Ankur Barua

At the end of the session, the learner will be able to:

Understand the basic Experimental studies.

concepts

of

Understand the basic concepts of Survival Analysis.

Basic concepts of Experimental studies

Basic concepts of Survival Analysis

The study of the distribution and determinants of health-related states or events in specified populations, and

the application of this study to the

control of health problems.
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Word clinical is derived from the Greek kline which means bed so the term seems to be related to the bedside aspect of the patient/physician relationship.
A clinical trial is a type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease.

The best time to contemplate the quality of evidence from a clinical trial is before it begins. Conceptualizing and designing

good clinical trials is never an accident but results from careful planning.
Steven Piantadosi in Clinical Trials; a Methodologic Perspective

 Phase I: Primarily dose-finding trials. Primary concern: safety. A great deal of the pharmacology and biological effects in vivo is

learned in these trials. Phase II: Primarily feasibility and estimating treatment efficacy trials. A fixed dose of a drug is used on a small number of patients. A balance between efficacy and feasibility (side effects & toxicity) is considered for a large-scale study. Phase III: Large comparative efficacy clinical trials. A new treatment vs. standard or placebo (if no standard therapy exists). Such trials will favorable to the new treatment only when they demonstrate large benefits that can not be explained by chance alone. Phase IV: Post-marketing observational studies. Attempts to catch rare adverse reactions to the medication or procedure.

NULL HYPOTHESIS: There is no Association between a determinant or an intervention and an outcome. If at all any association is observed, it is merely due to chance. STATISTICAL QUESTION: How likely is it (what is the probability) that the actual findings in the sample would be obtained if the null hypothesis was true? STATISTICAL ANSWER: p-value (probability p = 0.05) There is a 5% (5 in 100) chance that the actual findings in the sample could be obtained if the null hypothesis is true (i.e., without any real association).
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Main research question and statistical procedure on anaemia in pregnancy as an example:

Main Research Question

1. What is the prevalence of anaemia among pregnant women in study area?

Statistical Procedure
Estimation of proportion (95% CI) Estimation of mean (95% CI) Difference in proportion (95% CI)

2. What is the average Haemoglobin level of pregnant women in study area? 3. Does the incidence of low birth weight differ in anaemic and non-anaemic mothers?

4. Does the average birth weight differ in babies born to anaemic & non-anaemic mothers? Difference in mean (95% CI) 5. Does anaemia during pregnancy in a risk factor for low birth weight? Case-control study (OR) or Cohort study (RR) Intervention trial (RR)

6. Can Iron/Folic supplementation increase the Haemoglobin level?

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Qualitative data
Need large enough sample sizes at each level of the variable of

interest

Quantitative data
distribution of response or residuals from modeling procedure (usually

assume normality or log-normality) Equal variances in response across groups (in ANOVA)

Time to Event data

Censoring independent of follow-up time Proportional hazards (for Proportional Hazards model) Specific time distribution (e.g., Weibull, Gompertz, exponential) for

parametric models

Main purposes are to accrue patients in reasonable amount of time and increase generalizability. Statistical issues

Delays in submitting data for monitoring Pooling the data across centers Treating center effect as fixed vs. random Heterogeneous treatment effect across centers (interaction)

identify problem
publication

Literature review

Report writing

Plan research design

Determining sample size

Generalization interpretation

Hypothesis testing

Write protocol

Presentation & analysis of results

Pilot study and main study

Ethical committee approval

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Observational studies
Descriptive studies Analytical studies Case-control or case-reference studies Cohort or follow-up studies

Experimental or intervention studies

Case studies, Case series analysis Ecological or correlational studies

Randomized controlled trials or clinical trials

Lab experiments, Animal experiments

Field trials or community intervention studies

Community trials

Cross-sectional or prevalence studies, Incidence studies

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Can ONLY show Association You will never know all the possible confounders!

Can show Association and Causality Well done randomization means unknown confounders should not create problems

AIMS
To establish temporal (cause and effect) relationship

between an etiological factor and a disease.

To measure the effectiveness and efficiency of health

services.

They have all advantages and disadvantages of a cohort study.

Critical considerations on ethical issues, cost, acceptance and feasibility are also important for the intervention.
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Human studies: - To investigate disease etiology and the preventive ,therapeutic measures

to evaluate

1747-James Lind-scurvy 1796-Edward Jennar-cowpox

1. 2. 3.

Ethical and logistic considerations, benefits weighed against the risks involved Volunteers made fully aware of the experiment WHO (1980)-strict code of practice

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RANDOMIZATION

outcome Intervention no outcome

Study population outcome Control no outcome baseline future

Study begins here (baseline point)

time

Meta-analysis of Multi-centric RCTs (Cochrane) Systematic Reviews on Multi-centric RCTs (Cochrane)

Randomized Controlled Trials (Lab, Clinical, Field & Community Trials)

(Retrospective, Prospective, Retro-prospective)

Cohort Studies

Case-control studies
(Matched or Unmatched)

Cross-sectional studies
(Prevalence studies)

Case Reports & Case Series Analysis

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In many medical studies, the primary endpoint is time until an event occurs (e.g. death, remission). Data are typically subject to censoring when a study ends before the event occurs. Survival Function - A function describing the proportion of individuals surviving to or beyond a given point of time.

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Problems arise when non-adherence may be related to outcome or prognosis, leading to biased representation. In full ITT analyses, all participants who do not receive the assigned intervention according to the protocol as well as those who were lost to follow up are also included in the final analysis.

ITT analyses all patients according to randomised treatment irrespective of protocol violations (censored data).
However, it does not solve all problems.
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The beginning of each interval is determined by death

Each interval contains one death (or more if there are ties) N(t) includes individuals with censored data at t

Time Interval 0104172276383418487609-

N 10 10 9 7 6 5 4 2

D 0 1 1 1 1 1 1 1

(N-D)/N 1.0 0.9 0.889 0.857 0.833 0.8 0.75 0.5

S(t) 1.0 0.9 0.801 0.686 0.571 0.457 0.343 0.171

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Survival Analysis for DAY Total Number Events 9 9 18 Number Censored 40 6 46 Percent Censored 81.63 40.00 71.88

REGIMEN REGIMEN Overall

1 2

49 15 64

Test Statistics for Equality of Survival Distributions for REGIMEN

Statistic Log Rank 10.93

df 1

Significance .0009

This is conducted as a chi-square test, compare with notes.

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BMT subsample (N=10)

1.0 0.8

Survival Functions
0.6

1.1 1.0 .9

Survival 0.2 0.4

.8
0.0

.7
0 200 400 600 Number of Days 800 1000

REGIMEN
2 2-censored 1 1-censored 0 10 20 30 40 50 60 70

.6

Cum Survival

.5 .4 .3

DAY

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The hazard function of survival time gives the conditional failure rate. The hazard function is also known as the instantaneous failure rate, force of mortality and age-specific failure rate.

The hazard function gives the risk of failure per unit time during the aging process.

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It compares two or more groups (treatments), adjusting for other risk factors on survival times (like Multiple regression).

Models the Relative Risk (RR) of an event as function of time and covariates.
Common assumption: Relative Risk is constant over time - Proportional Hazards Follows a Log-linear Model
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Nonparametric Survival Plot for Time linoleic-Time Cntrol

Kaplan-Meier Method Censoring Column in Death-Censored
1.0 0.9 0.8 0.7 Time linoleic Time Cntrol 1.0 0.9 0.8 0.7 0.6

Nonparametric Hazard Plot for Time linoleic-Time Cntrol

Empirical Hazard Function Censoring Column in Death-Censored
Time linoleic Time Cntrol

Probability

0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 30 35 40 45

Rate

0.5 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 30 35 40 45

Time to Failure

Time to Failure

Comparison of Survival Curves Test Statistics Method Chi-Square Log-Rank 0.06986 Wilcoxon 0.7048

DF 1 1

P-Value 0.7915 0.4012

There is no significant difference in survival between the two groups.

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Abramson JH. Survey Methods in Community Medicine. 4th Edition, Ch 1. UK: Churchill Livingstone; 1990.

The World Health Organization. Health research methodology - a guide for training in research methods. Geneva: The WHO ; 1992.
K.Park. Parks text book of preventive and social medicine. 19th edition. Jabalpur, India: Benarasidas Bhanot Publishers; 2007. Berry D. Bayesian Clinical Trials. Nature Reviews 2006; 5:27-36. OBrien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35:549-56. Piantadosi S. Clinical Trials. A Methodologic Perspective. New York: John Wiley and Sons; 1997. Porta M. A dictionary of epidemiology. 5th edition. Oxford, New York: Oxford University Press, 2008. Rothman KJ, Greenland S, eds. Modern epidemiology. 2nd ed. Philadelphia, PA: Lippincott - Raven Publishers, 1998. Gordis L. Epidemiology. 2nd ed. Philadelphia, PA: W. B. Saunders Co; 2000.
Altman DG. Practical statistics for medical research. London: Chapman & Hall;1991.

DS Moore and GP McCabe. Introduction to the practice of statistics. 3rd ed. New York: WH Freeman and Company;1999.

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T H A N K Y O U
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