INTRODUCTIONWhy Do I Need to Know About Methodology ?

???????As a graduate student... To be able to read and understand the empirical literature in your field; to become a critical consumer of information.As a graduate student preparing for a thesis or dissertation To be able to both design and implement your thesis or dissertation as well as future studies that interest you.

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As a future practitioner To be able to intelligently participate in research projects, evaluations, and studies undertaken by your institution. As an educated citizen ...To understand the difference between scientifically acquired knowledge and other kinds of information.

Whats the Difference Between Method and Methodology?

Method:Techniques for gathering evidenceThe various ways of proceeding in gathering informationMethodology:The underlying theory and analysis of how research does or should proceed. (Sandra Harding)

Creativity Open mind CuriosityPatiencePersistencePositive Attitude Discipline and focusWhat It Takes?

Research Sequence Topic selection Research planning Literature survey Formulating the problem Creating new solutions Verification of analytical resultsCommunication of results Commercialization of research outcomes

How Extraordinary Creative Ideas Occur? Sudden spontaneous visions Dreams Cross-pollination from different fields

Stories of Extraordinary Inventors Sudden Vision DiscoveriesTesla's idea of the rotating magnetic field came to him instantly while he was walking in a park. He drew a picture of the rotating magnetic field in the ground of the park.

Stories of Extraordinary Inventors Sudden Vision Discoveries The great mathematician Gauss proved in an instant a theorem on which he had worked unsuccessfully for four years. "As a sudden flash of light, the enigma was solved. . . .Similar accounts given by extraordinary creative people such as Mozart, Tchaikovsky, Poincare etc.

Stories of Extraordinary Inventors Dream Discoveries Frederick Kekule fell asleep and dreamed of the benzene molecule as a snake biting its tail. Otto Loewi had a dream that led to his discovery of the chemical transmission of nerve impulses.

.HOW TO SEARCH THE LITERATURE

. BASIC SEARCH ADVANCED SEARCH

National Library of Medicine(PUBMED): www.ncbi.nlm.nih.gov/pubmed

.MEDLINE Medline is the National Library of Medicine's (NLM) premier bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the health care system, and the preclinical sciences as far back as 1966.

.MeSH a Medical Subject Heading.

A controlled vocabulary term used by all the indexers in an organization to ensure consistency in assigning terms to articles (or records) on the same topic. They are also used in searching to avoid having to think of all the possible words that various authors could have used to express the same concept.

For example: The MeSH AGED is assigned instead of: aging, older, elderly, senior citizen, geriatric person.

BASIC SEARCH STRATEGY

Pick a search topic: for example, previous BMD studies in the literature? Divide topic into concepts Find words (keywords) or subject headings (MeSH) to represent these concepts Combine concepts with AND, OR, or NOT

When should I Use Basic or Advanced Search Mode?

Here are some general rules to go by !

Basic

Use the Basic Search when you have only a single term to search. Use the Basic Search when you are only searching by the author.

Advanced

Use the Advanced Search when you have more than one concept to search. Use the Advanced Search when you want to search in a specific field. Use the Advanced Search when you want to limit search by language or publication type

BASIC SEARCH

Enter your search term(s) in the query box. You may use "OR", "AND", or "NOT"; PubMed will automatically combine terms with "AND" using automatic term mapping.

Terms are matched against a MeSH translation table, a Journals translation table, a phrase list, and an Author index -- in that order.

.PubMed will display your results as brief citations in batches of 20 per page, by default. To change the "Number of documents to display per page:", select a higher number from the pull-down menu below the query box.

.The Entrez Date is the date the citation was added to the PubMed database, which differs from the Date of Publication. Use the "Entrez Date limit" pull-down menu to select a range of days or years

Author names should be entered in the form Smith JB, but initials are optional. PubMed automatically truncates the author's last name to allow for varying initials and designations such as Jr. or 2nd. If only the author's last name is entered (no initials), PubMed will search that name in All Fields not just the Author field.

Citation display format displays the source, title, author and affiliation, abstract, MeSH and unique identifier

Advanced Search Searching in the different fieldsIn Advanced search, you now have the option to search in the different Medline fields Just click on the arrow in the Search field box to see the list Highlight the one you want and click once

How to combine search termsAdvanced searchs main feature is the ability to do a search with 2 or more terms The first step is to select the search terms that apply to your question using MeSH BrowserExample: are there any articles on the diagnosis and chemoprevention of TB? The search terms for this query would be: tuberculosis diagnosis prevention

.Article Types

ORIGINAL RESEARCH Original Articles are scientific reports of the results of original clinical research. The text is limited to 2700 words, with an abstract, a maximum of 5 tables and figures (total), and up to 40 references.

ORIGINAL RESEARCH Special Articles are scientific reports of original research in such areas as economic policy, ethics, law, and health care delivery. The text is limited to 2700 words, with an abstract, a maximum of 5 tables and figures (total), and up to 40 references

CLINICAL CASES Brief Reports usually describe one to three patients or a single family. The text is limited to 2000 words, a maximum of 3 tables and figures (total), and up to 25 references. They begin with a brief summary of no more than 100 words.

CLINICAL CASESClinical Problem-Solving manuscripts consider the step-by-step process of clinical decision making. Information about a patient is presented to an expert clinician.

CLINICAL CASESThe clinician responds (in regular type) as new information is presented, sharing his or her reasoning with the reader. The text should not exceed 2500 words, and there should be no more than 20 references

REVIEW articlesReview articles are usually solicited by the editors. All review articles undergo the same peer-review and editorial process as original research reports.

Clinical Practice articles Are evidence-based reviews of topics relevant to practicing physicians, both primary care providers and specialists.

Clinical Practice articles Articles in this series should include:

-the clinical problem -strategies and evidence -areas of uncertainty -guidelines from professional societies -conclusions and recommendations.

Clinical Practice articles The text is limited to 2500 words and a small number of figures and tables. These articles do not include an abstract.

Clinical Therapeutics articles Are evidence-based reviews of topics relevant to practicing physicians. The series focuses on clinically oriented information about specific forms of therapy: -drugs -devices -procedures

Clinical Therapeutics articles Each article in the series begins with a clinical vignette describing a patient with a specified condition for whom the treatment under discussion has been recommended.

Clinical Therapeutics articles definition of the clinical problempatho- physiology and how the therapy works clinical evidenceclinical use (including costs) adverse effects areas of uncertainty guidelinesrecommendations

The text is limited to 2500 words. These articles do not include an abstract.

Current Concepts articles Focus on clinical topics, including those in specialty areas but of wide interest. The text is limited to 2400 words, with a maximum of 4 figures and tables (total), and up to 50 references. These articles do not include an abstract.

Drug Therapy articles Detail the pharmacology and use of specific drugs or classes of drugs, or the various drugs used to treat particular diseases. The text is limited to 4000 words, with a maximum of 6 figures and tables (total), and up to 120 references. These articles do not include an abstract.

Mechanisms of Disease articles Discuss the cellular and molecular mechanisms of diseases or categories of diseases. The text is limited to 3500 words, with a maximum of 6 figures and tables (total), and up to 100 references. These articles do not include an abstract.

Medical Progress articles Provide comprehensive, scholarly overviews of important clinical subjects, with the principal (but not exclusive) focus on developments during the past five years.

Medical Progress articles Each article details how the perception of a disease, disease category, diagnostic approach, or therapeutic intervention has evolved in recent years. The text is limited to 3500 words, with a maximum of 6 tables and figures (total), and up to 100 references. These articles do not include an abstract.

OTHER SUBMISSIONS .

Editorials Usually provide commentary and analysis concerning an article in the issue of the Journal in which they appear. They may include 1 figure or table. They are nearly always solicited, although unsolicited editorials may occasionally be considered. Editorials are limited to 1000 words, with up to 15 references

Perspective articles Cover a wide variety of topics of current interest in health care, medicine, and the intersection between medicine and society. Perspective articles are limited to 1000 to 1200 words and usually include one figure. There is a maximum of 5 references

Sounding Board articles Are opinion essays. They are similar to editorials but are not tied to a particular article. They often present opinions on health policy issues and are normally unsolicited. The text is limited to 2000 words.

Clinical Implications of Basic Research articles Discuss single papers from preclinical journals. The purpose is to explain the findings and comment on their possible clinical applications in fewer than 750 words. There may be 1 figure and up to 4 references.

Special Reports Are miscellaneous articles of special interest to the medical community. They are limited to 2700 words.

Letters to the Editor Provide a forum for readers to comment about articles recently published in the Journal, and they are a place to publish concise articles, such as reports of novel cases.

.Reading medical articles critically

Getting Ready

Choose a few good peer-reviewed journal articles

Relevant to biomedical informatics Interesting for you & audience Important result or approach

Getting Ready

Send choices to instructor for feedback(2 weeks before your presentation)Choose one articleRead criticallyTake notes while readingReread even more criticallySkim related articles or web information

Creating the Content

Introduce yourselfWhy did you choose this paper?How does it relate to your interests?Summarize article (briefly!)Provide contextCritique, question, reactConclude

Summarize ArticleAssume audience read the paperDo not assume audience understood it Provide context When? Where? Why?State authors take home messagesFocus on interesting/controversial issues

Critique, Question, ReactObjectively Did the author(s) support their point? Was their support valid?Subjectively How does it relate to your own experiences? Why did you find this paper interesting orimportant? What do you think the impact of this paper is?

ConcludeRestate authors take-home messageState your own take-home messageProvide a personal perspectiveBe provocative

SummaryChoose a good articleIntroduce yourselfSummarize articleProvide contextCritique, question, reactConclude

.Clinical Trials

What Are Clinical Trials?Research studies involving people.

Try to answer scientific questions and find better ways to prevent, diagnose, or treat disease

Why Are Clinical Trials Important?Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat diseaseThe more people take part, the faster we can: - Answer critical research questions - Find better treatments and ways to prevent disease

What Are the Different Types of Clinical Trials?TreatmentPreventionEarly detection/screeningDiagnosticQuality of life/supportive care

Treatment Trials

What new treatments can help people with a particular disease?

What is the most of effective treatment for people with that disease?

Prevention Trials Evaluate the effectiveness of ways to reduce the risk of a particular disease Enroll healthy people at high risk for developing that disease

Prevention Trials

Action studies (doing something)

Agent studies (taking something)also called chemoprevention studies

Chemoprevention Trials

Phase 3 chemoprevention trials compare a promising new agent with either a: --Standard agent --Placebo

Fundamentals of Clinical Trials A clinical trial is a prospective study assessing the effect and value of intervention(s) vs. control in human subjects Each clinical trial has a PRIMARY question (outcome) There may be multiple SECONDARY outcomes

Clinical Trial Phases

Phase 1 trialsHow does the agent affect the human body?

What dosage is safe?

Clinical Trial Phases

Phase 2 trialsDoes the agent or intervention have an effect on the disease?

Clinical Trial Phases

Phase 3 trialsIs the new agent or intervention (or new use of a treatment) better than the standard?Participants have an equal chance to be assigned to one of two or more groups

Randomized TrialsParticipants have an equal chance to be assigned to one of two or more groups:

One gets the most widely accepted treatment (standard treatment).The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than the standard treatment.

Why is Randomization Important?

So all groups are as alike as possible.

Provides the best way to prove the effectiveness of a new agent or intervention.

Clinical Trial Protocol

Strict scientific guidelines: -Purpose of study -How many people will participate -Who is eligible to participate -How the study will be carried out -What information will be gathered about participants -Endpoints

Benefits of ParticipationPossible benefits:Patients will receive, at a minimum, the best standard treatment (if one exists)If the new treatment or intervention is proven to work, patients may be among the first to benefitPatients have a chance to help others and improve patient care

Risks of ParticipationPossible risks:

New treatments or interventions under study are not always better than, or even as good as, standard careEven if a new treatment has benefits, it may not work for every patient

Patient ProtectionThere have, unfortunately, been past abuses in patient protectionFederal regulations ensure that people are told about the benefits, risks, and purpose of research before they agree to participate

How Are Patients Rights Protected?

Informed consentScientific reviewInstitutional review boards (IRBs)Data safety and monitoring boards (DSMBs)

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Time (In Years) To Develop A New Drug (Average) Pre-Clinical Testing To Approval 1960s-1990s (US FDA)

Pitfalls Of The Current Model Of Drug Discovery & Development.- High and unaffordable costs of R&D and consequently of new drugs.- Too many products with identical pharmacological profile and mechanism the milligram battle.- Low therapeutic rationale and advance for new drugs.- Many products especially biotech products developed through technology push rather than medical demand pull.

Can We Make Regulatory Submissions More Crisp And MeaningfulNo. of Words In Documents

At The Same Time Regulations in New Drugs Research Are Needed To:- To ensure safety and efficacy of New Drugs by an independent authority- To ensure that uniform and well-laid out standards apply to all products- To ensure that products are continuously monitored, post-marketing- To review safety and efficacy standards based on new knowledge- To recommend appropriate amendments to Drugs and Cosmetics Act

FDA REGULATIONS MOSTLY A REACTIVE RESPONSE

1906History of FDA, USA, concerned only with purity.1936Elixir Sulfanilamide 10% solution in 70% Diethylene Glycol implicated in 105 deaths.1938Federal Food, Drug & Cosmetic Act passed concerned with safety, not efficacy NDA to be approved.1961Thalidomide disaster in Europe. .1962Kefauver-Harris Amendment passed regarding extensive safety and efficacy studies IND mandatory.1987Format of IND changed.

Criticisms & Negative Perceptions On Clinical Trials Trial objectives skewed in favor of potential positive outcomes. Cutting out tests likely to end in negative results. Manipulation of Subject inclusion & exclusion criteria. Outright fraud in selection of investigators with vested interests. Suppression of publication of negative results.

To Eliminate Or Minimize These Negatives, Clinical Trials Need To Be Conducted Under Internationally Accepted Good Clinical Practice (GCP) Guidelines.

GCP protects patients/subjects. GCP ensures that clinical trials produce accurate, credible data by:- defining standards- defining responsibilities

Good Clinical PracticeORIGINS 1961Thalidomide 1962Drug Amendments Act 1963IND Procedure 1964Declaration of Helsinki 1977Proposed FDA Regulations covering obligations of Sponsors, Monitors and Clinical Investigators

The Emergence Of ICH GuidelinesICH was evolved to negotiate common standards for the regulation of pharmaceutical products in Europe, Japan and U.S.A.According to its Mission Statement ICH exists to provide a forum for a constructive dialogue between the regulatory authorities and the pharma industry on the real and perceived differences in the technical requirements for product registration.

ICH -International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (Objectives)- Eliminate redundant & duplicative technical development.- Expedite global development.- Expedite availability of new medicines.- Maintaining safeguards on quality, safety & efficacy.

ICHSafety reporting/Adverse Events (definitions and timings)New standards/templates (e.g., protocol, investigators brochure)Essential documents

Some key areas of interest :

Clinical Research An important Component Of The Regulatory System Has The Following Components Candidate DrugTrial Sponsor CRO/Monitor Investigators & Trial Centers Trial Subjects : Healthy Volunteers & Patients Biostatisticians

The Investigators Obligations are spread over three phases.

Prior to Initiation of the trial

During The Trial 3) Post Trial

Prior To The Trials- The investigator should be excited about the study for its scientific merit rather than other considerations.- Should ensure that confidentiality should be maintained.- Should have sufficient time allocated to involve in the trials- Should be familiar with the product and well acquainted all pre-clinical data & IND dossier.- Ensure that there are adequate resources available & allocated.- Should discuss the Protocol & details of trials with Sponsor/Monitor.- Finalize local clearances, IEC, IRB etc as per the ICH guidelines, Informed Consent Forms .

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During The Clinical Studies- Investigator should prepare a File containing all documents related to the Trial which should be kept in a secure area accessible to only him & his staff. Patient identification codes & details should be preserved at least for 15 years and should be destroyed only with prior permission from the sponsor. General medical Care should be provided to all subjects by the investigator or family physician. Ensure strict adherence to randomization, unblinding etc as per the protocol.- Safety & adverse reaction reports to be regularly obtained and action taken as per protocol to cause no or least damage to subjects. (ICH 4.11)- Ensure proper completion/validation of the Case record Forms.. Assess causality in terms of not related, unlikely, possible, probable and most probable, send reports and take corrective action.

INVESTIGATOR SOPsObjectivesEnsuring that the investigator understands the responsibilities and obligations of the study.Planning & conducting the study as per the approved protocols and complying with ICH/GCP guidelines.Ensuring that the safety & welfare of the subjects are always the prime concern.Proper and accurate collection , Documentation & analysis of Data from the trials.Cooperate in inspections, monitoring and auditing of the study by third parties.

Investigators To Be Familiar With Documents Used By Ethics Committee.-GCP Guideline same-Investigator Brochure and safety Information.Trial Protocol.Consent Forms & Trial Information SheetsSubject Recruitment Procedures.Information on payment & remuneration to subjects.Any Amendments To The Protocols Or SOPs..Any other document required by IEC/IRB.

See ICH Guidelines 3.1.2.

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Nature Of Regulatory InspectionsStudy related InspectionsInvestigator Related InspectionsBased on the pivotal nature of the studySponsors Difficulties in getting some Reports.Violation of trial protocol.Work involved turns out to be outside competence of the investigator .Results at variance with those of other investigators.

Inspection Reporting SystemsNo lapse.Requires corrective action for remediable lapses.Warning letter if corrective action not taken or delayed, with copies to sponsor &reviewing IRB. Inviting for possible hearings. Disqualification when the Investigator has deliberately violated the Agencys regulatory standards or submitted false information.

Clinical Trials Deficiencies* (1999) Apart From Deliberate Fraud, Clinical Trials fail due to following categories of deficiencies Protocols - 28% Records & Documentation - 20% Adverse Drug Reaction Reporting - 15% Informed Consent - 10% Drug Accounting - 10%

*Data From U.S.FDA.

FIDDES CASE- FRAUD AT ITS WORSTFrom early 1990s Dr. Fiddes, President of a California based CRO had conducted over 200 Clinical Trials for 47 companies. Engaged in extensive fraudulent and falsified data, he was sentenced and jailed in Federal Prison for 15 months, a penalty of $ 800000 imposed in 1998 and was disqualified as a clinical investigator in 1999.

Glaxo Paxil Case-Emergence Of Transparency In Clinical TrialsIn the lawsuit against GSK, New York Attorney General Eliot Spitzer asserted that a novel fraud of suppression of information was committed in the promotion of Paxil for use as an anti-depressant.In August 2004, Glaxo started posting the full details of Clinical trials in their Website, creating a Clinical register and started inclusion of Safety & Efficacy data, off-label drug use issues etc in Medical Information Letters to Physicians... GSK also paid a fine of $ 2.5 million.

Profile of Regulatory Agencies: More applicable to Developing Countries- Need to balance the interests of the consumers as well as the industry.- Under-staffed and over-burdened: working on shoestring budgets.- No independent database to arrive at timely and scientific judgements.Vulnerable to pressures from politicians and consumer activists.-No control on recruitment of Clinical Centers & Investigators.- Dependency on Experts who have little stake in the impact of their judgements on consumers or producers.- Not equipped physically or technically to ensure compliance with GCP/ICH Guidelines

Fundamentals of Clinical Trials The study population must be defined inadvance, with clear rationale andeligibility criteria A control group must always be usedagainst which the new intervention canbe compared Randomization is the most reliable wayto assign participants to the treatmentgroups

Fundamentals of Clinical TrialsA double blind design is the best way to avoid bias during collection of dataIf not possible, single blind and other methods should be utilizedCalculation of sample size should besufficient to provide adequate powerand levels of statistical significance

Fundamentals of Clinical TrialsRelevant BASELINE data should beacquired before initiation of interventionAll efforts should be made to collectaccurate and consistent dataNeed plan for assessment, analysis and reporting of adverse effects (AEs) and serious adverse events (SAEs)

Evidence Based Medicine: Levels of EvidenceClass I1. Randomized double-blind, placebo-controlled trials2. Meta-analyses of such RDBPC trialsClass II Observational trials (case-control studies or concurrent control studies)Class III All other controlled trials (including well-defined naturalhistory controls or patients serving as own controls) in arepresentative population, where outcome assessmentis independent of patient treatment.Class IV: Evidence from uncontrolled studies, case series, casereports, or expert opinion.

Fundamentals of Clinical TrialsFDA requires evidence of SAFETY andEFFICACY to consider approving medicationsfor prescription use.The process by which medications come tomarket goes through: preclinical development dose finding then safety trials exploratory efficacy/safety trials larger scale trials to determine the size andconsistency of clinical effects, and develop moresafety data

Drug Development ProcessDiscovery(2 - 10 years)

Pre-clinical TestingLaboratory and animal testingPhase 1- 20-80 healthy volunteers used to determine safety and dosagePhase 2 - 100-300 patient volunteers used to look for efficacy (POC) and side effectsPhase 3 - 3,000-5,000 patient volunteers used to monitor adverse reactions to long-term useFDA Review/Approval

Diagnostic Test StudiesHow well does a test identify people with the disease?exclude people without the disease?Compare test results on people with the disease with test results on people without the disease.Need to know who has the disease.

Diagnostic Test StudiesTwo designsProspective or cohort design, or cross-sectional design: take a sample of subject eligible for the test, test them all and get true diagnosis on them all.Retrospective or case-control design: take a sample with true diagnosis established as positive and another sample of controls. We may have negative diagnosis established on controls and we may not.

Who has the disease?True diagnosis.We can never be absolutely sure that the true diagnosis is correct.We decide to accept one method as true: call this the gold standard or reference standard.Often more invasive than the test, e.g. histopathology compared to ultrasound image.It is always possible that the reference standard is wrong for some subjects.

Statistics of diagnostic test studies Sensitivity Specificity Receiver operating characteristic curve (ROC curve) Likelihood ratio (LR) for positive test Likelihood ratio (LR) for negative test Odds ratio (OR) Positive predictive value (PPV) Negative predictive value (NPV)

Statistics of diagnostic test studiesExample: diabetic eye tests (cross-sectional) test = direct opthalmoscopy reference standard = slit lamp stereoscopic biomicroscopySingle sample of subjects all received reference standard test.

Statistics of diagnostic test studiesSensitivity = proportion of reference positive cases who are positive on the test = proportion of true cases that the test finds.Specificity = proportion of reference negative cases who are negative on the test = proportion of true non-cases that the test finds.

Example: eye disease in diabetics

45 reference standard positive cases of whom 40 were positive on the test, 275 reference standard negative noncases of whom 237 were negative on the test.Sensitivity = 40/45 = 0.89 = 89%.Specificity = 237/275 = 0.86 = 86%.

Statistics of diagnostic test studiesPositive predictive value (PPV) = proportion of test positives who are reference positive.Negative predictive value (NPV) = proportion of test negatives who are reference negative.

Example: eye disease in diabetics78 test positives of whom 40 were positive on the reference standard, 242 test negatives of whom 237 were negative on the reference standard.PPV = 40/78 = 51%.NPV = 237/242 = 98%.

.Types of medical studies.

Classification of types of clinical research Lancet 2002; 359: 57-61

The evidence pyramid

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Observational StudiesCohortQuestion answered: what will happen?Prospective/forwarde.g. Framingham study of cardiovascular disease: started in 1948, 6000 citizens participated, followed for 20 years (study in 1970 by Gordon and Kannel)Possible uses:Typical cohort studyOutcome assessment (patient outcomes: economic, functional, satisfaction, QOL, ..)

Cohort Studies

Cohort StudiesAdvantages:Design of choice for studying cause of a disease, course, risk factorsDisadvantages: Cannot be used to prove causationLong studies can be costlyVulnerable to patient attrition, migration

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Observational StudiesCase-ControlRetrospectiveQuestion answered: What happened?Matching needed for controls

Case Control Studies

Case-control Studies: research in reverse Example: association between smoking and lung cancer. People with lung cancer are enrolled to form the case group, and people without lung cancer are identified as controls. Researchers then look back in time to ascertain each person's exposure status (smoking history), (retrospective design). Investigators compare the frequency of smoking exposure in the case group with that in the control group, and calculate a measure of association.

Case-Control StudiesAdvantages: QuickestLeast expensiveGood for rare diseases and diseases that take long timeGood for investigation of a preliminary hypothesisTime factor researchDisadvantages: Large biasesDifficult to find matching controls

Both Cohort and Case-Control studies are called

Longitudinal StudiesNotion of time

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Cross Sectional StudiesAdvantages: Best for:Determining status quo of a diseasePrevalence of diseaseEvaluation of diagnostic proceduresRelatively quick and inexpensiveDisadvantages: Provide only a snapshot in time

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Observational StudiesCase SeriesCase-ControlCross SectionalCohortLongitudinal Studies

Experimental StudiesAKA Clinical Trials (Involve humans)Easier to identify (usually explicitly stated in the abstract)Two main categories of clinical trials:Controlled trialsUncontrolled trials

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Experimental StudiesControlled TrialsTrials with independent concurrent controlsDouble or single blindBest is randomized assignmentSame point in timeThese include:RCT: The epitome of all research designsProvides the strongest evidence of concluding causationBest insurance that results are due to the interventionNonrandomized trials:Assignment not randomizedOpened to biasesTrials with self controlsSubject to bias (Hawthorne effect)Can do crossover study (with washout period in between)Trials with external controlUses the results of another investigators research as a comparisonHistorical controls can also be used: for disease with no cures yet

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Randomized Controlled Studies

The Double Blind Method

Experimental StudiesUncontrolled trialsInvestigators experience with the new drug or procedure is described but not formally compared with another one

More likely to be used for interventions that are procedures rather than drug

Clinical TrialsAdvantages:RCT is the gold standard or referenceDisadvantages: ExpensiveLong duration

Experimental StudiesControlled trials Uncontrolled trials Self controls Independent concurrent controls External controls RCTNon-randomized

Systematic Reviews &Meta-analyses

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Study PyramidBestWorst

EXPERIMENT 1A researcher assembles two groups of study participants with Lyme Disease. She administers the antibiotic doxycycline to one group and amoxicillin to the other. The researcher then measures which has more of a beneficial effect.

EXPERIMENT 2 A researcher identifies two groups of elderly immobilized patients in a nursing home. One group of patients is repositioned every two hours. The other group is repositioned every 1.5 hours. The researcher measures whether the incidence of bed sores is lower in the group repositioned every 1.5 hours than the group repositioned every 2 hours .

EXPERIMENT 3 A researcher develops a counseling program designed to increase medication compliance in AIDS patients. The researcher delivers the program to one group of patients but not another, then studies whether the group that underwent the counseling program adhered to their medication better than the group that did not .

What do all three experiments have in common? ?

.In each case the researcher actively interfered with one group of study subjects and then compared the outcome with a similar group of subject that did not receive the same intervention. Experiments in which researchers interfere with their study subjects are known as clinical investigations. All examples above pertain to humans, but many clinical investigations are done using animal subjects, particularly for new or risky interventions

EXPERIMENT 1A researcher identifies a group of patients who were incorrectly diagnosed with Lyme Disease, then records whether the patients experienced adverse effects from the antibiotics they were prescribed for treatment of Lyme

EXPERIMENT 2 A researcher identifies a group of elderly immobilized patients in a nursing home. The researcher follows the patients for 6 months and records the administration of any topical (skin) agent. At the end of the study period, the researcher conducts an analysis to determine whether certain topical regimens related to reduced incidence of bed sores

EXPERIMENT 3A researcher identifies a group of individuals with AIDS who have low medication compliance. The researcher administers a questionnaire to the patients to determine what factors relate to their poor compliance

What do all three experiments have in common?

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.In each case the researcher does not actively manipulate or intervene with patients; rather, the researcher merely observes the effect of one or more factors on an outcome. It is easy to see why observational studies received their moniker

.Medical Writing

The Basic Structure of ArticleTITLE(S)Summary (Structured Abstract)(I) Introduction (What Question was asked?)(M)Methods (How was it Studied?)(R)Results (What was Found?)(A)Analysis (How data was analysed?)(D)Discussion (What Do the Findings Mean?)AcknowledgementsReferences

TitleShould be specific but comprehensiveShort but sufficiently descriptiveNo abbreviationsShould be easy to catalogue

Structured abstract

Objective Design Setting Patients and methods Results Conclusions Key words

Abstract most important part of your paperIntroduction/background: what was the purpose (10%)Material and methods: what was the study design, techniques, and statistical methods (30-35%)Results: what are the most important findings (35-45%)Conclusions: why are the results important (20-25%) Cornett, 2001

Goals of abstractmaximum info into minimum spaceStructuredUse headings to identify Follows IMRAD formatTypical in North American journals250 wordsUnstructuredArranged in 1 paragraphFollows IMRAD formatTypical in European journals125-150 words

6 steps for writing your abstract Identify guidelines, meeting or journalHighlight key features Insert sentences into abstract formatWrite, revise, and condenseEdit sentences and wordsCheck final

IntroductionExisting state of knowledgeGaps in knowledge which research will fill.State what you Intend to doGive pertinent referencesIt does notReview the history of the subjectDoes not identify all the other gaps in knowledgeDon not include methods, results and discussion

Introduction begin to tell a story

Part 1Begin with what is known2State what is unknown3End with what your study will answer

Methods What Subjects/patients/animals/specimens techniques were used? Reason for selecting the experimental design of the study Statistical methods used for analysis The section should be called "Materiel and Methods" only if inanimate specimens have been used.

Material and Methods reads like a cookbookWrite this section first!How was the problem studiedUsually arranged chronologicallySubdivided into subsections according to type of informationMaterial: chemicals, experimental materials, animals or humansMethods: preparation, protocol, purposes of protocol and methods, methods, data analysis

TechniquesGive enough details for readers to assess the validity of the results, and repeat the studyIf standard techniques is used, give appropriate reference,any modifications should be clearly explainedIf drug trial- clear description of trial

StatisticsClearly mention the statistical methods used for appropriate verification of reported results.

(consult a statistician before starting the study)

Example Material & MethodsClinical Patient populationProtocol (independent, dependent, control)

Methods for each

Analysis of data

AnatomicalMaterials

Sample preparation for each

Procedures for the dependent variables

Analysis of data

Results Communication of facts, measurements, and observations gathered by the author

Start with the results that are easier to interpret

Results should be set out in tables and figures

Do not duplicate illustrations

Results what were the findingsFunctions: state results of experiments and present data that supports resultsContent: results and dataConsistency: check this in results, discussion, and abstractOrganization: chronological or from most to least important

Results uses the same order as Methods

Material & MethodsStudy subjectsStudy protocolCalculationsStatistical analysisResultsClinical characteristicsSystemic effectsSpecific effectsAdverse effects

Results see the forest through the treesBe brief and unclutteredMention species and material againUse past tenseGive specific comparisonsPresent detailed data in figures and tables to keep written data to a minimumExpress results, give dataProvide appropriate statistical detailsBegin each paragraph with a result

Visual data

Discussion what do your findings meanAnswers the question posed in IntroductionExplain the significance of your resultsExplain the findings, relationships, and generalizations of your resultsExplains how results support answers and how answers fit with existing knowledge on the topicHas a beginning, middle, and end

Discussion What gaps in knowledge remain to be filled?

Main results should be summarised at the beginning of discussion

Only mention previous results or comments which illuminate or which are illuminated by the present results.

Discussion Final paragraph in which the message of the article is firmly stated.

Point out where further gaps in knowledge could usefully be filled instead of "further research is needed".

Intention of author to explore the "Gaps" further.

Discussion Part 1, beginningThe question posed in Introduction to test whether abnormal vasospasm before angioplasty increases the likelihood of restenosis.Is answered in your Discussionthe presence of abnormal vasospasm before angioplasty was associated with an increased likelihood

Part 1, Beginning present strongest evidence firstBegin with significance of your resultsNever begin with background informationNever repeat information from IntroductionNever begin with historical overviews

This is what everyone is waiting for!

Part 2, Middle interpret your resultsShow how your results fit into the literature and how they support your answer Give in descending order of importanceCompare your results with other studies, your work or others Use one idea per paragraph

Part 3, Endingbe strongRestate answer to question, and signal this endingMention possible applications, implications, or speculationsPull out as a separate Conclusions section Suggest future work if needed

References1.Standard journal articleVega K., Pina I., Krevisky B. Heart transplantation is associated with an increased risk for pancreaticobiliary disease. Ann Intern Med 1996 Jun 1: 124(11): 980-3

2.Books and other monographsPhillips SJ, Whisnant JP. Hypertension and stroke. In: Laragh JH, Bremier BM, editors. Hypertension: pathophysiology, diagnosis, and management. 2nd ed. New York: Raven Press; 1995. P.465-78.

References3.DisertationKaplan SJ. Post-hospital home health care: the elderly's access and untilizaiion (dissertation]. St. Louis (MO): Washington Univ: 1995.4. Unpublished materialLeshner AL. Molecular mechanisms of cocaine. N Engl J Med. In press 1996.5. Electronic materialMorse SS. Factors in the emergence of infectious disease. Emerg Inftect Dis [serial online] 1995 Jan-Mar (cited 1996 Jun 5]; 1(1): [24 screens]. Available from URL: http:/www.cdc.gov/ncdod/EID/eid.htm

******Clinical trials are research studies involving people. Clinical trials are the final step in a long research process that includes preliminary laboratory research and animal testing.Clinical trials try to answer specific scientific questions to find better ways to prevent, detect, or treat diseases, or to improve care for people with diseases. In cancer research, for example, a clinical trial is designed to show how a certain anticancer approachfor instance, a promising drug, a new surgical procedure, a new diagnostic test, or a possible way to prevent canceraffects the people who receive it.It is important to understand what clinical trials do to fight disease: Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease. Clinical trials contribute to knowledge and progress against disease. Many of todays most effective treatments are based on previous study results. Because of progress made through clinical trials, many people treated for various diseases are now living longer. The more people that participate in clinical trials, the faster we can answer the critical research questions that will lead us to better treatment and prevention options for a range of diseases. There are at least 5 types of clinical trials:

1. Treatment trials seek to find out: What new treatment approaches can help people who have a disease What is the most effective treatment for people with that disease2. Prevention trials seek to find out what approaches can prevent a disease from developing in people who have never had it

3. Early-detection/screening trials seek to discover new ways of finding a disease in people before they have any symptoms4. Diagnostic trials seek to find out how new tests or procedures can better identify a disease in people when we think it is there5. Quality-of-life/supportive care trials seek to find out what kinds of new approaches can improve the comfort and quality of life of people with a disease

Most clinical trials are treatment trials. These clinical trials involve people who already have a particular disease.

These studies try to answer specific questions about the effectiveness of a new treatment or a new way of using an existing treatment.Unlike treatment trials, prevention clinical trials are studies involving healthy people who are at high risk for developing a particular disease. These studies try to answer specific questions about and evaluate the effectiveness of ways to reduce the risk of disease. There are two kinds of prevention trials: Action studies (doing something) focus on finding out whether actions people take, such as exercising more or quitting smoking, can prevent disease. Agent studies (taking something) focus on finding out whether taking certain medicines, vitamins, minerals, or food supplements (or a combination of them) may lower the risk of disease. Agent studies are also called chemoprevention studies.

Chemoprevention trials also go through phases, as outlined earlier for treatment trials. However, phase 3 chemoprevention trials compare a promising new agent with either a standard agent or a placebo with two or more groups of people. 1. One group takes the promising new agent (called the study agent). 2. The other group takes either: A standard agent, already being used for disease prevention A placeboPlacebos are used in prevention trials when we dont yet have a known approach (standard agent) for prevention.

Clinical trials take place in phases.

Once laboratory studies (in test tubes and animals) show that a new approach has promise, a phase 1 trial can begin. A phase 1 trial is the first step in testing a new agent (drug or compound) in humans.In these studies, researchers look for the best way to give people the new agent (for example, by pill or by injection), how often it should be given, and what the safest dose is. These studies also include special laboratory tests such as blood tests and biopsies to evaluate how the new agent is working in the body.In phase 1 trials, small groups of people with a disease are treated with a certain dose of a new agent that has already been extensively studied in the laboratory. The dose is usually increased group by group in order to find the highest dose that does not cause harmful side effects. This process determines a safe and appropriate dose to use in a phase 2 trial. While the primary purpose of phase 1 trials is to find the safest dose of a new agent, researchers also evaluate whether the new agent benefits patients.

People with a disease who are eligible for phase 1 studies have no known effective treatment options, or they have already tried other treatment options. Many participate in these trials because they want to help others and contribute to research. Phase 1 trials usually have 15 to 30 participants.

Phase 2 trials continue to test the safety of the new agent, and begin to evaluate how well it works against a particular disease. In phase 2 trials, the new agent is given to groups of people with the disease in question, using the dosage found to be safe in phase 1 trials. If a new agent has demonstrated that it works against the disease and is safe for people in phase 2 trials, it enters a phase 3 trial.In general, people who take part in phase 2 trials have other treatments, but those treatments have not been effective. Participation in these trials is often restricted based on the previous treatment received. Phase 2 trials usually have less than 100 participants.

Phase 3 trials focus on learning how a new treatment compares to standard treatment (the most widely accepted treatment, based on results of past research). Researchers want to learn whether the new treatment is better than, the same as, or worse than the standard treatment.In most cases, trials move into phase 3 testing only after a treatment shows positive results in phase 2 trials. In phase 3 trials, participants have an equal chance of being assigned to one of two or more groups (also called arms).

The process of assigning participants to groups is called randomization.

Many people choose to get their first treatment in a phase 3 trial. The type of participant varies, depending on the kind of question being asked about a particular disease. Phase 3 trials usually have hundreds to thousands of participants, in order to find out if true differences exist in the effectiveness of the treatments being tested.

Phase 3 trials are randomized clinical trials, and some phase 2 trials may also be randomized.

Randomization is a method used to prevent bias in research. Treatment assignments are generated by a computer, and each participant has an equal chance of being assigned to one of two or more groups, the control group and the treatment group: The control group is made up of the people who get the most widely accepted treatment (standard treatment) for the disease The investigational group is made up of the people who get the new treatment being tested.

The next slide illustrates how randomization works.

If participants or health care providers choose a particular group based on what they think is best, then one of the groups would likely be very different than the other, making comparison between the groups difficult.

Randomization eliminates this bias because participants have an equal chance of being assigned to either group and the subgroups are as similar as possible.

Comparing similar groups of people taking different treatments for the same disease (or class of disease) is a way to ensure that the study results are caused by the treatments rather than by chance or other factors.

Clinical trials follow strict scientific guidelines. These guidelines clearly state the studys design and who will be able to participate in the study.

Every trial has a head person in charge, usually a doctor, who is called the principal investigator. The principal investigator prepares a plan for the study, called a protocol, which acts like a recipe for conducting a clinical trial. The protocol explains what the trial will do, how the study will be carried out, and why each part of the study is necessary. Every doctor or research center that takes part in the trial uses the same protocol. This ensures that participants are treated identically no matter where they are receiving treatment, and that information from all the participating sites can be combined and compared.

Making a decision about taking part in a clinical trial is a very personal one. This is a question that only the person with disease in question (or at high risk for that disease) can answer for him or herself.

Some of the possible benefits of participating in a clinical trial are listed here.

While a clinical trial is a good choice for some people, there are possible risks. People need to consider these as they think about joining a trial.

Some of the possible risks of participating in a clinical trial are:

New treatments or interventions under study are not always better than, or even as good as, standard care. New approaches may have unknown side effects or other risks.Even if a new treatment has benefits, it may not work for every patientHealth insurance and managed care providers do not always cover clinical trials. Participants may have to deal with the costs of travel, childcare, lost work hours, and meals.

Although we now have strong safeguards for protecting those who participate in research, these protections have resulted from notorious abuses of human rights in the past.

The first formal statement of protection for individuals in research emerged from the Nuremberg trial in Germany where Nazi scientists and physicians who conducted experiments on World War II concentration camp victims were convicted. The Nuremberg Code outlined broad concepts for the protection of human subjects and forms the basis of todays international code of ethics for the conduct of research.In the United States, several controversial research studies alerted us to the critical need for protection for those participating in clinical trials. None of these studies sought to inform the participants about the research or gain their consent for participating. From 1932 to 1972, the infamous Tuskegee Syphilis Study followed poor African American men with syphilis but did not treat them. During the study, the men were offered free medical care and were told that they would be treated for bad blood. In the 1960s, two other research studies received major public attention. The first was a series of experiments with mentally retarded children; another involved debilitated elderly participants. In response to these tragedies, regulations and policies were developed to ensure that people are told about the benefits, risks, and purpose of research for which they volunteer.

Participant rights and safety are protected in four main ways:Informed consentScientific reviewInstitutional review boards (IRBs)Data safety and monitoring boardsRobert Day, in How to Write and Publish a Scientific Paper, a brief summary of each of the main sections of the paper: introduction, material and methods, results, and discussion, aside from the title most often read, most easily accessed, Whether abstract is structured or not, headings can be broken down further, pick structured if you have a choice Structure the Introduction like a funnel, from what is known to the question, tips to do thismake sentences move the story forward, use transition words (too determine X, we.), if sentences is not moving story forward know its purpose, identify your experimental approach and the independent and dependent variable,

Describe what was done to answer the research question, clearly state the study design and research methodology (material, subjects, population), provide enough detail to enable a trained scientist to evaluate your work, organize chronologically and by type of info, Independent variable, set or manipulate at the beginning of the experiment; dependent variable, variable that you observe or measure, basically describe study design and study protocol

2 functions, Include results whether or not they support the hypothesis, report only results pertinent to research question and can include important data (figures, tables), data cannot stand alone

Be brief and uncluttered-there are exceptions, begin each paragraph with stating a result, keep data to a minimum, present data after the result they support, rather than exact data give magnitude of response or % of difference, be sure data are internally consistent, organize paragraphs from most to least important, also within paragraphs, subordinate data within parenthesis, use significant and significantly for statistical terms, Short focused presentation of data, summarize data, give a result for each methodAnswers your research question in the beginning, only those items that relate to the focus of your resultsDont begin with a historical review, dont repeat results