitoring prostate cancer recurrence

\ritem {\blue \em How} does it change? {\blue \em Rate} of change?
{\blue \em Different} for different treatments?
\end{itemize}
\end{overlay}


\begin{overlay}{1}
\slbf{\red A BIG problem:} Subjects {\blue \em drop out} of the study
\end{overlay}
\end{slide}

%\begin{slide}
%\begin{center}
%\includegraphics[height=2.8in]{dental.ps}
%\end{center}
%\end{slide}

%\begin{slide}
%\begin{center}
%\includegraphics[height=2.8in]{hiv.ps}
%\end{center}
%\end{slide}

%\begin{slide}
%\begin{center}
%\includegraphics[height=2.8in]{q.ps}
%\end{center}
%\end{slide}

\begin{slide}
\slbf{\red Needed:}
\begin{itemize}
\ritem A {\blue \em statistical model} in which the question can be
formally stated

\ritem With analysis methods to take into account that the data are
{\blue \em repeated measurements} on the {\blue \em same subjects}

\ritem \ldots And that subjects tend to {\blue \em drop out}

\ritem {\blue \em Longitudinal data analysis}
\end{itemize}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\begin{center}
\myheading{{\blue 5.  Should this study be stopped?}}
\end{center}
\slbf{\red Recall:} The {\blue \em WHI estrogen+progestin trial}
\begin{itemize}
\ritem Was {\blue \em stopped} due to increased breast cancer risk

\ritem {\blue \em How was this decision made}\,?

\ritem {\blue \em Data Safety Monitoring Board}\,: includes physicians,
ethicists, patient advocates, and {\blue \em statisticians} (DSMB)

\ritem DSMB meets periodically, reviews data {\blue \em available so
far}, makes a {\blue \em decision} whether to continue or stop

\ritem Today, it is {\blue \em routine} (and sometimes {\blue \em required}\,)
for a clinical trial to have a DSMB
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red How is the decision made?} 
\end{overlay}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red Why stop?} 
\begin{itemize}
\ritem Serious {\blue \em adverse events}

\ritem Overwhelming {\blue \em superiority} of one treatment 

\ritem {\blue \em No apparent difference} between treatments

\ritem Logistical or design problems {\blue \em too difficult} to fix

\ritem Clinical trials are {\blue \em expensive}
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red How to stop?}  Need a {\blue \em formal set of rules} for
stopping {\blue \em early}
\end{overlay}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red Ordinarily:} Do a study, collect {\blue \em all} data,
analyze at the end
\begin{itemize}
\ritem Single {\blue \em hypothesis test} at level of significance $\alpha$
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red Here:} Look at data {\blue \em sequentially}
\begin{itemize}
\ritem DSMB meets, looks at {\blue \em partial} data so far

\ritem {\blue \em Interim} hypothesis test to look at the difference based
on partial data

\ritem If trial is {\blue \em never} stopped, want level of
significance $\alpha$ at the end

\ritem {\blue \em How large} does the test statistic need to be at an
``{\blue \em interim look}\,'' (all data not available) so that at the
end, the chance we would make a mistake is $\leq \alpha$?

\ritem {\blue \em Group sequential statistical methods} for design
and analysis
\end{itemize}
\end{overlay}
\end{slide}

\begin{slide}
\begin{center}
\myheading{{\blue 6.  Pharmacokinetics}}
\end{center}
\slbf{\red How does a drug work?} From a {\blue \em pharmacologist's
point of view}
\begin{itemize}
\ritem Achieve {\blue \em therapeutic objective}

\ritem Minimize {\blue \em problems}

\ritem Come up with {\blue \em dosing regimen} to do this

\ritem How {\blue \em much}\,?  How {\blue \em often}\,? 
Under what {\blue \em conditions}\,?

\ritem Need to understand ``{\blue \em what the body does to the drug}\,''
\end{itemize}
\end{slide}

\begin{slide}

\vspace*{0.75in}

\hspace*{-0.4in}
\setlength{\unitlength}{1in}
\begin{picture}(6,1)
\put(0.5,0.5){\framebox(1.25,1){\red \it PK}}
\put(1.75,1){\red \vector(1,0){1.00}}
\put(2.25,1.25){\makebox(0,0){\blue concentration}}
\put(2.75,0.5){\framebox(1.25,1){\red \it PD}}
\put(0,1){\red \vector(1,0){0.5}}
\put(4.0,1){\red \vector(1,0){0.5}}
\put(0.25,1.25){\makebox(0,0){\blue dose}}
\put(4.30,1.25){\makebox(0,0){\blue response}}
\end{picture}
\end{slide}

\begin{slide}
\slbf{\red What goes on inside:} {\blue \em Absorption, Distribution,
Metabolism, Elimination}
\vspace*{0.15in}

%\begin{center}
%\includegraphics[height=2.0in]{processes.ps}
%\end{center}

\vspace*{0.15in}

\slbf{\red Routes of drug administration:} {\blue \em Intravenously}, 
{\blue \em Intramuscularly}, {\blue \em Subcutaneously}, {\blue \em
Orally}, \ldots
\end{slide}


\begin{slide}
\slbf{\red Data for 4 subjects given same oral dose of anti-asthmatic
theophylline:}

%\begin{center}
%\includegraphics[height=2.8in]{theo.ps}
%\end{center}
\end{slide}

\begin{slide}
\slbf{\red One-compartment model with first-order
absorption, elimination:}  oral dose $D$
\vspace*{0.1in}
\begin{center}
\setlength{\unitlength}{0.9in}
\begin{picture}(4,1)
\put(-0.01,0.5){\makebox(0,0){$D$}}
\put(1,0){\framebox(2,1){$X(t)$}}
\put(3,0.5){\vector(1,0){0.75}}
\put(0.25,0.5){\vector(1,0){0.75}}
\put(3.3,0.25){\makebox(0,0){$k_{e}$}}
\put(0.5,0.25){\makebox(0,0){$k_{a}$}}
\end{picture}
\vspace{0.1in}
\begin{eqnarray*}
\begin{array}{rcll}
\displaystyle \frac{dX(t)}{dt}& = & k_{a}X_{a}(t)-k_{e}X(t), & 
X(0)=0 \\*[0.08in]
\displaystyle \frac{dX_{a}(t)}{dt} & = & -k_{a}X_{a}(t), & X_{a}(0)=FX(0)
\end{array}
\end{eqnarray*}
$$\hspace*{-0.3in}X(t) \mbox{ = amount in ``blood'' compartment},
\mbox{ }X_{a}(t) \mbox{ = amount at absorption site}$$
\vspace*{-0.07in}
$$C(t) = \frac{X(t)}{V} =
\frac{k_{a}DF}{V(k_{a}-k_{e})}\{\exp(-k_{e}t)-\exp(-k_{a}t)\},$$
$$V \mbox{ = ``{\blue \em volume}\,'' of compartment}$$
\end{center}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\slbf{\red Pharmacokinetics:} Learn about {\blue \em pharmacokinetic
parameters} like $k_a$, $k_e$, $V$ that {\blue \em govern}
how concentrations arise
\begin{itemize}
\ritem For {\blue \em individual} subjects

\ritem And how {\blue \em variable} they are across subjects
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red Needed:}
\begin{itemize}
\ritem A {\blue \em statistical model} that allows each subject
to have his/her {\blue \em own} parameters

\ritem And describes how these {\blue \em vary}

\ritem \ldots From which the parameters and their variability can
be {\blue \em estimated}

\ritem {\blue \em Nonlinear mixed effects models}
\end{itemize}
\end{overlay}
\end{slide}

\begin{slide}
\begin{center}
\myheading{{\blue 7.  Biostatistical research}}
\end{center}
\slbf{\red Biomedical and public health research:} 
\begin{itemize}
\ritem {\blue \em Statistics} plays an {\blue \em indispensable} role

\ritem {\blue \em New challenges} require {\blue \em new methods}

\ritem {\blue \em Research} to develop new methods is required

\ritem Such research is {\blue \em supported} by {\blue \em grants} to
provide biostatistical researchers {\blue \em time}, {\blue \em
computing support}, and {\blue \em research assistants} (aka {\blue
\em graduate students}) 

\ritem Theoretical properties, computer simulations, tests on 
data from real studies
\end{itemize}
\end{slide}

\begin{slide}
\begin{center}
\myheading{{\blue 8.  Where do biostatisticians work?}}
\end{center}
\begin{overlay}{0}
\slbf{\red Everywhere biomedical and public health research takes place:}
\begin{itemize}
\ritem {\blue \em Pharmaceutical industry}

\ritem Industry {\blue \em supporting} the pharmaceutical industry,
{\blue \em contract research organizations} (CROs, e.g. {\blue \em
Quintiles})

\ritem {\blue \em Government}\,: NIH, FDA, NCHS, \ldots

\ritem {\blue \em Institutions}\,: E.g., Cancer centers 
(Sloan-Kettering, Dana-Farber, M.D. Anderson), Medical centers
(Mayo Clinic, Cleveland Clinic, Duke Clinical Research Institute)

\ritem {\blue \em Academia}\,: {\blue \em Biostatistics} departments
in schools of medicine or public health, {\blue \em Statistics} departments
like this one!
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red Opportunities:} {\blue \em There is a serious and 
growing shortage of biostatisticians with advanced degrees}\,!
\end{overlay}
\end{slide}

\begin{slide}
\begin{overlay}{0}
\begin{center}
\myheading{{\blue 9.  Training to be a biostatistician}}
\end{center}
\slbf{\red Background:} {\blue \em Undergraduate} training in 
\begin{itemize}
\ritem Statistics, mathematics, engineering, biological sciences
\end{itemize}
\end{overlay}

\vspace*{0.1in}

\begin{overlay}{1}
\slbf{\red Where?} Departments of {\blue \em biostatistics} or {\blue
\em statistics}
\begin{itemize}
\ritem Advantage of biostatistics department: {\blue \em Proximity} to
medical and public health research

\ritem Advantage of statistics department: Often more theoretical
{\blue \em foundations} in curricula
\end{itemize}
\end{overlay}

\begin{overlay}{2}
\slbf{\red Degrees:} Masters and Doctoral
\end{overlay}
\end{slide}

\begin{slide}
\begin{overlay}{0}
e\slbf{\red Coursework:} {\blue \em Bread and butter}
\begin{itemize}
\ritem Survival analysis
\ritem Longitudinal data analysis
\ritem Categorical data analysis
\ritem Clinical trials and epidemiology
\end{itemize}
\end{overlay}

\vspace*{0.1in}
\begin{overlay}{1}
\slbf{\red Coursework:} {\blue \em Specialized}
\begin{itemize}
\ritem Missing data methods
\ritem Statistical computing
\ritem Genetics/genomics
\ritem Advanced statistical modeling
\end{itemize}
\end{overlay}
\end{slide}

\begin{slide}
\slbf{\red Practical experience:} {\blue \em Very desirable}\,!
\begin{itemize}
\ritem {\blue \em Graduate Industrial Traineeship}\,: Work in
pharmaceutical industry, research institutions

\ritem{\blue \em Research Assistantship}
\end{itemize}
\end{slide}

\begin{slide}
\begin{center}
\myheading{{\blue 10.  Concluding remarks}}
\end{center}
\slbf{\red Biostatistics:} A {\blue \em huge} field with {\blue \em
many opportunities}
\begin{itemize}
\ritem Chance to apply quantitative skills and training to {\blue
\em betterment of human health}

\ritem Chance to work a part of a {\blue \em team} with physicians and
other experts 

\ritem {\blue \em Huge shortage} means lots of opportunities
\end{itemize}
\end{slide}

\end{document}