How to Read a Clinical Paper

Dr Devendra Khandke MD Head-Medical Services Alembic Pharmaceuticals Ltd

Outline For Today

Do I Need to Read a Paper Types of Readings Source of Literature Tricks at Searching Literature Types of Clinical Research Designs RCT Cohort Studies Case-Control Studies Cross-sectional Surveys Case Reports Meta-analysis Reading A Scientific Paper Reflections & Criticisms

Do I need to read the paper

For general interest or background information To find out exactly what the latest developments are in a field To seek evidence to support or refute your ideas To find out how a certain piece of research was done Help circulate research among your physicians Start a dialogue with your physicians by

Types of Readings
Dr David Jewell, writing in the excellent book Critical reading for primary care reminds us of three levels of reading
Browsing, in which we flick through books and journals looking for anything that might interest us. Reading for information, in which we approach the literature looking for answers to a specific question, usually related to a problem we have met in real life. Reading for research, in which we seek to gain a comprehensive view of the existing state of

Source of Literature
Google PubMed Medscape Sites of Specific Organizations American Heart Association American Diabetes Association European Society of Cardiology Association of Physicians of India National Institute for Health & Clinical Excellence

The Cochrane Library- for meta-analysis Paid Websites

UpToDate MDConsult

Tricks at Searching Literature

You are trying to find a particular paper which you know exists
Solution: Search the database by field suffix (title, author, journal, institution, etc.) or by text-words

Research design

Randomized controlled clinical trial (RCT) Participants are randomly allocated either one intervention (drug treatment) or other (placebo) Both groups are followed up for a specified time period Analyzed in terms of a Specified outcomes Gold Standard in Medical Research Are mostly useful to decide on therapy or prevention E.g ONTARGET study, TRANSCEND study

Cohort Studies
Two or more groups of people are selected on the basis of differences in their exposure to particular agent ( such as vaccine, a medicine or an environmental toxin) & followed up to see how many each group develop particular disease of outcome. Follow up period In years or decades RCTs are usually on patients who already have the disease & Cohort begun on subjects who may or may not develop disease

Cohort Studies

Does the contraceptive pill cause breast cancer? Does smoking cause lung cancer?

Cohort Studies
Example: Smoking vs. Non-Smoking British Physicians

Doll, R., Peto, R., Boreham, J., & Sutherland, I. (2004). Mortality in Relation to Smoking: 50 years' observations on male British doctors. BMJ, doi:10.1136/bmj.38142.554479.AE 50 years (and counting) Cohort Study of British doctors Most recent of a series of reports Compared health outcomes of smokers vs. health outcomes of non-smokers

Case Control Study

Patients with a disease or exposure --compared to-Similar group without disease or exposure Data are then collected on past exposure to be possible causal agent for the disease Best uses Rare conditions Diseases or conditions that may take a long time to develop

Case Control Study Diethylsilbesterone and clear cell carcinoma

Used in the United States from 1947 until 1971 Boston area doctors noted an unusual cancer Study compared the group with the cancer to similar people without the cancer The major difference between the cases and the controls was DES exposure

Cross Sectional Surveys

Surveys conducted by epidemiologists: a representative sample of subjects (or patients) is interviewed, examined or otherwise studied to gain answers to a specific clinical question
E.g Diabetologist asked at a conference about their usage of GLP-1 agents Number of diabetic obese patients in their practice

Case Reports
A case report describes the medical history of a single patient in the form of a story (Mrs B is a 54 year old secretary who developed chest pain in June 2000 . . .) Case reports are often run together to form a case series, in which the medical histories of more than one patient with a particular condition are described

Case Reports
Although traditionally considered to be relatively weak scientific evidence, a great deal of information can be conveyed in a case report that would be lost in a clinical trial or survey In addition, case reports are immediately understandable by non-academic clinicians and by the lay public If necessary, be written up and published within days

Meta-Analysis
Meta-analysis, defined as a statistical synthesis of the numerical results of several trials which all addressed the same question General aim of a meta-analysis is to more powerfully estimate the true "effect size" as opposed to a smaller "effect size" derived in a single study under a given single set of assumptions and conditions

Meta Analysis
Numeric data from separate studies combined in meta analysis Combining data increases the confidence we have in the conclusions reached by a meta analysis

Article Type

What kind of question is it good for? -Rare disorders or conditions -Slow developing disorders -Causation* - Prognosis -Causation*

Strengths

Weaknesses

Identifying Characteristics -Cross sectional

Case-Control (Herbst, 1971) (Peled, 2008)

-Short time frame to -Susceptible to bias examine correlations -Limited validity between disorder and other factors

Cohort** (Doll, et al, 2004) (Metcalf, 2008)

- Feasible when studying conditions or exposures over which the investigator has no control

-Susceptible to bias -Limited validity -May require large groups, long durations, great cost

-Longitudinal -Usually prospective -Can be retrospective (less cost)

Randomized Control Trial (RCT) (An et al, 2008) (Gordon, 1997) Systematic Review (Techakehakij,2008) (Gallicchio, 2008)

-Drug treatment -Medical interventions -Drug treatment -Medical interventions

-Strong level of -Feasibility (e.g. evidence Ethical limitations) -Low susceptibility to -Generalizability** bias -Low susceptibility to -Many topics have no bias systematic review -Strongest level of evidence

-Randomization method -Experimental and control groups -Methods section has explicit information about information sources, how articles were chosen or excluded

* - used loosely here; not distinguishing between correlation and causation (in medicine etiology is used for the cause of a disease or condition) ** - can results of an RCT be applied to groups that do not match the study group?

The Evidence Pyramid Used for Evidence-Based Medicine

Reading a Scientific Paper

This is not a novel Struggle with the paper
active not passive reading use highlighter, underline text, scribble comments or questions on it, make notes if at first you dont understand, read and re-read, spiraling in on central points

Reading a Scientific Paper

Get into questionasking mode
doubt everything nit-pick find fault just because its published, doesnt mean its right get used to doing peer review

Reading a Scientific Paper

Move beyond the text of the paper
talk to other people about it read commentaries consult, dictionaries, textbooks, online links to references, figure legends to clarify things you dont understand

The Typical Anatomy of a Paper

Title and authors Abstract/summary Introduction Materials and Methods Results Discussion Acknowledgements References Figures/Tables

Judge Quality
Consider the journal: Good papers are usually published in good journals, by reputed health organizations and reliable websites BUT

Critical appraisal questions remain

What is the paper about?

Critical appraisal questions remain

What is the paper about? Why was the study done?
The introductory sentence of a research paper should state, in a nutshell, what the background to the research is Unless it has already been covered in the introduction, the methods section of the paper should state clearly the hypothesis such as This study aimed to determine whether day case hernia surgery was safer and more acceptable to patients than the standard inpatient procedure.

Critical appraisal questions

What is the paper about? Why was the study done? What type of study was done?
Whether the paper describes a primary or secondary study

Primary or Secondary Study

Primary study reports research first hand Secondary study attempt to summarize & draw conclusion from primary study

Critical appraisal questions

What is the paper about? Why was the study done? What type of study was done? Was the study ethical?
Very Important in Todays world Check if Study had an Independent Ethics Committee Check if study done under ICH/GCP guidelines Check if informed consent/ ascend obtained before study participation

Critical appraisal questions

What is the paper about? Why was the study done? What type of study was done? Was the study ethical? Was the design right?.
A Double Blind Randomised Trial is very suitable

Essentials of a Good Research Paper

Well organised Clear and concise Flows logically Accurate Consistent Control of bias Handle criticisms.

Blame the authors if

Logical connections left out
Instead of saying why something was done, the procedure is simply described.

Cluttered with jargon, acronyms Lack of clear road-map through the paper
side issues given equal air time with main thread

Difficulties determining what was done

Ambiguous or sketchy description Endless citation trail back to first paper

Data mixed up with interpretation and speculation

Finally Getting Started

What is this paper about

Plus Title, abstract, authors, acknowledgements, declarations, references Tables and figures; legends

Most Important Clues

Read In This Order

Title Abstract Introduction/ Discussion Methods/ Results

The discussion section occurs before the author presents the results of the study.
1. True 2. False

Which occurs first in a scientific journal article?

1. 2. 3. 4. 5. Abstract Discussion Introduction Methods Results

3 questions to get your bearings *

1. What was the research question? 2. What was the research design? 3. Was the research design appropriate to the question?
* - Greenhalgh, T. (2006). How to read a paper: the basis of evidencebased medicine. Malden, MA: Blackwell

Evaluating a paper
What questions does the paper address? What are the main conclusions of the paper? What evidence supports those conclusions? Do the data actually support the conclusions? What is the quality of the evidence? Why are the conclusions important?

The places to find information about a papers subject matter The title The abstract, and The introduction
Note The discussion contains further ideas, but it is not worth reading the discussion in any detail until we have good idea what is being discussed.

Title and Authors

Title is very descriptive (often states the main finding) and is not about being creative and catchy! Order of authors is important. What can you tell from it? Many PIs simply refer to work from other PIs labsso as you keep a catalogue in your mindDO associate work with lab.
Example:

VEGF, a prosurvival factor, acts in concert with TGF-beta1 to induce endothelial cell apoptosis.
Ferrari G, Pintucci G, Seghezzi G, Hyman K, Galloway AC, Mignatti P.

Why you are reading determines how you should read The abstract & introduction should tell you whether it is worth reading in depth or only worth skimming The answer will depend on what you are looking for

Abstract & Introduction

Abstract should give you a brief summary of the papers main finding Introduction provide a background to the paper and a rationale for the investigation in more detail than is possible
Purpose for the study Major findings of the study Relationship between these findings and the field The abstract an introduction help you to decide whether, why and how to read

How to approach the introduction

Grab a blank piece of paper:
Take notes Draw mini figures - Define vocabulary (wikipedia is a quick reference)

Answer these questions:

What data led directly to the work of this paper? What is the hypothesis being tested? What are the basic conclusions? (Scientists dont really like surprise endings and this is usually stated in the last paragraph.)

Notes allow you to take a break (hours to days) and come back to your thoughtsyou wont have to re-read the parts you completed.

Materials and Methods

Should be detailed enough for another scientist to replicate the work (volumes, times, company material was purchased from etc.) In reality, often compressed and you may need to look up another paper that is referenced for more detail.

Materials and Methods: Contents

Sample size Study centre Inclusion/ exclusion criteria End points- primary/secondary Statistical methods

Statistical Analysis
Intention to Treat
Outcomes of all patients are analyzed with the group to which they were originally assigned, whether of not they completed the protocol

Interim Analysis
As most large clinical trials are conducted over long periods, analysis of the data is done in the period before completion of the study to monitor progress and detect problems

Per-protocol
Outcomes of the patients who complete the study according to the protocol is analyzed

Statistical Analysis
Standard Deviation (SD)
Indicates the variability of actual data around the mean of a single sample of population

E.g: Mean weight of a sample of 100 men is 72 kg and SD is 8 kg, then about 68% of men are expected to have weight between 64 and 80 kg

Statistical Analysis
Terms: Statistical significance
A quantitative estimate of the probability that a particular study result could occur by chance alone

p < 0.05 (Signifies that probability of the result occurring by chance is <1 in 20) p < 0.01 (Signifies that probability of the result occurring by chance is <1 in 100)

Statistical Analysis
Terms: Clinical significance
E.g two drugs were tested for decreasing BP The result showed that drug A was more effective that drug B in decreasing BP The results were also statistically significant p< 0.05 But the total decrease in BP by drug A was 2 mm Hg while drug B was 1 mm Hg Is this clinically significant? No Thus look at the clinical end-points every-time Important for CVS and Oncology Trials

Statistical Analysis
Terms: Relative Risk (RR)
The ratio of the risk of an event in one group to that in another group usually expressed as a percentage A risk ratio of 1 indicates that neither group is more at risk for the event that other E.g ONTARGET Study: Angioedema Telmisartan vs Ramipril RR= 0.4, p < 0.01

Statistical Analysis
Terms: Hazard Ratio (RR)
A ratio of the risk of an event in one group to that in another group when time to event is the primary response variable A hazard ratio of 1 indicates that neither group is more at risk for the event that other E.g TRANSCEND Study: Hazard Ratio 0.92 (95% CI 0.81-1.05); p= 0.216

Statistical Analysis

Terms: Confidence Interval- (CI)

If a given study is repeated 100 times, the range into which results would be expected to fall in 95% of the trials is 95% CI Narrower CI indicates a more precise result Larger studies produce narrower CI

Statistical Analysis
Terms: Confidence Interval- CI

E.g 1- When 95% CI for difference between groups (or in same group before or after treatment) does not include zero the result are significant at 0.05 level

The difference in mean pulmonary function measurement between 2 groups was 0.51 L/min (95% CI= 0.23 to 0.79 L/min) Here there is no zero in the CI so the difference is statistically significant at 0.05 level The difference in mean pulmonary function measurement between 2 groups was 0.12 L/min (95% CI= -0.16 to 0.40 L/min) Here there is a zero in the CI so the difference is not statistically significant at 0.05 level

Statistical Analysis
Terms: Confidence Interval- CI E.g 1- When 95% CI for an odds ratio or relative risk that compares two groups does not include 1 the result are significant at 0.05 level The odds ratio of the incidence of stroke for smokers and non smokers is 4.2 (95% CI = 1.32 to 13.33) Here there is no 1 in the CI so the difference is statistically significant at 0.05 level The odds ratio of the incidence of stroke for smokers and non smokers is 4.2 (95% CI = 0.92 to 18.66) Here there is a 1 in the CI so the difference is not statistically significant at

Results
Report of data Tables and graphs Statistical results No interpretation

Discussion
Interpretation of results Answer to research question Goals met? Often includes
relation to previous research limitations future directions

How to read a discussion

Take notes and answer these questions:
What conclusions do the authors draw? Be sure to separate fact from their opinion/interpretation? Describe for yourself why these data significant. (Does it contribute to knowledge or correct errors?)

Which should allow other researchers to replicate the study? 1. 2. 3. 4. 5. Abstract Discussion Introduction Methods Results

Limitations of the study are found in the 1. 2. 3. 4. 5. Abstract Discussion Introduction Methods Results

Conclusion Peer review: you are the judge!

Conflicts of Interests

References
List of sources cited in intro Usually other journal articles Previous studies in same field Citation styles differ depending on
Vancouver style preferred

EndNote and RefWorks

Understanding Journal Article References

Weiss, PA. Does smoking marijuana contribute to the risk of developing lung cancer? Clinical Journal of Oncology Nursing. 2008;12(3):517-519.

Journal Volume Number Issue Number Researchers Article

Which cannot be determined from a reference list citation?

1. Title of the journal 2. Title of the journal article 3. Number of pages in the journal 4. Number of pages in the journal article 5. None of the above

Always consider

Can the results be applied to my patient?

By now, you may be tired of this paper but dont relax yet. Save energy for the overall reflection and criticism

Reflections and Criticisms

(Cite specific example for yourself)

Do you agree with the authors rationale for setting up the clinical trial as they did? Did they perform the clinical trial appropriately? (Repeated a number of times, used correct control groups, used appropriate measurements etc) Were there enough patients to support the one major finding they are claiming? Do you see patterns/trends in their data that are problems that were not mentioned? Do you agree with the authors conclusions from these data? Are they over-generalized or too grand? Or are there other factors that they neglect that could have accounted for their data? What further questions do you have? What might you suggest they do next?

Tips for Success

Spend a lot of time on each paper NOW look up every detail that you are unsure of. (Time you invest now will payoff in the long run). Discovering the answers for yourself is one of the best ways to learn and have the information be retained Imagine yourself teaching the paper or figures to colleagues teaching something to others is also another great way to learn

Tips for Success

Read papers when you are awake and interested in reading. If you are going to break up a paper and read it over several days be sure to summarize before continuing each day. If you are already in the field you plan to stay in, consider starting a database on papers that relate to your products. You will want to be able to impress your Physician with your quick analysis and summary of a monumental paper from another paper

Group Work
Groups of 4 Every group will be assigned one clinical trial Each team member will go through the clinical paper Each team will present the highlights of each section of the clinical paper Title, Authors, Introduction, Material and Methods, result & discussion Remarks by Dr. Khandke

Thank You