How to Read a Clinical PaperDr Devendra Khandke MD Head-Medical Services Alembic Pharmaceuticals Ltd

Outline For TodayDo 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 ReadingsDr 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 StudiesExample: 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 StudyPatients 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 introductionNote 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