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STAT 250 Dr. Kari Lock Morgan Knee Surgery for Arthritis Researchers conducted a study on the effectiveness of a knee surgery to cure arthritis. Collecting : It was randomly determined whether people got Randomized the knee surgery. Everyone who underwent the surgery reported feeling less pain. SECTION 1.3 Is this evidence that the surgery causes a • Control/comparison group decrease in pain? • Clinical trials • Placebo Effect (a) Yes • Blinding • Crossover studies / Matched pairs (b) No

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Control Group Clinical Trials — Clinical trials are randomized experiments — When determining whether a treatment is dealing with medicine or medical interventions, effective, it is important to have a comparison conducted on human subjects group, known as the control group — Clinical trials require additional aspects, beyond just to treatment groups:

—All randomized experiments need a control or ¡ Placebo comparison group (could be two different ¡ Double-blind treatments)

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Placebo Effect Study on Placebos — Often, people will experience the effect they think they should be experiencing, even if they aren’t actually — Blue pills are better than yellow pills receiving the treatment. This is known as the placebo effect. — Red pills are better than blue pills — Example: Eurotrip — 2 pills are better than 1 pill — One study estimated that 75% of the effectiveness of anti-depressant medication is due to the placebo effect — 4 pills are better than 2 pills — A review of 15 clinical trials with different diseases found that 35% of patients were satisfactorily relieved by — And shots are the best of all! the placebo alone (The Powerful Placebo)

— For more information on the placebo effect (it’s pretty amazing!) read The Placebo Prescription or listen to Radiolab’s podcast Placebo

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Placebo Effect Placebo-controlled studies — Control groups should be given a placebo, a fake treatment that resembles the active treatment as much as possible

— This allows researchers to separate effect of treatment itself from effect of the placebo effect

— Often instead of a placebo, new treatment is compared to the existing standard treatment (not ethical to not help a patient in need)

Should doctors be allowed to prescribe placebos?

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Double-Blind Experiments Question of the Day

— If possible, randomized experiments should be double-blinded: neither the participants or the researchers involved should know which What is the effect of treatment the patients are actually getting Sildenail as a drug? — The participants should be blinded because of the placebo effect — The researchers should be blinded to avoid conscious or unconscious of the results

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Sildenail and cGMP Sildenail — 1980s: Pizer develops sildenail citrate, which The molecule cGMP is a natural vasodilator: it inhibits phosphodiesterase, hoping to increase increases blood low by relaxing muscle in the blood low in the coronary arteries of individuals walls of blood vessels. with heart disease. cGMP Blood vessel — 1991: Phase I clinical trials are begun. — 1992: Pizer gets reports of an unexpected “side Sildenail inhibits phosphodiesterase (an effect” in men. enzyme), which degrades cGMP. — 1994: After sildenail fails to show any cardiac beneit, Pizer begins pilot studies for treatment sildenail phosphodiesterase degrades of erectile dysfunction (ED). cGMP — 1998: FDA approves sildenail for ED.

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Atenonol: A randomized Silvestri et al assigned 96 men to take atenolol, a heart drug which can cause ED as a side effect: • 32 men were told they were taking either atenolol or placebo • 32 were told only that they were taking atenolol • 32 were told that they were taking atenolol, and that it can cause ED as a side effect. After 3 months, the researchers asked men to report any experience of ED.

• Silvestri A, Galetta P, Cerquetani E, Marazzi G, Patrizi R, Fini M, Rosano GM. Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of They were all on the same drug! side effects and is reversed by placebo. Eur Heart J. 2003 Nov;24(21):1928-32. Statistics: Unlocking the Power of Data Lock5 Statistics: Unlocking the Power of Data Lock5

Sildenail: A Randomized Experiment 32 men had been randomized to atenolol and told it can cause ED

The researchers then assigned all men who’d experienced ED to either 50mg sildenail or placebo. 10 reported experiencing ED The men were blinded regarding this treatment.

5 randomized to take 5 randomized to take Viagra (blinded) placebo (blinded)

After a week the researchers asked the men if their ED had improved. Any guesses what the men reported? All improved!

Control, placebos and blinding are important! Statistics: Unlocking the Power of Data Lock5 Statistics: Unlocking the Power of Data Lock5

Trustworthy Clinical Trials http://onlinelibrary.wiley.com/doi/10.1046/j.1464-410X.1996.10220.x/epdf

— To assess the trustworthiness of results from clinical trials (or any medical result), ask…

¡ Was the treatment randomly assigned?

¡ Was the control group given a placebo or other treatment?

¡ Was the study double-blind?

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Crossover Studies and Matched Pairs Gatorade and Running — Does drinking Gatorade make you run faster? In a , each unit gets both treatments. — Variables: ¡ Explanatory: drink Gatorade or placebo before running This is a special case of a matched pairs study, in ¡ Response: time to run a certain distance (a mile?) which either each unit gets both treatments or units — Completely randomized: Randomize half of the are paired and each pair gets both treatments. people to drink Gatorade half to drink a placebo (colored water? with sugar?) — For randomized experiments, the order of — Matched pairs: have each person run twice (on treatment or treatment assignment within a different days?), one time drinking Gatorade, one pair is randomly determined time drinking placebo. Randomize order.

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Matched Pairs: Identical Twins Crossover/Matched Pairs

— Compare a unit to itself or a similar unit — Analyze by looking at differences in response within the pair

— Useful when the response variable varies a lot from unit to unit

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Why not always randomize? Randomization in

— Randomized experiments are ideal, but sometimes not ethical or feasible Was the sample Was the explanatory variable randomly — Ethics: Can’t force someone to partake in a randomly selected? treatment known or suspected to cause harm assigned?

— Feasibility: Often, randomized experiments are Yes No Yes No simply not feasible (cost, time, and practical issues are limiting factors) Possible to Should not Possible to Can not make generalize to generalize to make conclusions — Often, you have to do the best you can with the population the conclusions about causality data from observational studies population about causality

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Two Fundamental Questions in Randomization Data Collection — Doing a randomized experiment on a random Random sample is ideal, but rarely achievable sample??? — If the focus of the study is using a sample to Population estimate a value for the entire population, you need a random sample, but do not need a randomized Sample experiment (example: election polling) — If the focus of the study is establishing causality Randomized from one variable to another, you need a experiment??? randomized experiment and can settle for a non- random sample (example: clinical trials) DATA

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Summary To Do — A control or comparison group is — Read Section 1.3 necessary — HW 1.3 due Friday, 9/11. — The placebo effect exists, so a placebo and blinding should be used — Matched pair experiments can be useful when the response variable varies a lot from unit to unit

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