Bios 6648: Design and Conduct of Clinical...

Course AdministationObjectives, syllabus, andschedule

Content and objectives

0. Motivation andcontext0.1 Examples

Case Study 1: Neural tubedefects

Bios 6648- pg 1

Bios 6648: Design and Conduct ofClinical Research

Fall Semester 2013

John M. KittelsonDepartment of Biostatistics & Informatics

Colorado School of Public HealthUniversity of Colorado Denver

Bios 6648- pg 2

Bios 6648:Design and Conduct of Clinical Research

Course Objectives and Administration

I SyllabusI Course objectives and lecture topicsI Textbooks

I Required: Piantadosi S. Clinical Trials: A MethodologicPerspective. 2nd edition (2005) John Wiley & Sons, Inc.Hoboken, NJ.

I Recommended: Meinert CL, Clinial Trials: Design, Conduct,and Analysis. 2nd edition (2012) Oxford University Press,NY.

I Additional materials: www.RCTdesign.org

Bios 6648- pg 3

The course is organized around the 5 main objectives:0. Motivation, context, and objectives for clinical trials (and

clinical research)1. Specifying the study setting and objectives2. Formulating the scientific and statistical design3. Essential principles of trial conduct: assuring unbiased

and reproducible results.4. Documenting the study5. Software to support study design and monitoring

Bios 6648- pg 4

Section 0: Course motivation, context, and objectives

I Purpose: describe the overall clinical, scientific, andethical context for clinical studies

I Approach0.1 Examples:

I Historic approach to coronary artery diseaseI Neural tube defectsI Selenium supplementation

0.2 Public health objective for clinical researchI Reading : Piantadosi chapters 1-4

I Notice in particular:I Scientific, clinical, and ethical context for clinical researchI Breadth of possibilitiesI Science/design follows from context

Bios 6648- pg 5

Section 0: Course motivation, context, and objectives

0.1 Examples

I A very early approach to surgery for coronary arterydisease

I Other useful examplesI Two case studies:

(a) Folic acid and neural tube defects(b) Selenium supplementation for cancer prevention

Bios 6648- pg 6

0.1 Examples

Surgery for coronary artery disease

“Medicine at the Crossroads: Part 6 Random Cuts"(PBS / BBC video, 1993)

Bios 6648- pg 7

0.1 Examples

Notes: Surgical treatment for coronary artery disease

I “Experience has shown"I Testimonials are not sufficientI There are (too) many examples of treatments that seemed

logical but which turned out to be harmful:I Retrolentil fibroplasia (Scientific American 236:100-107;

1977).I Cardiac arrhythmias (NEJM, 321:406-412; 1989).I Coronary bypass surgery (NEJM, 297:621-627; 1977).I Chest physiotherapy (J. Pediatrics 132:400-444; 1998).I Cholesterol lowering treatments and suicide (e.g., JAMA

226:652-657; 1973)I Beta carotene for prevention of lung cancer (e.g., NEJM,

330:1029-35; 1994).

Bios 6648- pg 8

0.1 Examples

Notes (con’t):

I There are (too) many examples of treatments that seemedlogical but turned out to be harmful:

I Hormone replacement therapy for postmenopausal women;Womens Health Initiative:

I Effect on coronary heart disease and cancer (JAMA288:321-333; 2002).

I Effect on quality of life (NEJM 348:1839-1854; 2003).I Effect on mental health (JAMA 289:2651-2672; 2002).

I VioxxI Thiazolidinediones (rosiglitazone)I Alendronate (fosamax)I All-metal hip replacements?

Question:

So when do we have enough information to use a new therapy?

Bios 6648- pg 9

0.1 Examples

Notes (con’t):

I There are (too) many examples of treatments that seemedlogical but turned out to be harmful:

I Hormone replacement therapy for postmenopausal women;Womens Health Initiative:

I Effect on coronary heart disease and cancer (JAMA288:321-333; 2002).

I Effect on quality of life (NEJM 348:1839-1854; 2003).I Effect on mental health (JAMA 289:2651-2672; 2002).

I VioxxI Thiazolidinediones (rosiglitazone)I Alendronate (fosamax)I All-metal hip replacements?

Question:

So when do we have enough information to use a new therapy?

Bios 6648- pg 10

0.1 Examples

Case study 1: folic acid for prevention of neural tube defects

I Neural tube defects (NTD):I Incomplete formation of the neural tube (spine and head)

during fetal development (risk of about 1 per 1000 births).I Common outcomes:

I Spontaneous abortion or still-birthI Spina bifida.

I Causes for NTD have been extensively studied from1950’s through 1990’s

I Hypothesized causes (circa 1960-80):I Environmental exposures during pregnancyI Maternal illness (and drug exposure) during pregnancyI Maternal occupational exposuresI DietI Genetic causes

I Extensive epidemiology from 1950 through 1990’s(Elwood 1993) included:

I Descriptive epidemiologyI Case-control studiesI Cohort studies

Bios 6648- pg 11

Bios 6648- pg 12

Bios 6648- pg 13

Bios 6648- pg 14

The dietary hypothesis

I Evidence in support of dietary hypothesis:I Geographical and seasonal variation in NTD risk consistent

with folic acid deficiencyI Specific dietary hypotheses:

I Malnutrition or poor diet in motherI Low hemoglobinI Blighted potatoesI Tea or coffee drinking (caffeine)I Exposure to nitrates/nitritesI Excess of: vitamin D or vitamin AI Deficiencies: Calcium/magnesium; folate; nicotinic acid,

riboflavin, thiamin, vitamin B12, vitamin C, zinc.

Bios 6648- pg 15

Early studies related to the dietary hypothesis:I A“Natural experiment" (non-randomized trial; 1964-66):

I (New South Wales) Women with previous NTD birth werecounseled to improve their diet and stop smoking at the timethey stopped contraceptive measures.

I Women in a neighboring area were not counseled.I Collected data that showed diets changed as a result of

counselingI Results:

I Among counseled women 2.8% (2/128) pregnancies had NTDI Among non-counseled women 6.5% (5/77) had NTDI Difference is not significant (p > 0.10)I Secondary evaluation supported dietary role in NTD

Bios 6648- pg 16

Early studies related to the dietary hypothesis:I Case-control study (Western Australia, 1989):

I Cases (n = 77) identified from Western AustraliaMalformations Registry

I Normal controls (n = 154) (matched on date of lastmenstrual period) selected from population birth registry.

I Detailed dietary survey administered and used to estimatepericonceptional nutrient intake.

I Results:Odds ratios for estimated periconceptional nutrient intake

Free TotalQuartile folate folate Fibre Calcium Riboflavin Vit C Carotene

Low 1(ref) 1(ref) 1(ref) 1(ref) 1(ref) 1(ref) 1(ref)2 0.44 0.94 0.41 0.73 0.31 0.65 1.203 0.34 0.61 0.37 0.49 0.33 0.51 0.47Hi 0.16 0.38 0.29 0.27 0.48 0.18 0.31

p-val < 0.001 0.03 0.005 0.006 0.22 < 0.001 0.002

Bios 6648- pg 17

Early studies related to the dietary hypothesis:I Cohort study (Milunsky, 1989):

I Prospective prenatal screening (both blood tests and dietrecall) on 23491 women

I Results show protective effect of folic acid:

Bios 6648- pg 18

Early studies related to the dietary hypothesis:I UK multicenter non-randomized trial (Smithells, 1980):

I Periconceptional vitamins to prevent recurrent NTD.I Women with previous NTD-affected child who wanted more

childrenI Fully supplemented group: 454 women who became

pregnant and took a multivitamin prior to pregnancyI Comparison group: 519 women who were already pregnant

when seen or who refused to take a vitamin.

Bios 6648- pg 19

I Randomized trials for recurrence of NTD (MRC vitamintrial; Lancet 1991):

I Intense debate over the ethics of a randomized trial.I Randomized 1817 women at high risk of having a

pregnancy with NTD (because of previous NTD birth)* 2 × 2 factorial design (depicted on pg 132).

I Results show 72% reduction in risk of NTD.I Other highlights of this example:

* Required new methods for monitoring a trial (allowing earlytermination)

* Questions remain regarding utility of primary prevention ofNTD.

Bios 6648- pg 20

I Randomized trials for primary prevention of NTD(Hungarian Family Planning Program; NEJM 1992):

I Evaluated primary prevention as opposed to prevention ofrecurrence

I Randomized 4753 women who were planning a pregnancy* 2420 to receive vitamin supplement; 2333 to receive

trace-element supplement.I Results show 0 cases of NTD with vitamin and 6 cases with

control treatment.

Bios 6648- pg 21

I Has the question been answered?I Debate continues over risks of supplementation for

individuals who are not planning to get pregnant.

Bios 6648- pg 22

I Has the question been answered?I Debate continues over risks of supplementation for

individuals who are not planning to get pregnant.

Bios 6648: Design and Conduct of Clinical...

Documents

Dietary Supplements and INDs - Emory Compliancecompliance.emory.edu/documents/Dietary_Supplements_and_IND_5_… · Regulation of Dietary Supplements •Dietary Supplement Health and

DIETARY CARBOHYDRATE INTERACTS WITH DIETARY FAT TO

Digestion of Dietary Lipids Digestion of Dietary Lipids

Scientific Method Collect Facts and Data Hypothesis Test hypothesis Modify hypothesis Conclusion

Bios 6648: Design & conduct of clinical researchcsph.ucdenver.edu/sites/kittelson/Bios6648-2013/L... · Date: 28 Aug 2013 0. Motivation and context 0.1 Examples Case Study 1: Neural

Let’s Review! The Nebular Hypothesis The Nebular Hypothesis Several, Alternative, Hypothesis Several, Alternative, Hypothesis The Structure of our Solar

DIETARY MYTHS AND HEALTHY DIETARY ADVICE€¦ · DIETARY MYTHS AND HEALTHY DIETARY ADVICE . LENNY LESSER, MD MSHS . FAMILY DOC, RESEARCHER, QUALITY TEAM, ONE MEDICAL, SAN FRANCISCO

Dietary intakes consistent with the DASH dietary pattern ...apjcn.nhri.org.tw/server/APJCN/22/3/482.pdf · Dietary intakes consistent with the DASH dietary pattern ... ease (CVD)

Dietary Reference Intake & Dietary Guidelines Implementation · 2010-07-28 · Dietary Reference Intake & Dietary Guidelines Implementation ... setting, and evaluation of all State

“Closing the Dietary Fiber Gap: Aligning Dietary Fiber Policy, Research… · 2017-04-05 · “Closing the Dietary Fiber Gap: Aligning Dietary Fiber Policy, Research, ... • Discuss

Null hypothesis AND ALTERNAT HYPOTHESIS

Hypothesis Tests Hypothesis Tests One Sample Proportion

Introduction Hypothesis testing for one mean Hypothesis testing for one proportion Hypothesis testing for two mean (difference) Hypothesis testing for

Introduction to statistics for hypothesis testing...Detection and Hypothesis testing Rejecting a hypothesis aka detection H 0: The \null" hypothesis i.e., the hypothesis that the data

araicom Hypothesis Generation Algorithmsaraicom.net/pdf/Hypothesis _Algorithms.pdf · araicom Hypothesis Generation Algorithms Current research on conceptual biology focuses on hypothesis

Approaches to Dietary Pattern Analyses: Potential … · Approaches to Dietary Pattern Analyses: Potential to Inform Guidance ... Analysis How do dietary patterns ... Dietary Patterns

Bios 6648: Design & conduct of clinical researchcsph.ucdenver.edu/sites/kittelson/Bios6648-2013/Lctnotes/... · 2013. 9. 4. · Date: 4 Sep 2013 1. Setting and Objectives 1.0 Background

HYPOTHESIS TESTING Null Hypothesis and Research Hypothesis ?

ANSI Dietary Supplements Documents/Dietary Supplements/Meeting... · ANSI Meeting Report: Dietary Supplements Standardization Coordination Page 1 of 22 ANSI Meeting Report Dietary

Hypothesis Tests Hypothesis Tests One Sample Means