Statistical Thinking In Statistical Thinking In MedicineMedicine

A brief history of statistical A brief history of statistical concepts endeavors in Medical concepts endeavors in Medical

Science Science

Christos Argyropoulos MD,Cincinnati 29th April 2005

Permeation of Statistics in Permeation of Statistics in Modern BiomedicineModern Biomedicine

Statistical ideas, tools are paramount in conducting Statistical ideas, tools are paramount in conducting medical research “experiments”medical research “experiments”

NIH grant applications demand the incorporation of NIH grant applications demand the incorporation of statistical considerations and require statisticians to be statistical considerations and require statisticians to be collaborators collaborators

Health Policy and Quality Improvement initiatives are Health Policy and Quality Improvement initiatives are motivated and motivated and enabledenabled by quantitative arguments by quantitative arguments

Individual physicians are asked to utilize (or at least have Individual physicians are asked to utilize (or at least have an appreciation of) quantitative reasoning approaches to an appreciation of) quantitative reasoning approaches to the interpretation of medical research in the Boards and the interpretation of medical research in the Boards and the “real world” the “real world”

How did we get here?How did we get here?

Purpose of this presentationPurpose of this presentation Describe the historical evolution of ideas Describe the historical evolution of ideas

about statistical methods in Western about statistical methods in Western Medicine and the culmination in the Medicine and the culmination in the randomized control clinical trialrandomized control clinical trial

Demonstrate the Demonstrate the two-waytwo-way interaction interaction between modern Medicine and Statistical between modern Medicine and Statistical ScienceScience

Understand the historical roots of Understand the historical roots of controversies and ambivalences about controversies and ambivalences about modern evidence based medicine modern evidence based medicine

What is Medicine?What is Medicine? Medicine is both an area of knowledge (a Medicine is both an area of knowledge (a

science), and the ), and the applicationapplication of that of that knowledgeknowledge

The The science of medicine is the knowledge of of medicine is the knowledge of

body systems and diseasesbody systems and diseases

TThe he profession of medicine refers to the social of medicine refers to the social structure of the group of people formally structure of the group of people formally trained to apply that knowledgetrained to apply that knowledge

MedicineMedicine

APPLICATION PROFESSION

SCIENCE

MEDICINE

What is Statistics?What is Statistics? StatisticsStatistics is the is the science and practice of and practice of

developing developing knowledge through the use of through the use of empiricalempirical quantitative quantitative data

RRandomness and uncertainty are modelled by andomness and uncertainty are modelled by probability theory..

Statistical practice also involvesalso involves rational rational decision makingdecision making in situations of uncertaintyin situations of uncertainty

StatisticsStatistics

DATA ANALYSIS

INFERENCE

DECISION ANALYSIS

PROBABILITY

STATISTICS

The first clinical trial (606BC)The first clinical trial (606BC)““Prove thy servants, I beseech thee, Prove thy servants, I beseech thee, ten ten

daysdays; and let them give us pulse to ; and let them give us pulse to eat, and water to drink. eat, and water to drink.

Then let our countenances be looked Then let our countenances be looked upon before thee, and the upon before thee, and the countenance of the children that countenance of the children that eat of the portion of the king’s eat of the portion of the king’s meat: and asmeat: and as thou seest,deal with thou seest,deal with thy servants.thy servants.

So he consented to them in this matter, So he consented to them in this matter, and proved them ten days. And at and proved them ten days. And at the end of ten days their counte-the end of ten days their counte-nances appeared nances appeared fairerfairer and fatter and fatter in flesh than all the children which in flesh than all the children which did eat the portion of the king’s did eat the portion of the king’s meat.meat.

Thus Melzar took away the portion of Thus Melzar took away the portion of their meat, and the wine that they their meat, and the wine that they should drink and gave them pulse.should drink and gave them pulse.

Quality Control questions about the Quality Control questions about the Study:Study:

1.1. Was there a stopping rule? Was there a stopping rule? 2.2. Why ten days?Why ten days?3.3. What was the outcome measured What was the outcome measured

(“fairness”)(“fairness”)4.4. Was there a discrete or continuous Was there a discrete or continuous

scale employed?scale employed?5.5. How were the inferences How were the inferences

summarized?summarized?

Daniel may not be Fisher butDaniel may not be Fisher but1.1. Use of experimental evidence to Use of experimental evidence to

settle a (health-related) issuesettle a (health-related) issue2.2. Control group was employed (with Control group was employed (with

similar characteristics?)similar characteristics?)3.3. The evidence was used to change The evidence was used to change

state policy and Daniel and his state policy and Daniel and his companions were allowed to companions were allowed to continue their cosher dietcontinue their cosher diet

4.4. Red meat is bad for one’s health!Red meat is bad for one’s health!Old Testament Book of Daniel Chapter 1 12-16Old Testament Book of Daniel Chapter 1 12-16

Empiricism in Hippocratic Empiricism in Hippocratic Medicine (~400BC) IMedicine (~400BC) I

Hippocrates: meticulous Hippocrates: meticulous collection of clinical collection of clinical case case descriptionsdescriptions and and outcomesoutcomes

Inductive Inductive approach to medical approach to medical sciencescience

Semi-quantitative reasoning Semi-quantitative reasoning was applied i.e. was applied i.e. “Those who “Those who are constitutionally very fat are constitutionally very fat are are more apt to diemore apt to die quickly than quickly than those who are thin”those who are thin”..

Empiricism in Hippocratic Empiricism in Hippocratic Medicine (~400BC) IIMedicine (~400BC) II

““Case-based reasoning” (CBR) can be Case-based reasoning” (CBR) can be either qualitative or quantitative either qualitative or quantitative

Hippocratic medicine has been claimed to Hippocratic medicine has been claimed to “pro or anti EBM” by modern writers“pro or anti EBM” by modern writers

Paradigm transferred to non-medical fields Paradigm transferred to non-medical fields in the 80s-90s by Artificial Intelligence in the 80s-90s by Artificial Intelligence scientistsscientists

Modern CBR systems are used to solve Modern CBR systems are used to solve problems in scientific – technical fieldsproblems in scientific – technical fields

Stat Wars: The (Roman) Empire Stat Wars: The (Roman) Empire strikes backstrikes back

For the next 500 years, the Hippocratic system of For the next 500 years, the Hippocratic system of observation-based objects was the dominant observation-based objects was the dominant scientific paradigm in medicine.scientific paradigm in medicine.

During the consolidation of the Roman Empire (1-During the consolidation of the Roman Empire (1-200 AD) a number of “alternative” medical 200 AD) a number of “alternative” medical systems appeared and the orthodoxy was systems appeared and the orthodoxy was challengedchallenged

A 20 year old physician (who would later dominate A 20 year old physician (who would later dominate medical thinking for a millennium) came to the medical thinking for a millennium) came to the rescue by raising questions about the rescue by raising questions about the evaluation evaluation of evidenceof evidence

Statistical Ideas in Galen’s work – Statistical Ideas in Galen’s work – The context The context

The The dogmatists dogmatists argued for the primacy of argued for the primacy of logical theorieslogical theories

The empiricists maintained that The empiricists maintained that only dataonly data (in (in the form of clinical observations) and the form of clinical observations) and experimentation could serve the same goalsexperimentation could serve the same goals

The empirico-rationalists supported a The empirico-rationalists supported a middle-out approachmiddle-out approach

Statistical Ideas in Galen’s work – Statistical Ideas in Galen’s work – The context The context

““Experience” Experience” → Observation → Observation

→ → Counts of CasesCounts of Cases

Galen. (c. 150). Galen. (c. 150). Galen on Medical ExperienceGalen on Medical Experience Oxford: Oxford University Press, 1944.Oxford: Oxford University Press, 1944.

How can we assert that the empirical weight of evidence points towards a particular cause of a disease or an efficacious treatment?

“I assert that experience has shown that what has produced a like result in three cases can produce the reverse in three others. I say that a thing seen may be seen exactly as before, and yet belong to those things which are of both kinds, or to those things that happen often or to those things that take place but rarely. […] What is to prevent the medicine that is being tested from having a given effect on two hundred people and the reverse effect on twenty others; and to prevent that of the first six people who were seen at first and on whom the remedy took effect, three belong to the two hundred and three to the twenty, without you being able to know which three belong to the two hundred and which to the twenty, even if you were a soothsayer? … Therefore I say of what has been seen but once, that it is not technical, just as the single grain of wheat is not a perfect heap; but if it is a thing that is seen many times in the same way, then I call it technical…”

Probabilistic Ideas in Galen’s Probabilistic Ideas in Galen’s work Iwork I

18 centuries before the work of Kiaer who stated that “the part (sample) can replace the whole (population)” a physician described the formal foundation of sample based inference and the need for representativeness

Statistical Ideas in Galen’s work IIStatistical Ideas in Galen’s work II

Can one use finite number of observations to add to the weight of evidence?

Statistical Ideas in Galen’s work IIStatistical Ideas in Galen’s work II

Can one use finite number of observations to add to the weight of evidence?

“Having learnt in advance from the works of nature you have already seen, you should hope that its art concerning all other [creatures] is the same. In the same way we form an opinion about the arts of people, because we do not expect to see all the statues that Phidias and Polycleitus had made, but from the ones we have seen, we hope the others [are the same], accordingly, the one who gained experience [in selecting] the works of nature, can conclude about [any other] from what he has already seen”

Galen. De anatomicis administrationibus libri ix. In: Kühn CG. Claudii Galeni opera omnia, volume 2. Olms, Hildelsheim: 1964:545 pp. line 11-17.

Statistical Ideas in Galen’s work IIStatistical Ideas in Galen’s work II

Can one use finite number of observations to add to the weight of evidence?

Galen. De sanitate tuenda libri vi. In Kuhn Corpus medicorum Graecorum, Koch K., Leipzig, 1923 vol. 6, p. 212, line 1 to p. 214, line 5.

“Theon (a contemporary gymnast) made a mistake by saying that hot baths are of great beneficence to all people, because Theon used hot baths after hard workouts. But he [made his observations] only on good athletes in very good shape who had hot baths after hard workouts and benefited from them “

Extrapolating from a small group of cases can be dangerous

“[…] But if it happened once in every three or four successful deliveries that the fetus be prevented [to exit the uterus because of its wrong position], it follows that in every four hundred fetuses one hundred will be prevented. But ... this is seen to happen once in multiple thousands ...”

Galen. De usu partium. In: Helmreich G.. Galeni de usu partium libri xvii. Hakkert, Amsterdam: 1968; volume 4, page 248, line 4-17.

Statistical Ideas in Galen’s work IIIStatistical Ideas in Galen’s work III

Statistical Ideas in Galen’s work IIIStatistical Ideas in Galen’s work IIIIn modern bio-statistical notation we express the same concepts as :

•“Let n denote the number of people in the sample studied, p the proportion of the sample possessing the characteristic under study, and P the underlying (but unknown) proportion who possess the characteristic. Inferences about P may be made using the binomial probability distribution …. A confidence interval may be assigned to the underlying proportion”

Joseph L Fleiss. Statistical methods for rates and proportions. Wiley Series in Probability and Mathematical Statistics. 1981 page 13, line 12-15

Statistical Ideas in Galen’s work IIIStatistical Ideas in Galen’s work III

200 400 600 800 1000Size of Trial

0.2

0.4

0.6

0.8

1

Probability P p34

Probabilistic Ideas in Galen’s Probabilistic Ideas in Galen’s work IVwork IV

1.1. highlight the significance of an experiment’s highlight the significance of an experiment’s result repeatability in order to arrive at a reliable result repeatability in order to arrive at a reliable scientific conclusionscientific conclusion

(“.. (“.. you must deny me faith in my wordsyou must deny me faith in my words .. .. I transfer I transfer the authority to anyone who wishes, to come and the authority to anyone who wishes, to come and show me if what I say concerning the findings of show me if what I say concerning the findings of anatomies is really true. For I have already anatomies is really true. For I have already shown thousands of timesshown thousands of times … … And this must be And this must be shown by anyoneshown by anyone after I and my pupils have diedafter I and my pupils have died “)“)

Among other things, was probably the first to:Among other things, was probably the first to:

Statistical Ideas in Galen’s work VStatistical Ideas in Galen’s work V

2.2. Understood that the definition of health v.s. disease is Understood that the definition of health v.s. disease is not always clear, and a quantitative definition might be not always clear, and a quantitative definition might be required required

““So, what is the concept of a healthy body construction, and So, what is the concept of a healthy body construction, and what of a diseased? The healthy one has all its systems what of a diseased? The healthy one has all its systems functioning; the diseased, not functioning. But if functioning; the diseased, not functioning. But if someone who is healthy has his someone who is healthy has his systems not systems not functioningfunctioning so well as someone else's, but not so well as someone else's, but not malfunctioning, he is said to have a malfunctioning, he is said to have a bad constitutionbad constitution, , not a disease. … So, it is necessary to define what is the not a disease. … So, it is necessary to define what is the amplitude of health, since there are many many amplitude of health, since there are many many differences between healthy bodies on its differences between healthy bodies on its [health’s] [health’s] upper and lower limitsupper and lower limits.. “ “

Among other things, was probably the first to:Among other things, was probably the first to:

Statistical Ideas in Galen’s work Statistical Ideas in Galen’s work VIVI

3.3. Provide the first statistical description of a medical object Provide the first statistical description of a medical object (i.e. the expected day of delivery) (i.e. the expected day of delivery)

““For the seven month births I transfer my whole life's For the seven month births I transfer my whole life's knowledge as I always very carefully acquainted the knowledge as I always very carefully acquainted the exact time of the conception of the sperm by women, exact time of the conception of the sperm by women, which time if you ignore it is impossible to find the date of which time if you ignore it is impossible to find the date of birth. And I found birth. And I found most of them between 190 and 200 most of them between 190 and 200 daysdays, , a few of them some days earlier or some days a few of them some days earlier or some days laterlater, but , but none before day 184 or after day 204none before day 184 or after day 204.”.”

Among other things, was probably the first to:Among other things, was probably the first to:

Galen. De septimestri partu. "Galenos' Schrift uber die Sieben-monatskinder". Quellen und Studien zur Geschichte der Naturwissenschaften und Medizin 3.4.

1933, 127-130

Statistical Ideas in Galen’s work Statistical Ideas in Galen’s work VIIVII

The previous passage also demonstrates the use of The previous passage also demonstrates the use of quantitative data to define the quantitative data to define the boundaries of an objectboundaries of an object . .

After defining the object in terms of a quantitative co-After defining the object in terms of a quantitative co-variate of its members, the former would become an variate of its members, the former would become an independent entity for study. independent entity for study.

It will take 1700 years for the same concepts to re-It will take 1700 years for the same concepts to re-appear in the biomedical and social sciences with the appear in the biomedical and social sciences with the creation of the “average man” by Quatelet and creation of the “average man” by Quatelet and regression analysis by Galtonregression analysis by Galton

Statistical Ideas in Galen’s work Statistical Ideas in Galen’s work EpilogueEpilogue

In his writings, Galen uses the word In his writings, Galen uses the word probability probability 300 times, without a formal (i.e. mathematical) 300 times, without a formal (i.e. mathematical) framework. framework.

The word admits both a “The word admits both a “degrees-of-belief”degrees-of-belief” and “and “frequencyfrequency of event” interpretation . of event” interpretation .

Upper limit of qualitative approaches to Upper limit of qualitative approaches to uncertaintyuncertainty

Enabling events of Modern Statistics Enabling events of Modern Statistics Over the next 1500 years, developments in Over the next 1500 years, developments in

science, technology and world-politics science, technology and world-politics would enable the creation of statistical would enable the creation of statistical science.science.

1.1. Modern Numerals and Modern Numerals and zerozero (0-9) in India (0-9) in India (~500 AD). (~500 AD).

2. Rules for adding, subtracting, multiplying, and dividing (Khowarizmi~AD 800) .

3. Introduction of the numerical system in Europe (Fibonacci 1202 AD)

Enabling events of Modern Statistics Enabling events of Modern Statistics Over the next 1500 years, developments in Over the next 1500 years, developments in

science, technology and world-politics science, technology and world-politics would enable the creation of statistical would enable the creation of statistical science.science.

4. Mercantilism and the birth of the “nation-state”

5. Gambling houses and casinos are established across Europe

6. Mathematical analysis and differential calculus (Isaac Newton and Gottfried Wilhelm von Leibniz 17 17thth century) century)

The birth of ProbabilityThe birth of Probability

The concept of “probability” is grounded in The concept of “probability” is grounded in mathematical (i.e. quantitative) terms in the mathematical (i.e. quantitative) terms in the 1818thth century. century.

1.1. Probability = long-run frequency of an event Probability = long-run frequency of an event (Bernoulli-law of large numbers) (Bernoulli-law of large numbers)

2.2. Probability = degree of belief about an Probability = degree of belief about an uncertain event (Laplace, Bayes - theorem). uncertain event (Laplace, Bayes - theorem).

Bayes and his TheoremBayes and his Theorem

"An Essay Toward Solving a "An Essay Toward Solving a Problem in the Doctrine of Problem in the Doctrine of Chances" (Bayes 1764)Chances" (Bayes 1764)””

method by which wemethod by which we might judge might judge concerning the probability that concerning the probability that an event has to happen, in an event has to happen, in given circumstances, upon given circumstances, upon supposition that we know supposition that we know nothing concerning it but that, nothing concerning it but that, under the same circumstances, under the same circumstances, it has happened a certain it has happened a certain number of times, and failed a number of times, and failed a certain other number of times.certain other number of times.

Bayes and his TheoremBayes and his Theorem

)|(),|( )|(

),|(IEP

IHEPIHPIEHP

Likelihood ratio (positive):

= Sensitivity/(1-Specificity)= (TP/Disease +)/(FP/Disease –)

If ODDS = p(event)/[1-p(event)], then:

Pre-test odds x Likelihood ratio = Post-test odds

Prior odds x Likelihood ratio = Posterior odds

Likelihood ratio (positive):

= Sensitivity/(1-Specificity)= (TP/Disease +)/(FP/Disease –)

If ODDS = p(event)/[1-p(event)], then:

Pre-test odds x Likelihood ratio = Post-test odds

Prior odds x Likelihood ratio = Posterior odds

““Bedside” Bayes Bedside” Bayes

These formulas are behind the clinical use of These formulas are behind the clinical use of the PIOPED study data and the dreaded the PIOPED study data and the dreaded question by Nuclear Medicine physicians: question by Nuclear Medicine physicians: “What’s your pre-test probability doc?” “What’s your pre-test probability doc?”

Clinical use of any laboratory test can (and Clinical use of any laboratory test can (and should) be guided by the interplay of test – should) be guided by the interplay of test – characteristics (objectively quantifiable as characteristics (objectively quantifiable as sensitivity, specificity) and a subjective sensitivity, specificity) and a subjective judgment (pre-test probability) judgment (pre-test probability)

Probabilistic inference in Probabilistic inference in Medicine - the first yearsMedicine - the first years

Pierre-Simon LaplacePierre-Simon Laplace:: mathematical mathematical theory of scientific inference (18theory of scientific inference (18thth century) century)

Laplace applied his “hammer” to all sorts of Laplace applied his “hammer” to all sorts of “nails”: celestial mechanics, games of “nails”: celestial mechanics, games of chance and …chance and …

Medicine (“the preferred method of Medicine (“the preferred method of treatment would manifest increasingly in the treatment would manifest increasingly in the [probability] measure as the number of [probability] measure as the number of observations was increased”)observations was increased”)

Marquis de Laplace A philosophical Essay on Probabilities. English Translation Dover Publications ISBN 0486288757

Probabilistic inference in Probabilistic inference in Medicine - the first debateMedicine - the first debate

Laplace’s view was hotly debated within the Laplace’s view was hotly debated within the medical communitymedical community

Pieere-Jean Georges Cabanis (1757-1808): Pieere-Jean Georges Cabanis (1757-1808): proper professional behavior for a physician proper professional behavior for a physician is to match the characteristics of is to match the characteristics of each each patient with the patient with the personalpersonal knowledge knowledge acquired through practiceacquired through practice

Phillipe Pinel (1745-1726): the direct use of Phillipe Pinel (1745-1726): the direct use of success-failure success-failure samplesample frequencies frequencies

Case-Control Studies and Case-Control Studies and Statistical SummariesStatistical Summaries

The first case-control (actually case series) study was conducted in Paris The first case-control (actually case series) study was conducted in Paris by by Pierre-Charles-Alexandre Louis (1787–1872)between 1822-1827 between 1822-1827 during an outbreak of typhoid fever. during an outbreak of typhoid fever.

1.1. Case = fatal cases of typhoid (n=50, avg age=23)Case = fatal cases of typhoid (n=50, avg age=23)

2.2. Control = survivor of typhoid (n=88, avg age=21)Control = survivor of typhoid (n=88, avg age=21)

3.3. Hypothesis tested = efficacy of bloodletting (standard of treatment at Hypothesis tested = efficacy of bloodletting (standard of treatment at that time)that time)

4.4. Data reported : frequencies of the “exposure” factor i.e. bloodletting in Data reported : frequencies of the “exposure” factor i.e. bloodletting in survivors and non-survivors as well as the average survival timesurvivors and non-survivors as well as the average survival time

5.5. Inferences : conducted on the basis of enumeration of the various Inferences : conducted on the basis of enumeration of the various outcomes (“numerical method”)outcomes (“numerical method”)

6.6. Conclusion = bloodletting NOT helpfulConclusion = bloodletting NOT helpful

Louis, P. C. A. (1836). Anatomical, Pathological and Therapeutic Researches upon the Disease Known under the Name of Gastro-Enterite Putrid, Adynamic, Ataxic, or Typhoid Fever, etc., Compared with the Most Common Acute Diseases, Vols. 1 and 2, trans. Henry I. Bowditch. Issac R. Butts, Boston.

Case-Control Studies and Case-Control Studies and Statistical SummariesStatistical Summaries

SurvivorsSurvivors

YesYes NoNo

BLOOD-BLOOD-LETTINGLETTING

YESYES 6262 3939

NONO 2626 1313

Case-Control Studies and Case-Control Studies and Statistical SummariesStatistical Summaries

If we were given the same data today, we would summarize our inferences in the following way:

1. the OR for the exposure (“bloodletting”) is 1.258, with a 95% CI of 0.578-2.736

2.Χ2 = 0.148 with a p value of 0.701

Early American “EBM” IEarly American “EBM” I

Louis work was not received well Louis work was not received well However he spread the word to the spread the word to the foreign foreign

students who flocked to Paris, attracted by his students who flocked to Paris, attracted by his approachapproach..

Two of his most enthusiastic students were Two of his most enthusiastic students were William Gerhard and Caspar Pennock of Philadelphia who applied the methods to study an epidemic of highly malignant fever

Their study provided the earliest differentiation of typhus from typhoid

Early American “EBM” IIEarly American “EBM” II In 1843 Austin Flint in Buffalo, concluded

that typhoid was spread by contagion which he suspected was carried by water.

Oliver Wendell Holmes used Louis' method and an actuary to rule out chance as an explanation for spread of puerperal fever

Frank Hastings Hamilton applied the numerical method to his own practice (“fracture tables”)

The early appearance of the “P-The early appearance of the “P-value” Ivalue” I

The ideas of Louis, were applied 10 years later in The ideas of Louis, were applied 10 years later in another problem, the comparison of two competing another problem, the comparison of two competing therapiestherapies

The disease: Bladder StonesThe disease: Bladder Stones ““Standard of Care” = Open surgical extraction of Standard of Care” = Open surgical extraction of

stonesstones Modern Treatment = LithotrityModern Treatment = Lithotrity The death rate of the old procedure was 21.6%

(1,237/5,715); the death rate for lithotrity was 2.3% (6/257)

The surgeon Jean Civalie argues for abandoning the old procedure

The early appearance of the “P-The early appearance of the “P-value” IIvalue” II

The French Academy of Sciences and Medicine The French Academy of Sciences and Medicine appoints a committee to investigate the findings appoints a committee to investigate the findings of Civalie of Civalie

The mathematician Simeon-Denis Poisson (1781–1840) argues for the application of the law of large numbers

The physician Francois Double (1776–1842) argued that the whole method was inappropriate to “elevate the human spirit to that mathematical certainty found only in astronomy”

The early appearance of the “P-The early appearance of the “P-value” IIIvalue” III

Issue is finally settled by Issue is finally settled by Louis-Denis-Jules Gavarret (1809–1890) who had trained both as engineer and physician

Probability theory merely expresses the statistical results of inductive reasoning in a more formal and exact manner

Statistical results are useful only if, the cases are similar or comparable, and there must be many such observations

The early appearance of the “P-The early appearance of the “P-value” IVvalue” IV

Precision to be sought after is the 99.5% favoring the Precision to be sought after is the 99.5% favoring the new treatment versus the standard (the posterior new treatment versus the standard (the posterior Probability favoring Lithotrity was <0.0001)Probability favoring Lithotrity was <0.0001)

Used the same argument to criticize the small number Used the same argument to criticize the small number of observations in Louis studies on pneumonia, TB of observations in Louis studies on pneumonia, TB and typhoidand typhoid

In Germany, the ophthalmologist Julius Hirschberg (1843–1925), concerned about the number of observations required by Gavarret’s assumption of 212:1 odds, modified the formula by using a lower standard of confidence of 11:1 or 91.6%.

Eventually the standard would rise to the 95%, a number that would attain religious belief status

The “death” of the first period of The “death” of the first period of “EBM”“EBM”

With the retirement of Louis in the mid-1850s, his With the retirement of Louis in the mid-1850s, his influence begins to fade awayinfluence begins to fade away

Birth of modern Experimental and Laboratory Birth of modern Experimental and Laboratory medicine, by Pasteur - Koch (“germ theory”) and medicine, by Pasteur - Koch (“germ theory”) and Claude Bernard (“physiology”) Claude Bernard (“physiology”)

Experimental investigation of each individual patient could provide an “objective” scientific

Valid “scientific” results consists of the discovery of causation, not just the discovery of the correlation [Friedrich Oesterlen (1812–1877)]

First synthetic attempts failFirst synthetic attempts fail

Carl Wunderlich (1815–1877): collection of massive datasets of quantifiable physiological data

Principal contribution was the establishment of a range of normal temperature from 36.3 to 37.5°C which was compiled from which was compiled from 1 1 million readings in over 25,000 patientsmillion readings in over 25,000 patients

Fever IS a Fever IS a symptomsymptom NOT a NOT a diseasedisease

Valid scientific program in 21st centuryValid scientific program in 21st century

First synthetic attempts failFirst synthetic attempts failValid scientific program in 21st centuryValid scientific program in 21st century

Curtain: The “numerical” method Curtain: The “numerical” method Joseph Lister (1827–1912) publishes his

pioneering work with antiseptic surgery in 1870 Average mortality rate was 45.7% (16/35) for all

surgical procedures performed at the University of Edinburgh in the years 1864–1866

Reports that it was 15% (6/40) for all surgical procedures performed in the three-year period 1867–1869.

Although he used this statistical result to show the efficacy of the new antiseptic method, he claimed that the science behind this was the germ theory of disease as proposed by Louis Pasteur (1822–1895) and not the numbers!

Statistical Developments of the Statistical Developments of the late 19late 19thth Century – Early 20 Century – Early 20thth

Century Century 1877 -- F. Galton -- regression to the mean 1877 -- F. Galton -- regression to the mean 1888 -- F. Galton -- correlation 1888 -- F. Galton -- correlation 1900 -- Karl Pearson -- chi square; applied correlation 1900 -- Karl Pearson -- chi square; applied correlation

to natural selection to natural selection 1908 -- "Student" (W. S. Gossett) -- 1908 -- "Student" (W. S. Gossett) -- TThe t-test he t-test 1919 --  R. A. Fisher -- ANOVA1919 --  R. A. Fisher -- ANOVA 1930's 1930's -- -- Jerzy Neyman and Egon Pearson -- type II Jerzy Neyman and Egon Pearson -- type II

errors, power of a test, confidence intervalserrors, power of a test, confidence intervals 1920s-1940s -- Quantum mechanics and the need to 1920s-1940s -- Quantum mechanics and the need to

model outcomes of repetitive experiments -- “long-run model outcomes of repetitive experiments -- “long-run frequency” interpretation of probabilityfrequency” interpretation of probability

The birth of Medical Statistics IThe birth of Medical Statistics I Heavily influenced by Karl Pearson, who similarly

to Louis would try to “spread the word” through his students. They would go to subsequently establish the first statistic departments in Medical/Public Health Schools

Major Greenwood (1880–1949) makes the distinction between a “mathematical error” (measurement error) and “functional error” (Lister Institute for Preventive Medicine in 1903)

Raymond Pearl (1879–1940): The Johns Hopkins University as professor of biometry and vital statistics in the School of Hygiene and Public Health

The birth of Medical Statistics II The birth of Medical Statistics II Sir Ronald A. Fisher (1890–1962) statistical

methods for design and analysis of experiments.– replication – randomization, – organization of the data gathering aspect of the

experiment

Fisher, R. A. (1958). Statistical Methods for Research Workers, 13th edn.,Hafner, New York.

“To call in the statistician after the experiment is done may be no more than asking him to perform a post-mortem examination: he may be able to say what the experiment died of”

The First Modern Clinical Trial IThe First Modern Clinical Trial I

Sponsored in 1946 by the British Medical Sponsored in 1946 by the British Medical Research CouncilResearch Council

Study Question: Is Streptomycin an effective Study Question: Is Streptomycin an effective TB treatment?TB treatment?

Study Design: Randomized, controlled, Study Design: Randomized, controlled, multi-center comparison between two multi-center comparison between two groupsgroups

Treatment Group : Streptomycin + Bed RestTreatment Group : Streptomycin + Bed Rest Control Group: Bed Rest alone (Standard of Control Group: Bed Rest alone (Standard of

Care)Care)

The First Modern Clinical Trial IIThe First Modern Clinical Trial II End Points: End Points:

1.1. Radiographic Improvement (assessed by Radiographic Improvement (assessed by two Radiologists and an Internist “two Radiologists and an Internist “without without knowledge of whether the films being knowledge of whether the films being viewed were those of S or C patientsviewed were those of S or C patients”)”)

2.2. Differences in interpretation of XRs Differences in interpretation of XRs resolved by review sessionresolved by review session

3.3. Patient SurvivalPatient Survival

MRC. (1948). Streptomycin treatment of pulmonary tuberculosis: A Medical MRC. (1948). Streptomycin treatment of pulmonary tuberculosis: A Medical Research Council Investigation, Br. Med. J.Research Council Investigation, Br. Med. J.iiii::769-782769-782 hhttp://bmj.bmjjournals.com/cgi/content/full/317/7167/1248/bttp://bmj.bmjjournals.com/cgi/content/full/317/7167/1248/b

The First Modern Clinical Trial IIIThe First Modern Clinical Trial III Enrollment : January 1947 – September Enrollment : January 1947 – September

19471947 Number of patients enrolled : 55 (S), 52(C)Number of patients enrolled : 55 (S), 52(C) Study Results:Study Results:

““Four of the 55 S patients (7%) and 14 of Four of the 55 S patients (7%) and 14 of the 52 C patients (27%) died before the end the 52 C patients (27%) died before the end of six months. The difference between the of six months. The difference between the two series is statistically significant; the two series is statistically significant; the probability of it occurring by chance is less probability of it occurring by chance is less than one in a hundredthan one in a hundred””

MRC. (1948). Streptomycin treatment of pulmonary tuberculosis: A MRC. (1948). Streptomycin treatment of pulmonary tuberculosis: A Medical Research Council Investigation, Br. Med. J.Medical Research Council Investigation, Br. Med. J.iiii::769-782769-782 hhttp://bmj.bmjjournals.com/cgi/content/full/317/7167/1248/bttp://bmj.bmjjournals.com/cgi/content/full/317/7167/1248/b

Summary and ConclusionSummary and Conclusion

Statistical Ideas and Applications in Medicine are Statistical Ideas and Applications in Medicine are not the invention of the 20not the invention of the 20 thth century century

Physicians entertained the idea that medical Physicians entertained the idea that medical knowledge can be understood in quantitative knowledge can be understood in quantitative terms thousands of years agoterms thousands of years ago

However there has always been a significant However there has always been a significant resistance in accepting the idea, in spite of its resistance in accepting the idea, in spite of its effectiveness in practice (i.e. effectiveness in practice (i.e. The limits of The limits of evidence-based medicine.evidence-based medicine.RRespir Care. 2001 espir Care. 2001 Dec;46(12):1435-4Dec;46(12):1435-4 for a modern version of the for a modern version of the same arguments)same arguments)