Why the scientific literature is important of evidence... · periodontal therapy is only 68% of...

1

Why the scientific literature is important

• New knowledge generated by RCTs takes 17 years to be incorporated into practice (Institute of Medicine)

• Hodgkin – Prior to 1970: 5-10% for

4 year survival– 1970 study: 80% complete

remission– 11 years before results

were disseminated• Testicular cancer

– Cure rate 80%– 3 years before results

were disseminated

Concordance between clinical practice and published evidenceFindings from The National Dental Practice-Based Research NetworkJADA 2014

But many readers do not know how to assess the evidence critically, she said. "To be completely honest, probably it does have a big impact because most people who use the literature are not accustomed to doing critical analysis of it."

Medscape Medical News > Conference News Conflicts of Interest Prevalent in Dental Research Laird Harrison March 27, 2013

2

Levels of Evidence

1906: Pure Food and Drug Act

• Product Labeling– Cocaine

– Opiates

– Alcohol

• Electricity

http://www.orau.org/PTP/collection/quackcures/radithor1.jpg

1938: Federal Food, Drug, and Cosmetic Act

• diethylene glycol led to over a hundred deaths – mostly children

• “The Radium water worked fine until his jaw came off” WSJ, 1932

http://www.fda.gov/centennial/centennial_files/images/image13.png

1962: Kefauver-Harris Amendment

1976: Medical Device Amendment

• Dalkon Shield® 3

• TMJ implants: “... a new era in (Proplast-Teflon) TMJ reconstruction has begun, resulting in increased benefits to the patients whom we all serve.”

www.mjbovo.com

“GRASSLEY SECURES INDEPENDENT REVIEW OF FDA

APPROVALS”– Torcetrapib (2006)

raises HDL

– Avandia (2007) controls blood glucose

– Vytorin (2008) lowers cholesterol

– Trasylol (2008) lowers bleeding

Senator Charles Grassley (R, Idaho)

Picture from Washington Post

3

50% failure rate at 6 years“One of the biggest disasters in orthopedic history” BMJ

SR of RCTs

RCT

All-or-none

SR cohort studies

Cohort studies

Ecological studies

SR case-control studies

Case-control study

Case-reports and case-series

Expert opinion, Biological plausibility,Animal evidence, Bench research

3

2

1

Pre‐term

Perio 280(12.6%) 1948

261(11.7%) 1968No tx

2228

2229

+ -

Randomized Controlled Trial

CHX

Placebo

tooth loss

No tooth loss

tooth loss

No tooth loss

R

4

Randomized Trial on Tooth Loss

• 1101 elders

• Randomly assign to CHX (550) or placebo (551)

• Followed for 4.4 years

• Results:– CHX: 14 teeth/1000

tooth-years

– Placebo: 13.7/1000 tooth-years

RCTPre-natal fluoride/caries

caries-freecaries

Pre-natal F 30 368

36 364Control

398

400

7.5%

9.0%

Measures of Association

NNT, OR, RR, HR, RD, AR,

p -values

RCTLesion at day 6

376 878

526 757

+ -

Penciclovir

1254

1283

(30%)

(41%)

Data adapted from K. Kjaerheim et al., 1998

+

-


62.0526x878

376x757

526/1283) -(1

526/1283376/1254) -(1

376/1254

OR

RCTLesion at day 6

376 878

526 757

+ -

Penciclovir

1254

1283


+

-

5

Odds ratio = 0.62

The odds for a non-healed lesion at day 6 among individuals on penciclovir is only 62% of that for someone who was on placebo.

% odds decrease = |1 - 0.62| * 100%

The odds for a non-healing lesion among individuals on penciclovier decreased by 38%

The Atlantic 2010

SR of RCTs

RCT

All-or-none

SR cohort studies

Cohort studies

Ecological studies


Case-control study



3

2

1

6

Vertical “no-effect” line

Effect size & 95% confidence interval





NOTE: Weights are from random effects analysis

.

.

.Overall (I-squared = 57.6%, p = 0.009)

Ringelberg (1982)

Chikte (1996)

Heifetz (1981)

ID

Torell (1965)

Driscoll (1982)

0.09Fbiweekly

Poulsen (1983)

Subtotal (I-squared = 0.0%, p = 0.622)

Heifetz (1981)

0.09Fweekly



Craig (1981)

Horowitz (1971)

Ringelberg (1982)

Driscoll (1982)

0.09Fdaily

Study

29.81 (21.01, 38.60)

20.36 (0.60, 40.12)

15.34 (-6.09, 36.78)

30.64 (12.12, 49.15)

ES (95% CI)

49.10 (39.83, 58.38)

21.43 (-1.40, 44.26)

4.37 (-20.71, 29.45)

28.77 (20.40, 37.14)

40.69 (23.39, 57.98)

29.54 (16.81, 42.26)

28.32 (-15.41, 72.04)

30.77 (-6.52, 68.06)

35.92 (19.13, 52.72)

22.75 (3.79, 41.72)

36.61 (16.02, 57.20)

100.00

9.16

8.47

9.70

Weight

14.32

7.93

7.14

50.84

10.27

27.70

21.46

4.19

10.51

9.50

8.81

%

29.81 (21.01, 38.60)

20.36 (0.60, 40.12)

15.34 (-6.09, 36.78)

30.64 (12.12, 49.15)

ES (95% CI)

49.10 (39.83, 58.38)

21.43 (-1.40, 44.26)

4.37 (-20.71, 29.45)

28.77 (20.40, 37.14)

40.69 (23.39, 57.98)

29.54 (16.81, 42.26)

28.32 (-15.41, 72.04)

30.77 (-6.52, 68.06)

35.92 (19.13, 52.72)

22.75 (3.79, 41.72)

36.61 (16.02, 57.20)

100.00

9.16

8.47

9.70

Weight

14.32

7.93

7.14

50.84

10.27

27.70

21.46

4.19

10.51

9.50

8.81

%

A Systematic Review of Class IIs and Herbst Appliances -

AUTHORS' CONCLUSIONS:It is not possible to provide any evidence-based guidance to recommend or discourage any type of orthodontic treatment to correct Class II division 2 malocclusion in children.

Cochrane Database Syst Rev. 2006

7

“Caries of teeth is restricted to people and animals who eat liberally of carbohydrate containing foods. Carnivorous man and animals do not suffer from this disease”

McCollum, 1941

SR of RCTs

RCT

All-or-none

SR cohort studies

Cohort studies

Ecological studies


Case-control study



3

2

1

What is “normal” Blood Pressure

• Blood pressure history– Age 55 : 169/98– Age 59: 188/105– Age 63: 226/118

• Physician assessment:

“no more than normal for a man his age”

New England Journal of Medecine 1995 (332): 1038-1039

8

CHD and Lipids, October 1966

• Framingham– 2022 males

– 1689 females

• Livermore– 1961 males

Gofman et al., Circulation, 1966; 679

Ischemic Heart Disease, Atherosclerosis, and LongevityParameters Incident Heart Disease

Systolic blood pressure Sign. Elevated

Diastolic blood pressure Sign. Elevated

Weight Sign. Elevated

Cohort StudySmoking/Oral Cancer

• Follow-up a cohort of 10960 individuals; 8857 smokers, 2103 non-smokers

• Enumerate the number of smokers and non-smokers that develop oral cancer during a 20 year period

• Tabulate the data in a 2x2 table

Cohort StudyOral carcinoma

56 8801

4 2099

+ -

Smoking

8857

2103

(0.6%)

(0.2%)


+

-


3.34x8801

56x2099

4/1203) -(1

4/210356/8857) -(1

56/8857

OR

Cohort StudyOral carcinoma

56 8801

4 2099

+ -

Smoking

8857

2103


+

-

9

Odds ratio = 3.3

The odds for oral cancer among smokers is 3.3 times as high as the odds for oral cancer among non-smokers

% odds increase = |1 - 3.3| * 100%

The odds for oral cancer among smokers increased by 230% (0.00636 versus 0.00191)

Cohort Study≥ 1 lost tooth

159 460

26 51

+ -

Maintenance

619

77

(26%)

(34%)


+

-


68.026x460

159x51

26/77) -(1

26/77159/619) -(1

159/619

OR

Cohort Study≥ 1 lost tooth

159 460

26 51

+ -

Maintenance

619

77


+

-

Odds ratio = 0.68

The odds for tooth loss among individuals with periodontal therapy is only 68% of that for someone who has not had periodontal therapy.

% odds decrease = |1 - 0.68| * 100%

The odds for tooth loss among individuals with periodontal therapy decreased by 32%

10

“Sleep-disordered breathing was associated with 40% and 60% more behavioraldifficulties at 4 and 7 years, respectively.”

Hyperactivity, anxiety and depression, peer problems, aggressiveness and rule breaking, and sharing, helpfulness

Upper 10% (n=1218)

90% (n=7923)

Maternal smoking 31% 20%

Maternal Education (lower ) 72% 59%

Paternal Employment (manual) 52% 39%

Inadequate housing 19% 12%

Low birth weight (<2500 gram) 4.7% 3.5%

Premature, < 37 weeks 5.6% 4.3%

Karen Bonuck et al. Pediatrics, March 2012 -

SR of RCTs

RCT

All-or-none

SR cohort studies

Cohort studies

Ecological studies


Case-control study



3

2

1

birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroidHormone concentrations in npatientswithchronic kidney diseaserequiring dialysis is probable

Well-shaped head, well-formed jaws and chin…. Sound even and uncrowded teeth

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NOTE: Weights are from random effects analysis

.

.

.

Overall (I-squared = 72.5%, p = 0.000)

McBeath (1932)

Hubbel (1932)

MRC (1936)

McBeath (1934)

UV

MRC (1936)

Schoenthal (1933)

Jundell (1938)

McBeath (1932)

Brodski (1941)

McBeath (1942)

Strean (1945)

McKeag (1930)

McBeath (1931)


MRC (1936)

McBeath (1942)

Schoenthal (1933)

MRC (1936)

McBeath (1934)

Mellanby (1926)

Schoenthal (1933)

McBeath (1933)

Day (1934)

Hargreaves (1989)

Study

McKeag (1930)


Jameson (1933)


McBeath (1942)

Anderson (1934)

Schoenthal (1933)

Strean (1945)

Goll (1939)

McBeath (1933)

Mellanby (1924)

Mellanby (1926)

Mayron (1975)

vitamin D2

McBeath (1933)

ID

Brodski (1941)

Mellanby (1924)

Vitamin D3

McBeath (1942)

-0.64 (-0.83, -0.44)

-1.98 (-3.34, -0.62)

0.44 (-0.68, 1.55)

-0.65 (-1.17, -0.13)

-1.43 (-2.40, -0.45)

-0.35 (-0.79, 0.09)

0.03 (-0.70, 0.77)

-0.10 (-0.47, 0.26)

-0.22 (-0.89, 0.45)

-1.93 (-2.86, -1.01)

-0.61 (-0.90, -0.31)

-2.10 (-3.42, -0.78)

-0.44 (-1.85, 0.97)

-1.77 (-2.81, -0.73)

-0.45 (-0.74, -0.15)

-0.50 (-1.52, 0.51)

-0.69 (-1.03, -0.35)

0.08 (-0.39, 0.55)

-0.73 (-1.85, 0.39)

-0.02 (-0.62, 0.57)

-1.24 (-2.44, -0.05)

-0.11 (-0.60, 0.37)

-0.74 (-1.35, -0.13)

0.12 (-0.06, 0.29)

-1.36 (-2.23, -0.49)

-1.11 (-2.78, 0.57)

-1.01 (-1.77, -0.25)

0.71 (-0.52, 1.94)

-0.67 (-0.91, -0.43)

-1.02 (-1.51, -0.52)

-0.69 (-1.43, 0.06)

0.23 (-0.66, 1.12)

-0.19 (-1.28, 0.91)

-0.14 (-1.03, 0.74)

-1.49 (-2.21, -0.77)

-1.45 (-3.30, 0.40)

-1.53 (-2.89, -0.18)

-1.78 (-2.72, -0.84)

-0.66 (-1.21, -0.12)

ES (95% CI)

-1.10 (-1.91, -0.29)

-0.78 (-1.99, 0.42)

-0.61 (-0.90, -0.31)

100.00

1.46

1.87

3.52

2.19

3.77

2.84

4.02

3.03

2.31

4.21

1.52

1.38

2.03

43.86

2.09

4.09

3.69

1.87

3.27

1.72

3.64

3.24

4.49

2.44

%

1.07

14.27

1.66

41.87

3.59

2.80

2.40

1.92

2.40

2.87

0.92

1.46

2.26

3.44

Weight

2.61

1.70

4.21

-0.64 (-0.83, -0.44)

-1.98 (-3.34, -0.62)

0.44 (-0.68, 1.55)

-0.65 (-1.17, -0.13)

-1.43 (-2.40, -0.45)

-0.35 (-0.79, 0.09)

0.03 (-0.70, 0.77)

-0.10 (-0.47, 0.26)

-0.22 (-0.89, 0.45)

-1.93 (-2.86, -1.01)

-0.61 (-0.90, -0.31)

-2.10 (-3.42, -0.78)

-0.44 (-1.85, 0.97)

-1.77 (-2.81, -0.73)

-0.45 (-0.74, -0.15)

-0.50 (-1.52, 0.51)

-0.69 (-1.03, -0.35)

0.08 (-0.39, 0.55)

-0.73 (-1.85, 0.39)

-0.02 (-0.62, 0.57)

-1.24 (-2.44, -0.05)

-0.11 (-0.60, 0.37)

-0.74 (-1.35, -0.13)

0.12 (-0.06, 0.29)

-1.36 (-2.23, -0.49)

-1.11 (-2.78, 0.57)

-1.01 (-1.77, -0.25)

0.71 (-0.52, 1.94)

-0.67 (-0.91, -0.43)

-1.02 (-1.51, -0.52)

-0.69 (-1.43, 0.06)

0.23 (-0.66, 1.12)

-0.19 (-1.28, 0.91)

-0.14 (-1.03, 0.74)

-1.49 (-2.21, -0.77)

-1.45 (-3.30, 0.40)

-1.53 (-2.89, -0.18)

-1.78 (-2.72, -0.84)

-0.66 (-1.21, -0.12)

ES (95% CI)

-1.10 (-1.91, -0.29)

-0.78 (-1.99, 0.42)

-0.61 (-0.90, -0.31)

100.00

1.46

1.87

3.52

2.19

3.77

2.84

4.02

3.03

2.31

4.21

1.52

1.38

2.03

43.86

2.09

4.09

3.69

1.87

3.27

1.72

3.64

3.24

4.49

2.44

%

1.07

14.27

1.66

41.87

3.59

2.80

2.40

1.92

2.40

2.87

0.92

1.46

2.26

3.44

Weight

2.61

1.70

4.21

0-3.42 0 3.42

SR of RCTs

RCT

All-or-none

SR cohort studies

Cohort studies

Ecological studies


Case-control study



3

2

1

12

SR of RCTs

RCT

All-or-none

SR cohort studies

Cohort studies

Ecological studies


Case-control study



3

2

1• Cases: 200 intracranial

meningioma patients (1995 and 1999)

• Controls: Randomly selected people without intracranial meningioma

• Exposure: Dental radiographs

• Outcome : Intracranial meningioma

• Main Results: > 5 full-mouths doubled the intra-cranial meningioma risk

http://findaride.org/images/floaters/maps/sno_king_pierce_map.jpg

Case-Control StudyBrain Cancer and Dental X-rays

Case-Control StudyMeningioma

≥ 6 FMX19 21

181 379

+ -+

-

200 400

9.5% 5.3%

Oral Cancer and HPV

Case-Control StudyOropharyngeal carcinoma

HPV‐1632 4

68 196

+ ‐+

‐

100 200

32% 2%

NEJM; 2007: 356:1944‐56

Case-Control StudyTLBW

≥ 1 X-ray49 (14.5%) 465 (10.4%)

287 4003

+ -+

-

336 4468

13


47.1465x287

49x4003

465/4468) -(1465/4468

49/336) -(149/336

OR

Case-Control StudyTLBW

≥ 1 X-ray49 465

287 4003

+ -+

-

336 4468

Odds ratioOutcome

+ (failure) -

Exposure + a b

- c d

cb

daOR

*

*

95% confidence intervals

dcbaorOR lu

111196.1)ln(exp,

Fluorosis and Infant Formula

to compare infant formula consumption to breastfeeding or cow-milk consumption in relation to fluorosis

Photo: fluoriealert.org / Jeffrey Hamilton

14

"The possibility of an association between fluoride in infant formula and the risk for enamel fluorosis has been studied for many years. Until now, most researchers concluded that fluoride intake during a child's first 10 to 12 months had little impact on the development of this condition in permanent teeth."

http://www.cdc.gov/FLUORIDATION/safety/infant_formula.htm

SR of RCTs

RCT

All-or-none

SR cohort studies

Cohort studies

Ecological studies


Case-control study



3

2

1 Substance X in blood

• Among low-risk CHD people the level is ~0.5 nmol/liter, among high-risk people the level is ~0.4 nmol/liter

• Evidence on substance X is so convincing that individuals with low levels of substance X are labeled as diseased

• Without evidence that increasing substance X will lower disease risk, substance X becomes FDA approved

Better evidence

• Study on ~50,000 individuals

• 10 year follow-up

• Controlled for risk factors

• “the overall relative risk of major coronary disease with taking substance X was 0.56 (95 percent confidence interval, 0.40 to 0.80) (NEJM, 1991)”

• Longer follow-up confirms effects

Even better evidence;Systematic Reviews/Meta-

analyses• > 32 epidemiological studies

• “extensive and consistent observational evidence that substance X reduced the risk for CHD about 35%”

• Substance X for individuals with heart disease leads to a larger increase in life-expectancy than treatment for mild or moderate hypertension

15

Recommendations

• The American Heart Association,

• the American College of Physicians

• Managed care organizations considered prescription of substance X a criterion for good medical practice

0 1Belief that increasing protein X will lead to reduced CHD risk

Reliable Evidence

1: Fam Pract. 1999 Aug;16(4):335-4

Translation is working!

Randomized controlled trials on Estrogen-Progestin (JAMA 2002)

• Estrogen-Progestin increases the risk for CHD by 29% (95% confidence interval: 1.02-1.63)

• Premature translation caused ten of thousands of premature deaths among post-menopausal women

0 1Belief that increasing protein X will lead to reduced CHD risk

Substance X for caries prevention

• Biological plausibility• FDA approved: “ Substance X … to reduce

tooth decay.”1

• No epidemiological evidence of effectiveness• No randomized controlled trials in adults• Use of substance X under typical conditions

was not associated with reduced caries risk (relative risk, 1.01; 95% confidence interval, 0.85-1.20; p-value, 0.93)

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=872.6390


An important criterion for assessing causality

16

Quotes from Science Regarding the Size of the Associations

Richard Doll, one of the founders of epidemiology, said “No single epidemiological study is persuasive by itself unless the lower limit of its 95% confidence level falls above a threefold (200%) increased risk.”

Trichopoulos, past chair of epidemiology at Harvard, opts “for a fourfold (300%) increase at the lower limit.

Science, 1995, p.164

Quotes from Science Regarding the Size of the Associations

Marcia Angell, former editor of the New England Journal of Medicine, reported ” As a general rule of thumb we are looking for a relative risk of 3 or more (>200% increased risk) [before accepting a paper for publication].”

Robert Temple, Director of the Food and Drug Administration, stated: “My basic rule is if the relative risk isn't at least 3 or 4 (a 200% or 300% increased risk), forget it.”



• Odds ratio > 1 Harmful effects

• Odds ratio < 1 Protective effects

• Odds ratio = 1 No association

EBM: when to be impressed?

• Cohort study RR > 3

• Case-control study OR > 4

• RCT ?


Case ReportCase Series

Biological PlausibilityAnimal StudiesBench Research

ConcurrentControls

DarkAges

InductiveInference

DeductiveInference

Case-Series: Level 4

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Dead

+ -

Bone Marrow

Transplant

+ 21 (56%) 16

- - (100%) -

Aplastic Anemia & Bone Marrow Transplantation

N. Engl. J. Med. 1975 p.832

Donnall Thomas

Weston Price 1870 –1948

New Life in Glands – Dr. Brinkley’s Patients here show improvement –Many victims of incurable diseases are cures –twelve hundred operations are all successful

- Los Angeles Times, April 9, 1922

Quoted from Charlatan, Pope Bro

18

Periodontally Accelerated Osteogenic Orthodontics

(PAOO) Wilcko procedure

Wilckodontics

Patented

Pre-Treatment maxillary & Mandibular arch

41-year old man3-mm overjetSevere overbiteAverage Profile

CompendiumMay 2008Vol. 29, No.4pp. 200-207

1-year post op

Biological Plausibility

19

The treatment of periodontitis

• Complete removal of plaque and calculus in pockets deeper than 5 mm is difficult (true)

• Plaque and calculus cause periodontitis (true?)

• Therefore, surgical periodontal treatments are required in treating deep pockets to remove the bacterial plaque (true/false)

• Evidence: extracted teeth

Waerhaug, 1978

•“The judicious removal of dental foci of infection as a preventive measure will go a far way toward relief of suffering and prolongation of life” (E. C. Rosenow, 1936).

Biological Plausibility

Deductive Reasoning

Trephination

“Trephination in the Western Hemisphere is at least as old as Indian civilization. This surgical form is used to secure drainage and alleviate pain when exudates in the cancellous bone is dammed up behind the cortical plate. The tremendous pressure leads to excruciating pain of acute apical periodontitis”…”Scoring the bone with a heavy punch” speeds relief and healing”.

Endodontics. Ingle and Beveridge, 1976

20

Trephination

• Common sense– Trephination lowers the pressure build-up

(TRUE)

– Pressure build-up causes pain (TRUE)

– Trephinations lowers pain

Trephination

“This is a limited-use procedure and is fraught with peril and potential negative complications. … Literature pertaining to this procedure is very limited and consists primarily of case reports, opinions, and clinical experiences”.

Endodontics. Ingle and Bakland, 2002

Cooper et al. N Engl J Med 2011; 364:1493-1502

Decompressive Craniectomy

Cooper et al. N Engl J Med 2011; 364:1493-1502

Bench Research

21

Ferrule: 360 degree metal collar of the crown surrounding the parallel walls of the dentin extending coronal to the shoulder of the preparation

Taken from 3M ESPE

Systematic review J Adhes Dent 2007; 9 Suppl 1: 77-106

“Microleakage tests or quantitative marginal analysis should be abandoned”. Laboratory tests should be validated with respect to in vivo clinical performance

Dr. Bill Bowen

22

Boston terrier x dachshund

French bulldog x dachshund

English bulldog x German shepherd

English bulldog x bassethound

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