Information Resources for Clinical Research

Information Resources for
Clinical Research

Josh Duberman, MLIS

Informationist / Research Librarian, NIH Library,

Introduction to the Principles & Practices of Clinical

Research (IPPCR), National Institutes of Health

(NIH), 2/14/11

Johns Hopkins University (JHU) 2001 Asthma Study

Healthy volunteer died after being administered hexamethonium by inhalation

PI didn’t find potential toxicity despite

“standard PubMed search” &

consulting “standard current editions of textbooks

of pharmacology & pulmonary medicine”

JHU Report, 7/01: Report of Internal Investigation into the Death of a Volunteer Research Subject, Johns Hopkins University, 7/01, http://www.hopkinsmedicine.org/press/2001/JULY/report_of_internal_investigation.htm

also see: J Savulescu and M Spriggs, The Hexamethonium Asthma Study and the Death of a Normal Volunteer in Research, J. Med. Ethics, 2002; 28;3-4 , http://jme.bmj.com/cgi/content/full/28/1/3

JHU 2001 Asthma Study – results

JHU research oversight improved

“requiring investigators to collaborate with a librarian and a pharmacist to strengthen literature searches… to help search appropriate databases for potential side effects.”

Hopkins Response to FDA Observations, JHMI Office of

Communications and Public Affairs, 9/7/01, http://www.hopkinsmedicine.org/press/2001/SEPTEMBER/010907A.htm

Guidelines established at JHU & elsewhere

Guidelines for Determining an Adequate and Comprehensive Literature Search of Drug and Device Safety for Use by Investigator and Institutional Review Boards, Institutional Review Board, Mount Sinai School of Medicine, 1/03,

http://www.mssm.edu/static_files/Old%20Sites/www.mssm.edu/cmca/pdf/SearchGuidelines.pdf (class handout)

Intro to Information Sources

Health Care Specialists’ Use of Online Info Resources

Literature Databases 90%

Online Journals 83%

Physician Portals 73%

Government Web Sites 61%

Manufacturers’ Web Sites 41%

Medical/professional Blogs 37%

Sept 2008 Survey of 255 medical specialists by Jupiter Research, "U.S. Online Specialists Executive Survey, 2008", as quoted in “Which Online Resources Do Online Health Care Specialists Use?”, iHealthBeat, 1/7/09; http://www.ihealthbeat.org/Data-Points/2009/Which-Online-Resources-Do-Online-Health-Care-Specialists-Use.aspx , accessed 2/15/09

Classifying Information Sources

Classic - Proximity to Source Material

original publications & data

bibliographic databases & indexing/abstracting services

reviews & reference works, textbooks

Practical - Content & Search Capabilities

subjects covered, in what degree of comprehensiveness

full text of articles vs. titles / keywords / abstracts

search technology & interface: structured indexing terms, thesaurus, wildcards, Boolean logic

update frequency, reliability, reproducibility

Format & Access - sources readily available to you or to patients

online vs. paper formats (or the heritage of printed formats)

items in your collection vs. items to be ordered

“free” vs. fee - Patients more likely to get info from free sources

Business Model – Who Pays? Affiliations/Sponsorship/Bias?

Familiarity

Sources you know about, & know how to search

Sources you’ve heard about

Keeping up with changing info landscape

Focus - searching for adverse effects & protocol development

Relevant to textbook chapters:

3 - Researching a Bioethical Question

8 - Unanticipated Risk in Clinical Research

16 - Design & Conduct of Observational

Studies & Clinical Trials

24 - Writing a Protocol

Principles and Practice of Clinical Research,

JI Gallin & FP Ognibene, eds., 2nd ed., Elsevier, 2007

PubMed

US National Library of Medicine (NLM) database – refers to >20 M articles from 5,400 biomedical journals in 39 languages

medicine, nursing, dentistry, veterinary medicine, allied health & pre-clinical sciences

currently includes references from 1948 - present, with some older items

free online – www.pubmed.gov ; NIH staff should click

“PubMed@NIH” at the NIH Library web site http://nihlibrary.nih.gov

to enable full text access to subscribed journals

bibliographic database with author-provided abstracts

added indexing terms - MeSH (Medical Subject Headings) thesaurus

links to other resources

• PubMed – cont’d

JHU internal investigation found different PubMed results depending on the terms searched

• possibly due in part to limited coverage of older material & classification changes over time

Terms searched # Results # Useful

hexamethonium inhalation lung injury => 0 hits

hexamethonium inhalation => 42 hits 0

hexamethonium lung => not reported 3

hexamethonium lung toxicity => 4 hits 0

hexamethonium lung hypersensitivity => 16 hits 3

hexamethonium lung fibrosis => 3 hits 2

JHU Report, 7/01

Basic Searching Tips

How Search Works – typically every word in record is indexed & the index is searched; success depends on:

File content or scope

Individual record content (bibliographic info, abstract if avail.,indexing/keywords)

Problem of categories & group names - thesauri, classification schemes

Transparency/reproducibility of search algorithms & processes

Additional search terms automatically added – plurals, synonyms, etc.

Build concept-based searches - first broaden, then narrow

use synonyms & group similar concepts together: (A or B) and C

(ganglionic blockers OR hexamethonium) AND lung

PubMed - Older Information

PubMed now covers back to 1948 with some earlier coverage; older information is available in print sources – 3 relevant examples:

“Lung Changes During Hexamethonium Therapy for Hypertension”, British Heart J., 1954 – key article but

‘toxicity’ or ‘adverse effects’ not in PubMed record

phrase “hexamethonium lung” in titles of 2 articles from 1956 & 1962 - indexing included ‘toxicity’ or ‘adverse effects’

Cited reference searching could provide additional access - more recent articles refer to older articles

1966 and all that--when is a literature search done?, F McLellan, The Lancet, August 25, 2001, v358 i9282 p646

PubMed - Searching

Understand PubMed to get comprehensive results

Search Aids available by clicking “Help” - online book

includes Quick Start & FAQs at lower left

“PubMed Tutorials” - web-based & interactive

Distance Education Program Resources –online training, webcasts,

tutorials & handouts - http://www.nlm.nih.gov/bsd/dist_edu.html

NLM Training Manuals http://www.nlm.nih.gov/pubs/web_based.html

MeSH - added subject headings - often change over time

My NCBI – save searches, get updates while trial is in progress

Limits - not always obvious; “clinical trial” limits don’t include all observational studies

Advanced Search: Search Builder – combine search results;

Details - shows what was searched;

Use “ ” to ensure phrase (string) searching

Screenshot: http://nihlibrary.nih.gov

Screenshot:

Public access at www.pubmed.gov

Screen shot: PubMed search

Screenshot: PubMed search results

Screenshot: PubMed advanced search details

Screenshot: PubMed Advanced Search

Screenshot: PubMed search

Screenshot: PubMed search results

Screen shot: PubMed search results

Screenshot: PubMed search results

Screenshot: Pubmed search result

More Information Sources

Comprehensive searches usually require multiple information sources

Different sources have areas of specialization but may overlap

Many sources are fee-based, & only available by subscription

check your library/organization for institutional subscriptions

Examples of some information sources follow; see websites for tutorials & more information

different versions of these sources may be available with varying coverage and capabilities

many other sources may also be important for a given search

Embase™

Covers pharmacological & biomedical literature, with >24M records > 7,500 journals, 34 languages

key clinical medicine database, European based

NIH-accessible file www.embase.com covers 1947 – present

User guides http://info.embase.com/user_support/learning_tools.shtml

Includes all of PubMed, as well as additional material, but with different indexing & twice as many thesaurus terms (EMTREE)

Especially useful for drug side effects/interactions, toxicology, biotechnology, medical devices, health policy/management, public/occupational/environmental health, conferences, & alternative/complementary medicine

Embase™ vs PubMed

“Lung Changes During Hexamethonium Therapy for Hypertension”, British Heart J, 1954 PubMed – doesn’t include abstract, ‘toxicity’ or ‘adverse effects’ Embase – includes abstract, ‘dyspnea’ & ‘edema’ (& British spellings)

“Hexamethonium lung; report of a case associated with pregnancy”, J Obstet Gynaecol Br Emp, 1956 PubMed – no abstract, but good MeSH indexing terms – Hexamethonium Compounds/*adverse effects

Embase – includes ‘edema’ & abstract: “…a woman of 37, treated with hexamethonium compounds for severe hypertension during ... pregnancy. She died after the birth of a live infant…Treatment with hexamethonium drugs… from the 17th week. Severe, ultimately fatal, respiratory disease developed during the 35th week…”

Screenshot: Emabse search results

Screenshot: Emabase search results

Micromedex(R)

summaries & detailed monographs for drugs, diseases, alternative medicine, toxicological managements, emergency care & reproductive risks – see http://www.micromedex.com/products/hcs/ &

http://www.micromedex.com/support/training/HCSkit/

“had lung toxicity as the first side effect of hexamethonium” (JHU Report, 7/01)

BIOSIS Previews (R)

biological, biomedical & life science research - traditional, experimental & interdisciplinary subjects & technical notes/letters - includes NIH-accessible file Biological Abstracts® - see http://www.thomsonreuters.com/products_services/scientific/BIOSIS_Previews

• Cited Reference Searching

Web of Science (R) – includes multidisciplinary indexes;

Science Citation Index Expanded®, > 7,100 journals, 1900 - present

Social Sciences Citation Index®, >2,100 journals, 1956 – present

complete citation counts for all records; many lack abstracts/indexing

http://thomsonreuters.com/products_services/science/science_products/a-z/web_of_science/

Scopus (R) – scientific, technical, medical, & social science literature; includes patents & Scirus websearch engine, see http://www.scopus.com

>16,000 journals from 1823 – present; many records include abstracts

complete citation counts from 1996 – present

Both are also useful for conference coverage &

citation counts/ranking

Evidence-Based Information

Cochrane Library – http://www.cochrane.org/ - Regularly updated collection for practitioners & policy makers, includes:

evidence-based medicine reviews (systematic reviews)

effectiveness of health care interventions &

clinical trial registry (published/unpublished)

Guidelines.gov - evidence-based guideline clearinghouse

from the Agency for Healthcare Research & Quality (AHRQ),

US Dept of Health & Human Services, www.guidelines.gov

Screenshot: Cochrane Library search results

Screenshot: Agency for Healthcare Research and Quality National Guideline for Clearinghouse

Clinical Trial Information

ClinicalTrials.gov - NIH clinical trials list www.clinicaltrials.gov

CenterWatch - commercial Clinical Trials Listing Service™ http://www.centerwatch.com/

International Clinical Trials Registry Platform (ICTRP) – World Health Organization http://www.who.int/ictrp/en/

Note: Many trials are not properly registered - S. Mathieu et al., Comparison of registered and published primary outcomes in randomized controlled trials, JAMA 2009:302(9):977-984, PMID 19724045, http://www.ncbi.nlm.nih.gov/pubmed?term=19724045

TOXNET - http://toxnet.nlm.nih.gov cluster of databases covering toxicology, hazardous chemicals, environmental health & related areas from NLM - see http://www.nlm.nih.gov/pubs/factsheets/toxnetfs.html ToxSeek http://toxseek.nlm.nih.gov - meta-search engine, includes TOXNET, PubMed, PMC, Bookshelf, ClinicalTrials & others

Texts & References – either in print or online:

NCBI Bookshelf – free online books, available by clicking the arrow above the PubMed search window to search ‘Books’-

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books

Hexamethonium toxicity wasn’t mentioned in the last 4

editions of Goodman & Gillman, or in the current edition of Fishman’s Pulmonary Medicine – but was included in a previous edition of Fishman’s text (JHU Report, 7/01)

Screenshot: TOXNET Toxicology Data Network

Screenshot: ToxSeek search results

Specialized sources

Regulatory information – MedWatch - post-marketing surveillance from pharmaceutical companies, required by FDA http://www.fda.gov/medwatch/index.html (textbook pp.397-399)

Engineering databases - Compendex® & Inspec® information on medical devices

Others:

• patent literature

• drug pipeline (drugs in development) databases

• chemistry databases (Chemical Abstracts, etc.)

Screenshot: FDA

MedWatch: The FDA Safety Information and Adverse Event Reporting Program

Free full text on the internet

Increasing amount of readily available information

PubMed/MEDLINE – can limit to items with links to free full text

PubMed Central (PMC) – free digital biomedical/life sciences journal literature archive from NIH, >2M full text articles (>10% of PubMed) ; http://www.pubmedcentral.nih.gov/

Includes BioMed Central, http://www.biomedcentral.com/ , Public Library of Science, http://www.plos.org/ , & mandated public access to NIH-funded research

Directory of Open Access Journals – many are full text searchable - http://www.doaj.org/

MedlinePlus – consumer health information, NLM http://medlineplus.gov/

Internet Search Engines

Google, Google Scholar, Yahoo & others – access increasing amounts of information, some in full text

JHU PI found first evidence of hexamethonium pulmonary toxicity on the internet

Google and Yahoo found a hexamethonium toxicity site, but other search engines didn’t (JHU Report, 7/01)

Search most effectively with advanced search features

change preferences to see more, with less work

use different search engines for different scope/coverage, search

capabilities, & ranking algorithms

Google & Google Scholar

Google www.google.com; Advanced http://www.google.com/advanced_search?hl=en http://www.google.com/support/websearch/bin/answer.py?hl=en&answer=136861 ; Preferences www.google.com > Search settings > Number of Results > change ‘Display’ from 10 to 100 if “Do not use Google Instant” is clicked

Google Scholar http://scholar.google.com/ full text journal articles, books, patents, & dissertations ; Advanced http://scholar.google.com/advanced_scholar_search & http://scholar.google.com/intl/en/scholar/refinesearch.html ; Preferences http://scholar.google.com/scholar_preferences > Library Links> Search for “NIH” > check box “NIH Library - Full-Text Plus!” > save ; also search “worldcat”, check box “Open WorldCat – Library Search’, > change ‘Number of Results’ from 10 to 100; possibly also check “Show links to import citations into EndNote” ; > save

Advanced Search Operators: “Phrase Search” within double quotes; Must include/exclude +/- plus or minus sign immediately preceeding included or excluded word (no spaces) ; site: URL must include word immediately following colon; filetype:ppt or filetype:pdf

Yahoo, Bing, Exalead & Blekko

Yahoo www.yahoo.com ;Advanced search.yahoo.com/web/advanced?ei=UTF-8 > change ‘Number of Results’ from 10 to 100; Preferences search.yahoo.com/preferences

Bing www.bing.com ; > Preferences > ‘Results’ change from 10 to 50; more information http://www.bing.com/explore?q=&FORM=BXLH ; after searching click ‘Advanced’ above results; or see http://bit.ly/BingAdvn

Exalead www.exalead.com/search -the only search engine which allows true proximity searching, truncation, & phonetic searching; Advanced > ‘advanced search’ >menu of options; Preferences www.exalead.com/account/preferences/ > change ‘Results per page’ from ‘10’ to ‘100’ > ‘Save my preferences’; Information > FAQ at bottom left

Blekko http://blekko.com/ - uses slashtags as additional descriptors; Information > ‘help’ at bottom – offers reliable date indexing

Google & other web resources

Why is the information provided?

What is the business model - who pays?

Incentives for accuracy and completeness?

Search Engine Optimization industry - examples discussed in

D. Segal, Search Optimization and Its Dirty Little

Secrets, NYT 2/12/11 http://nyti.ms/optimiz

Promising technology - increasingly powerful capabilities

Cautions include possible

inconsistent results,

lack of search documentation

lack of confidentiality

Bioinformatics Resources

NCBI resources - access by clicking arrow above PubMed search window http://www.ncbi.nlm.nih.gov/Sitemap/index.html – site map http://www.ncbi.nlm.nih.gov/Database/ - shows overview & linkage

“Human Genome Project and Clinical Research”, Dr Chris Austin, IPPCR lecture tomorrow 2/15/11

Bioinformatics Resources, Dr. Medha Bhagwat, IPPCR lecture 1/26/10 https://webmeeting.nih.gov/p19902251/ -(starts at 34 min); ppts at http://ippcr.nihtraining.com/lecture_detail.php?lecture_id=49&year=2009 – HUGE Navigator, OMIM & dbSNP – predict success of using buproprion to quit smoking

NIH Library http://nihlibrary.nih.gov/ResearchTools/Pages/Bioinformatics.aspx >Bioinformatics (quick link at left of home page) ; resources include http://nihlibrary.nih.gov/ResearchTools/Pages/biotutorials.aspx with links to free online tutorials from EBI, MIT & Harvard

Screenshot: NCBI Site Map

Screenshot: Bioinformatics Research Tools

Screenshot: Bioinformatics Online Tutorials

Search Strategy & Updates

Ask the Right Questions – consider PICO outline & synonyms to help organize your thoughts, concepts & search terms: Patient/Population and/or Problem ; Intervention ; Comparison/Control ; Outcome or Effects - The Literature Searching Process Protocol for Researchers, Thames Valley Health Libraries Network, Mar. 2006, http://www.ieph.org/hase/Downloads/Lit_Search_Protocol_Researchers.pdf