1954 Salk polio vaccine trials

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1954 Salk polio vaccine trials

• Biggest public health experiment ever
• Polio epidemics hit U.S. in 20th century
• Struck hardest at children
• Responsible for 6 of deaths among 5- to 9-
  year-olds

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Salk vaccine trial Background

• Polio is rare but the virus itself is common
• Most adults experienced polio infection without
  being aware of it.
• Children from higher-income families were more
  vulnerable to polio!
• Children in less hygienic surroundings contract
  mild polio early in childhood while still
  protected from their mothers antibodies. They
  develop immunity early.
• Children from more hygienic surroundings dont
  develop such antibodies.

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Salk trial The need for testing

• By 1954, Salks research with a vaccine looked
  promising
• Government agencies were ready to try the vaccine
  in the general population but some scientists
  feared the vaccine was unsafe or ineffective.
• There was enormous fear and desperation
  throughout the country.
• Why not just distribute the vaccine to some and
  see if it lowered the polio rate?
• A yearly drop might mean the drug was effective,
  or that that year was not an epidemic year
• Vaccine could not be distributed without testing

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Salk vaccine trial The need for controls

• An experiment requires controls.
• To test if the vaccine was effective the only
  variable that should be considered is the vaccine
  itself
• This means that some children would get the
  vaccine and some would not.
• This raises enormous ethical questions
• Is it ethical to not give children the vaccine?
• Imagine yourself as a parent in these desperate
  times. Would you participate in such an
  experiment.
• Ultimately, does the benefit to society outweigh
  the risk to those children who would not get the
  vaccine?

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Salk vaccineThe need for massive trials

• Polio rate of occurrence is about 50 per 100,000
• Suppose the vaccine was 50 effective and 10,000
  subjects were recruited for each of the control
  and treatment groups
• You would expect 5 polio cases in control group
  and 2-3 in treatment group
• Such a difference could be attributed to random
  variation
• Clinical trials were needed on a massive scale
• The ultimate experiment involved over 1.6 million
  children, with over 600,000 children inoculated

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Controversy over the design of the experiment

• In order to isolate the vaccine as the only
  variable to be considered, the treatment and
  control groups need to be as similar as possible
• But how should subjects be recruited?
• Fact volunteers tend to be better educated and
  more well-to-do than those who dont participate
• In the context of the polio disease, relying on
  volunteers could potentially bias the results
• Subjects would tend to have higher rates of polio
• Subjects are not representative of the population
• Results would be biased against the vaccine
• After much debate, the trials proceeded with two
  different protocols.

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Observed Control approach

• Administer the experiment to 1st, 2nd, and 3rd
  graders
• Offer the vaccination to 2nd graders
• This group would rely on volunteers (parental
  consent)
• Use 1st and 3rd graders as control group
• These children would be observed for incidences
  of polio
• Supporters of this approach argued that there
  would not be much variability between grades so
  treatment and control groups would be similar
• And the control group would be observed
  controls
• But there were objections . . .

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NFIP Observed Control study

• Volunteers would result in more children from
  higher income families in treatment group
• Treatment group is thus more vulnerable to
  disease than control group
• Would expect more incidences of polio in the
  treatment group than in the control group
• Biases the experiment against the vaccine
• How would incidents of the disease be diagnosed?
• Many forms of polio are hard to diagnose
• In making the diagnosis physicians would
  naturally ask whether a child was vaccinated or
  not
• Diagnosis for borderline cases could be affected
  by knowledge of what grade the child was in and
  whether the child was vaccinated or not

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Randomized control approach

• This experiment relied on volunteer subjects
  overall.
• But subjects were randomly assigned to treatment
  and control groups
• Control group was given a placebo
• Placebo material was prepared to look
• exactly like the vaccine so subjects didnt
• know what treatment they were getting
• Placebo-control group guards against the
• placebo effect
• Many objected to the design on ethical
• grounds.
• Jonas Salk himself called it A beautiful
  experiment over which the epidemiologist could
  become quite ecstatic but which would make the
  humanitarian shudder.

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Randomized control approach

• Subjects were blind they did not know to which
  
• group they were assigned
• Also, those doing the evaluation
• didnt know which treatment
• any subject received
• Each vial was identified by a code
• number so no one involved in the
• vaccination or the diagnostic
• evaluation could know who got
• the vaccine.
• Experiment was double-blind
• neither subjects nor those doing
• the evaluation knew which
• treatment any subject received

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Results of vaccine trials
The randomized, controlled experiment
Size Rate (per 100,000)
Treatment 200,000 28
Control 200,000 71
No consent 350,000 46
The Observed Control study
Size Rate (per 100,000)
Grade 2 (vaccine) 225,000 25
Grade 1, 3 (control) 725,000 54
Grade 2 (no consent) 125,000 44
Source Thomas Francis, J r., An evaluation of
the 1954 Poliomyelitis vaccine trials---summary
report, American Journal of Public Health vol
45 (1955) pp. 1-63.
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Comparing the two studies

• Results show that the observed control study was
  biased against vaccine
• Treatment group got the vaccine but was more
  prone to higher polio rates
• Control group didnt get the vaccine but was more
  prone to lower polio rates
• Its impossible to determine whats the effect of
  the vaccine and whats the effect of
  socio-economic status
• This is called confoundingthe inability to
  distinguish the separate impacts of two or more
  variables on a single outcome.
• In a randomized controlled experiment, by making
  the treatment and control groups as similar as
  possible (by randomization), we are able to
  isolate the variable of interest and eliminate
  confounding

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Comparing the two studies are the results
significant?

• In the observed control approach, chance enters
  the study in an unplanned and haphazard way based
  on what families will volunteer
• By contrast, for the randomized controlled
  experiment chance enters the study in a planned
  and simple way
• Each child has 50-50 chance to be in the
  treatment or control group
• This allows for the use of probability to analyze
  the results

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Are the results significant?

• Two competing positionswhich side would you be
  on?
• Pro The vaccine is effective. There were less
  cases of polio in the treatment group than in the
  control group. We should undertake a massive
  vaccination program throughout the general
  population.
• Con We are not convinced. The two groups were
  randomly divided. There may have been fewer
  polio-prone people in the treatment group. It was
  all done by chance. We cant be sure and were
  not willing to commit millions of dollars of
  taxpayers money on a vaccination program that
  might not be effective.

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Are the results significant?

• Assume the cons are right and that the
• vaccine is worthless. What are the
• chances of seeing such a large
• difference in the two groups?
• Imagine a polio coin where the
• chance of heads is equal to the
• chance that a person gets polio.
• Flip the coin in Room A for 200,000 times. Then
  flip it in Room B for 200,000 times. Whats the
  chance that we would get such a large difference
  as 28 heads in A and 71 heads in B?
• They are over a billion to one against!
• In the face of such odds, we say that the outcome
  is statistically significant. The effect is so
  large that it would rarely occur by chance.

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Salk vaccine trials aftermath

• The results, announced in 1955, showed good
  statistical evidence that Jonas Salk's vaccine
  was 80-90 effective in preventing paralytic
  poliomyelitis.
• Postscript Polio was virtually eliminated from
  the Americas in 1994, but still circulates in
  Asia and Africa, paralyzing the worlds most
  vulnerable children.
• The Global Polio Eradication Initiative was begun
  in 1988. That year, an estimated 350,000 children
  were paralyzed with polio worldwide.
• In 2004, polio cases had fallen to just over
  1,200 cases globally.

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The language of experimental design

• In an experiment, we have at least one
  explanatory variable, called a factor, to
  manipulate and at least one response variable to
  measure
• The specific values that the experimenter chooses
  for a factor are called the levels of the factor.
• A treatment is a combination of specific levels
  from all the factors that an experimental unit
  receives.
• The ability to manipulate factors, apply
  treatments, and compare the responses is what
  differentiates an experiment from an
  observational study

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Observational studies

• Nurses Health Study often in the news
• Over 100,000 registered nurses aged 30 to 55 have
  been followed for more than 30 years
• Detailed questionnaires sent out every two years
  on a wide variety of health and nutrition issues
• 90 response rate
• One of the most significant studies ever
  conducted on the health of women. -- Donna
  Shalala, Former Secretary of the U.S. Department
  of Health and Human Services
• This is a prospective study. Subjects were
  identified in advance and data collected as
  events unfolded.
• Many observational studies are retrospective.
  Subjects are selected and their previous
  conditions or behaviors are determined.

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Confounding

• Observational studies can suffer from confounding
  and lurking variables
• Youll read about this over the weekend in
  Hormone Studies What Went Wrong?
• The ability to control and manipulate variables
  and compare groups allows for eliminating
  confounding and the effect of lurking variables

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Double-blind, placebo-controlled randomized
comparative experiment The gold standard of
statistics

• Massive clinical trials industry
• Complex ethical questions for experiments
  involving human subjects
• Informed Consent, Institutional Review Board,
  Confidentiality
• Placebo effect is a fascinating area of research
• In conditions such as pain, the percent of
  patients responding to placebos has been shown to
  be 20 to 50.
• Reflects the amount that the body can be
  coaxed/empowered to heal itself, in the absence
  of other active agents.
• Today, few clinical trials compare against
  placebo. Most new drugs are improvements over
  existing therapies. If an existing medicine
  exists it would be unethical to deny it to
  subjects

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Other experimental design issues Blocking

• When groups of experimental units are similar,
  its often a good idea to gather them together
  into blocks.
• Blocking isolates the variability due to the
  differences between the blocks so that we can see
  the differences due to the treatments more
  clearly.
• When randomization occurs only within the blocks,
  we call the design a randomized block design
• By contrast, a completely randomized design, all
  subjects have an equal chance of receiving any
  treatment.

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Diagram of a blocked experiment
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Hypertension pharmacogenetics study

• Hypertension is most prevalent risk factor for
  diseases of the heart, brain and kidneys,
  affecting 43 million in U.S.
• Complex disease affected by physical,
  physiological and environmental factors
• State-of-the-art for treatment is trial-and-error
• Less than 40 of treated patients achieve blood
  pressure control (systolic blood pressure lt 140)
• Ultimate goal of this study is to identify
  unknown genes that influence drug response with
  the potential of tailoring antihypertensive
  therapy for individuals

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GERA Clinical Trial

• Black and white patients react differently to
  blood pressure medicine
• Blocked experimental design
• Mayo Clinic Rochester, MN
• 300 white subjects with hypertension (150 women
  and 150 men, ages 30 to 60)
• Emory University Atlanta, GA
• 300 Black subjects with hypertension (150 women
  and 150 men, ages 30 to 60)
• Subjects had previous medications discontinued
  for 4 weeks blood pressure rose and stabilized
  in hypertensive range
• Hydrochlorothiazide administered for 4 weeks
• Blood pressure measured at the beginning of
  therapy and after 4 weeks
• In each group, identify 100 best responders and
  100 worst responders by change in blood
  pressure

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Yr N Race Drug Race N 1 100 B Hydrochlorothiazide
B 100 2 100 W W 100
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GERA clinical trial

• DNA collected for each patient
• Data consists of 100,000 genetic markers called
  Single-Nucleotide Polymorphisms (SNPs)
• Goal to find an association between blood
  pressure response and genetic makeup
• Ultimate goal to find those genes that affect
  blood pressure response
• What makes this complicated is that we have only
  400 observations (the patients) and over 100,000
  variables (the genetic markers)
• Classically in statistics we had a few
  variables and many observations. As datasets
  become larger and more complex, this classic
  paradigm is shifting and the challenges are
  enormous!