International CRD Workshop 2017 in Haiphong

Clinical Research Designing

-to Get Concrete Knowledge for World-level
Clinical Studies-

Takuo KUBOKI
Chair and Professor
Department of Oral Rehabilitation and Regenerative Medicine,
Okayama University Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences

August 3rd, 2017 in Haiphong University of Medicine and Pharmacy

 Reasons Why an Ineffective
Treatment Seems Effective
Sampling Intervention Outcome Measurement

Diagnostic good
Tools
& bad
Therapy
Unreported Unreported Drop-out
drop-out Drop-out drop-out

1) Unintended 1) Unintended 1) Unintended investigator’s

selection bias of practitioner’s bias on measurement
the subjects bias on treatment 2) Time effect
2) Too small 2) Placebo effect 3) Too small sample size
sample size 3) No control (=too much chance)
 Annual event of the post-
graduate course
 Collaboration with
International EBM working
group, iHope International
and CASP Japan
There are Some EBM Textbook, but
without any Activities of Research…
 Textbook (for Undergraduate
Medical/Dental Students in the US)
It is very useful, but might be a
little difficult for beginners.

6
 Today’s Target of This Seminar:
medical/dental version of this textbook
 To deliver an
internationally
recognized clinical
evidence (article) to the
world.
 It is very important for
us to learn a global
standard for clinical
research.
Seven Taboos of Clinical Research
 Considering study design after collecting the data
 Unclear and non-specific research question (RQ)
 Sampling is not systematic; no criteria of the sampling
method, inclusion and exclusion criteria
 No establishment of the major outcome, no considering the
properties of variables
 No evaluation of the reliability and validity of measurements
 No pre-consideration of statistical analysis, sample size,
power analysis and effect size
 Interpretation of the results: clinically meaningful difference
rather than statistical significance

Syun-ichi Fukuhara (2008)

 Research Protocol
① establish a conceptual model （ Null hypothesis ）
② determin a research design and a research team
③ select predictors, outcome(s) and check the
measurement reliability and validity
④ sample size estimation
⑤ sampling procedure
⑥ baseline measurement
⑦ random assignment
⑧ perform intervention
⑨ follow-up the subjects (compliance check)
⑩ measurement the outcome variables and data
analysis
 FINER criteria to be fulfilled
the excellent research theme
 Feasible （ possibility to achievement ）
 Interesting （ true interesting ）
 Novel （ originality ）
 Confirm or deny the previous findings
 Develop the previous findings
 Add the new findings
 Ethical （ morality ）
 Relevant （ necessity ）
 Contribute the scientific progress
 Contribute the clinical medicine and health policy
 Contribute the future research development
Proper usage of PECO and PICO
Identification/verification of the risk factor
→ Observational study:
PECO （ exposure ）
 Ex) Whether harm/gain trend to be occurred in subjects
with containing with factor A (without factor A or compared
to factor B)?
 Evaluation of treatment/prevention efficacy
→ Intervention study: PICO （ intervention ）
 Ex) Whether harm/gain trend to be occurred in subjects
with intervening with factor A (no intervening factor A or
compared to factor B)?
Conceptualization of Clinical Decision
Invasion Tx. term
Risk factor
Cost
Oral hygiene Post Tx trouble
Parafunction
Outcome
（ probability ） Effect Expected
Treatment Satisfaction （ benefit ） value
Lifestyle options 5 years after Tx

Implant Success (0.90 ） a

Mandibular supported x
denture Failure （ 0.10 ） b
unilateral
free-end Removable Success (0.33 ） c
partial ？
edentulous denture Failure （ 0.67 ） d
case
No Success (0.54 ） e
treatment ？
Failure 0.46 ） f
General disease
Genetic susceptibility
Aging Psychological Survival rate of
relief denture itself
Psychosocial Adjacent tooth protection Function/discomfort
status （ missing blockade effect ）
Esthetics
 Research Aim and Design ?
 To verify the cause (risk) of disease
 Case-control study
 Cohort study
 To detect diagnostic ability
 Relation between indicator and disease prevalence
 Verification of diagnostic accuracy (Sensitivity,
Specificity)
 To elucidate utility of diagnosis/treatment
 Cost-effectiveness analysis
 To clarify treatment efficacy/effectiveness
 Randomized blinded Clinical Trial ( ＲＢＣＴ )
 Cohort study
Selection of a Good Design will be Most Important!
Assignment Observation Inter- Observation
（ baseline ） vention （ Outcome ）

Experi- Inter-
ment vention Observation

Subjects
Pre-experimental
design
Control Observation
△
Experi- Inter-
Subjects ment Observation vention Observation

Experi- Inter-

○
Observation Observation
Quasi- ment vention
experimental Subjects
design Control Observation Observation

Experi- Inter-
ment vention Observation
Random
Subjects Assign-
ment
Control Observation
Experimental
design Experi-
ment Observation Inter-
vention
Observation ◎
Random
Assign-
Subjects ment Control Observation Placebo Observation

Control Observation Observation

14
SAMPLING
 Sampling Design for Recruiting Study
Subjects from the Accessible Population

Consecutive sample
Often the best option
Convenience
sample
Simple random
sample Judgmental
sample

Stratified random Cluster random

sample sample
 Structure of Clinical Study
Truth in the infer Truth in infer Findings in the
universe the study study

Research Study plan Actual

Random & Random &
question study
systematic systematic
error error

Target Intended Actual subjects

population sample
design implement
Phenomena Intended Actual
of interest variables measurements
External Internal
Validity Validity
Hulley and Cummings (1988)
Sampling Methods and Its Description
1) Design inclusion criteria that specify the age,
sex, and clinical characteristics of appropriate
subjects.

2) Design inclusion criteria that specify the time

frame and the geographic characteristics of a
suitable accessible population.

3) Design a parsimonious set of exclusion criteria

that eliminate unwanted individuals.
 Basis of Sampling Procedure
1. Use the raw sample that God sends to you. Don’t manipulate
the naïve sample to be the convenient sample.
Use a consecutive or probability sample whenever practical.
Apply consecutive sampling in clinical studies, and con-
secutive or a random sampling in epidemiological studies ．
2. Better handle an entire population rather than a “two extreme”
group sampling to select super-abnormal and super-normal
subjects from a population, except for case-control study.
3. A naïve sample would be better than a matching sample (less
manipulation would be better, preventing bias).
4. Compare the target sample and the actual (analyzed) sample
5. Improve the response rate in the target sample.
6. Record and Describe the specific reason if exclude the
sample.
Level Evidence-based Medical level of Evidence
(Therapy/Prevention, Aetiology/Harm)
1a Systematic Review (with homogeneity) of RCTs
1b Individual RCT (with narrow Confidence Interval)
1c all patients died before the Rx became available, but some now
survive on it; or when some patients died before the Rx became
available, but none now die on it.
2a SR (with homogeneity) of cohort studies
2b Individual cohort study (including low quality RCT; e.g., <80%
follow-up)
2c "Outcomes" Research; Ecological studies
3a SR (with homogeneity*) of case-control studies
3b Individual Case-Control Study
4 Case-series (and poor quality cohort and case-control studies)
5 Expert opinion without explicit critical appraisal, or based on
physiology, bench research or "first principles”
Level Evidence-based Medical level of Evidence (Prognosis)
1a Systematic Review (with homogeneity) of inception cohort studies
1b Individual inception cohort study with > 80% follow-up
1c all patients died before the Rx became available, but some now
survive on it; or when some patients died before the Rx became
available, but none now die on it.
2a SR (with homogeneity) of either retrospective cohort studies or
untreated control groups in RCTs
2b Retrospective cohort study or follow-up of untreated control
patients in an RCT
2c "Outcomes" Research
3a
3b
4 Case-series (and poor quality prognostic cohort studies)
5 Expert opinion without explicit critical appraisal, or based on
physiology, bench research or "first principles”
 Validation of Sampling
Procedure
 Sample size
 Sample Size Estimation
 Sampling bias
 Sampling Bias Estimation
 Assessment of homogeneity between Intended Sample and
Actual sample
 Matching procedure and its validation
 Case-Control study
 Random assignment and validation
 Randomized Blinded Clinical Trials
 Difference between Intended and
Actual Samples
Cause 1 ： Effect of random sampling error
Solution １： Increase the number of subjects
Solution ２： Consider stratified sampling to enlarge specified subgroups

Cause 2 ： Effect of systematic sampling error (bias)

i.e.,) Non-response bias

Failure to make contact

Subject refuses to participate
Solution １： Provide written orientation in advance, and discuss
potential source of anxiety
Solution ２： Consider incentives such as transportation,
reimbursement, and providing test results after the analysis
Solution ３： Consider special steps to inquire about the non-
respondents beforehand (call, visit their house etc. )

Incorrect coping plan ：

△Before the study, pretest the sampling method
×During the study, control the quality of the recruitment process
Measurement

Outcome variable
Predictor variable
 Basis of Measurement
 Outcome and predictor variables must
not measure the identical contents.
 Un-measurable predictors in research
(i.e., genetic factor ） can be canceled in
a RCT design.
 Non-randomized observational studies
(i.e., Cohort study) can not ignore the
effect of un-measurable predictors
(confounders) even if applying multiple
regression analysis.
 Soft and Hard Variables
Characteristics of the Individual

Symptom Amplification Personality, Values, Preferences

Motivation

Biological and General Overall

Symptom Functional
Physiological Health Quality of
Variables Status Status
Perception Life

Social and
Psychological Supports Economic Social and Psychological Supports
Supports

Nonmedical
Characteristics of the Environment
Factors
Evaluation of Reliability and Validity in
the Measurement
 Generally, measurement reliabiliy and validity should be
checked by a preliminary study and/or other precedent
study, even in clinical examination protocol and self-
administered questionnaire.
 The preliminary study sample should be equivalent to
the actual study.
 Test-retest consistency
 Internal consistency
 Intra- and inter-examiner reliability (kappa, weighted
kappa, ICC: >0.6 acceptable, >0.8 excellent)
 Validity (Specificity, Sensitivity, PPV, NPV)
 Criterion-related validity, content validity

 responsiveness
 Precision and Accuracy

Poor precision Poor precision

Good accuracy Poor accuracy
Good precision Good precision
Poor accuracy Good accuracy
 How to Improve the Reliability
of Measurement Process
1. Standardizing the measurement methods with an
operations manual
（ Making a movie including the examiner’s instructions,
for clinical examination. Brush-up the diagnostic
criteria ）
2. Training and certifying the observer
（ Calibration ）
3. Refining the instrument
（ Questionnaire ， device, clinical examination,
diagnostic criteria)
4. Automating the instrument
5. Repetitive measurement （ data reduction ）
 To Increase the Measurement
Accuracy
1 ． Blind to the research aim, anonymous survey
（ i.e., apply anonymous survey to concel the study aim for
the subjects)
2 ． Blind of therapeutic regimen, separate the physician and
observer
（ Patients is unaware of treatment content and aim,
examiner is unaware of patients’ receiving treatment ）
3. Calibration of equipment, examiner, diagnostic criteria
（ Training of examiner, brush-up of questionnaire and
clinical diagnostic protocol ）
 Dentocult system CRT system

SM

0 1 2 3 1 2 3 4

LB

1 2 3 4 1 2 3 4
 Process of saliva collection
Subjects: 35 students (male/female: 19/16,
mean age 25.1 yrs.)
1st Chewing paraffin wax (2 minutes)
collection Saliva collection (1 minutes)
7 minutes Incubation
2nd Chewing paraffin wax (2 minutes) (37℃)
collection Saliva collection (1 minutes)
7 minutes Dct SM (48h)
CHX mouth rinse (30 sampling
second) Dct LB (72h)
5 minutes later, distilled water
mouth rinse (30 second)
3rd CRT SM (48h)
Chewing paraffin wax (2 minutes)
collection
Saliva collection (1 minutes)
CRT LB (48h)
7 minutes
4th Chewing paraffin wax (2 minutes)
collection Saliva collection (1 minutes)
 Intra-examiner reliability
1st 2nd
1st collecting
assessment assessment
saliva

Examiner Examiner
2nd collecting Dct SM
saliva #1 #1
Dct LB
CHX CRT SM
CRT LB Examiner Examiner
3 collecting
rd
#2 #2
saliva

4th collecting ⋯ ⋯
saliva
⋯ ⋯
＊ Combinations are 5 patterns
CHX : chlorhexidine because of 5 examiners
 Intra-examiner reliability
1st 2nd
assessment assessment
1st collecting Examiner Examiner
saliva #1 #1

Examiner Examiner
2 collecting
nd
Dct SM #2 #2
saliva Dct LB
CHX CRT SM Examiner Examiner
CRT LB #3 #3
3rd collecting
saliva
Examiner Examiner
#4 #4
4th collecting
saliva Examiner Examiner
#5 #5

CHX : chlorhexidine ＊ Combinations are 5 patterns

because of 5 examiners
 Weighted-kappa value
Examiner 1
(2nd measurement)
score
1 2 3 4
Examiner Examiner 2 Weight
0 1 4 9 1
(1st measurement)

1
Score is matched 0
Examiner 1

2
1 0 1 4
Score is out of 1 point 1
3
4 1 0 1
Score is out of 2 point 4
4
9 4 1 0
Score is out of 3 point 9
score
 Weighted Kappa Value

Σwf0 f 0 = The number of term

Kw ＝1- f c = Coincidental match of term
Σwfc w = weighting coefficient

Reliability Parameters
More than 0.8 : Excellent
matching
More than 0.6 : Fair matching
0.4 〜 0.6 : Moderate
matching
Less than 0.4 : Unreliable
matching
(Landis and Koch, 1977)
 Intra-examiner Reliability
1

0.86
0.80
0.8
Weighted kappa value

0.71

0.6
0.54

0.4

0
SM LB SM LB
Dentocult CRT
 Inter-examiner reliability
1st collecting
saliva 1st 2nd
assessment assessment
2nd collecting
saliva Dct SM Examiner Examiner
Dct LB #1 #2
CHX
CRT SM
3rd collecting CRT LB
saliva Examiner Examiner
#2 #3

4th collecting
saliva ⋯ ⋯
⋯ ⋯
＊ Combinations are 10 patterns
CHX : chlorhexidine because of 5 examiners
 Inter-examiner reliability
1st 2nd
1st collecting assessment assessment
saliva
Examiner Examiner
#1 #1
2nd collecting
saliva Dct SM Examiner Examiner
Dct LB #2 #2
CHX
CRT SM
3rd collecting CRT LB Examiner Examiner
saliva #3 #3

Examiner Examiner
4 collecting
th
#4 #4
saliva
Examiner Examiner
#5 #5
CHX : chlorhexidine ＊ Combinations are 10 patterns
because of 5 examiners
 Inter-examiner Reliability
1
Weighted kappa value

0.75
0.8
0.72

0.6 0.57

0.44
0.4

0
SM LB SM LB
Dentocult CRT
 Intervention/Exposure
 Technical appraisal
 Need to check the compliance
 Medication
 Home-care, self-care protocol
 Blind (to prevent Hawthorne effect)
 Cross-over design （ in case considerable
individual variability)
 Control: Placebo group in experimental
researches. Naturally-generated multiple
treatment groups in observational
researches.
Research on the treatment
Efficacy or Effectiveness
Conceptualization of Clinical Decision
Risk factor Invasion Tx. term
Cost
Oral hygiene Post Tx trouble
Parafunction Outcome Effect
（ probability ） （ benefit ） Expected
Treatment Satisfaction （ Individual value
Lifestyle option 5 years after Tx philosophy ）

Implant Success (0.90 ） a

Mandibular supported x
denture Failure （ 0.10 ） b
unilateral
free-end Removable Success (0.33 ） c
partial ？
edentulous denture Failure （ 0.67 ） d
case
No Success (0.54 ） e
treatment ？
Failure 0.46 ） f
General disease
Inheritance
Aging Psychological Survival rate of
relief denture itself
Psychosoci Adjacent tooth protection Function/discomfort
al status （ missing blockade effect ）
Esthetics
 Comparison of QOL level among implant
denture, removable partial denture, and no
restoration patients with distal extension type
unilateral mandibular edentulism
Pooling
for age (ID patient age
ID group RPD group NR group ± 5 year) and sex

intended n=14 n=59 n=31

sample mean age : 56.6± 11.7yrs mean age : 58.1± 1.39yrs mean age : 57.4± 1.81yrs
male/female : 6/8 male/female : 21/38 male/female : 10/21
questionnaire
was sent to
Data Reduction and Statistical Analysis each subject
questionnaire n=12 n=46 n=25
respondents return rate: return rate: return rate:
85.7% 78.0% 81.0%
Matching
for age, sex and
missing-tooth units
actual n=12 n=24 n=24
mean age : 58.9± 9.6yrs mean age : 58.7± 9.7yrs mean age : 58.8± 1.95yrs
sample male/female : 6/6 male/female : 11/13 male/female : 8/16
missing : 2.58± 0.67teeth missing : 2.58± 4.91teeth

Research design: case-control design

 Compare the potential confounding
factors among actual 3-groups
final assessment of matching process
ID group RPD group NR group
Variable n=12 n=24 n=24 p-value
male/female 6(50.0)/6(50.0) 13(54.2)/11(45.8) 16(66.7)/8(33.3) 0.55 ＊

mean age (years) 58.9±9.59 58.8±9.57 58.7±9.74 0.99†

missing unit (teeth) 2.58±0.67 2.79±0.88 2.29±0.55 0.06†

functional duration (months) 37.2±6.32 20.8±4.91 — 0.06‡

occupation
white-collar 5(41.7) 5(20.8) 4(16.7)
blue-collar 2(16.6) 7(29.2) 7(29.2)
unemployed 5(41.7) 12(50.0) 13(54.1) 0.55 ＊

marital status
married/unmarried 12(100.0)/0(0.0) 22(91.7)/2(8.3) 22(91.7)/2(8.3) —

parcent in parenthesis
＊ : Chi-squared test
†: One-way Factorical ANOVA
‡: unpaired t-test
Comparison of QOL score among groups
ID group
＊＊ ＊＊＊ ＊＊ RPD group
＊＊ ＊＊＊ ＊＊ NR group
(%)
100

90

80

70

60

50

40

30

20

10 ＊＊ ＊＊＊

0
functional physical pain anxiety general mood general health psychological Dental treatment
limitation /discomfort dtsability
Oral Condition Daily Activity
 Validation of sample size

Sample size Required case

Case: Control
applied in this study sample size

ID group : RPD group 12 ： 24 10

ID group : NR group 12 ： 24 12
RPD group : NR group 24 ： 24 >1532 ＊

＊： this results support experimental design is as unfeasible, and is

also the proof of no group difference among these groups
 Weak points in this study

 No random assignment (difficult to solve

since involving the surgical intervention)
 Outcomes have not been observed at
baseline (impossible to verify the causal
relationship: Quasi-experimental
design)
Natural course: musculoskeletal pain
change with time regardless of the
treatment

No treatment
Pain intensity

Placebo

Active treatment

First visit Time course

(Howard L. Fields : Pain, 1987)

 Randomized Blinded Clinical Trial
Experimental Study

Population
Disease No disease
Intervention (non-
(alleviation)
group alleviation)

Random assignment
Target sample

Placebo group Disease

No disease
(control group) (non- (alleviation)
alleviation)
A Randomized Controlled Trial on Initial
Treatments for Anterior Disk
Displacement without Reduction
Diagnosed ADDwor (89 patients)

Inclusion and Exclusion Criteria (69 patients)

No treatment Pharmacology Tx. Physical Tx.

21 patients 23 patients 25 patients

Intended
male / female : 3/18 male / female : 2/21 male / female : 2/23
sample mean age : 36.3+/-17.3 mean age : 33.3+/-13.3 mean age : 32.7+/-15.8

Drop-out 2 persons 2 persons 4 persons

19 patients 21 patients 21 patients

Actual
male / female : 3/16 male / female : 2/19 male / female : 2/19
sample mean age : 35.4+/-16.5 mean age : 33.1+/-13.7 mean age : 33.3+/-17.1
 Baseline Comparison between Intended
and Actual Sample
N.S. N.S. N.S.
N.S.
60 N.S. 90 N.S. 9 50
80 8 45
50
70 7 40

(score)
(yrs.)

(mm)
(score)

40 60 6 35
30
50 5

Final sample
30

Target sample
25
Final sample

Final sample
Target sample

Target sample
Final sample

40
Target sample

N.S. 4
20
20 30 3
15
20 2
10 10
10 1 5
0 0 0 0Painless
Age Pain at Pain during Daily activity Maximum Assisted
rest function limitation jaw opening dimension
 Baseline Comparison after Assignment N.S.
N.S. N.S. N.S.
60 90 12 50 N.S.
N.S.
80
50 10
70 40

(mm)
40 60 8

(score)
(yrs.)

30
(mm)

50
30 6
N.S
40
. 20
Pharmaco. Tx
Physical Tx
Pharmaco. Tx
Physical Tx

20 30 4

Pharmaco. Tx

Pharmaco. Tx
Physical Tx

Physical Tx
Control
Control

Control

Control
20 10
10 2
10

0 0 0 0
Age Pain at Pain during Daily activity Painles MaximumAssisted
rest function limitation s
Jaw opening dimension

N.S. : p>0.05 One way factorial ANOVA

 Pain Intensity Change during
Mastication in ADDwoR Patients
Start of
treatment
80 Physical Tx. Main effects :
For group difference : p=0.81
Pharmaco. Tx. For time course : p<0.05
Interaction : p=0.17
No Tx. Two-way repeated measures ANOVA
60
VAS score (Score)

40

20

0
Initial visit 0w 2w 4w 8w (Time)
DAL Score Change among the Groups
Daily Activity Limitation Scores

8 ＊
＊ Physical Tx.
7 Pharmaco Tx.
No Tx.
DAL score (Score)

6
5
4
3
2
1
0
First Second Final
observation observation observation

＊ : p≦0.05 Kruskal-Wallis rank test

 Cost-Effectiveness Ratio
Expenses required for certain
amount of improvement

Total cost for the treatment (Yen)

=
Degree of alleviation by the treatment (mm, Score)
 Result of Cost-Effectiveness Ratio
(Yen) ＊
40000 Physical Tx ＊ ＊
＊
Pharmaco Tx
Control ＊
30000
＊ ＊
＊ ＊ ＊
＊ ＊

20000

10000

0
Painless Maximum Assisted DAL score Pain at Pain during
Mouth Mouth Mouth rest mastication
opening opening opening
＊ : p<0.05 (One-way Factorial ANOVA, Bonferroni test)
 Weak Points of the Study
 Sample size is slightly lower than initially
planed.
 Blind fashion would be difficult due to the
treatment nature.
 No monitoring the compliance in physical
and pharmacological treatments.
 Multicenter sampling would be better to
generalize the findings.
 It was so lucky that a similar study performed
in the US indicated the same finding.
 Current solution of clinical epidemiology
Need to adjust the baseline data of each
Intergroup study experimental group (Random
assignment ， Matching)

What baseline data was forced to be

adjusted yields the data that dose not
reflect the natural clinical situation, and
reduces external validity.

Cohort study
+ multivariate analysis (Cox proportional hazard model)

Increase the sampling flexibility and can

obtain the data what natural clinical Adjust confounding of
situation was reflected predictor
Put the element of group comparison as Identify independent risk
one of predictor into multivariate analysis factor
Level Evidence-based Medical level of Evidence (Prognosis)
1a Systematic Review (with homogeneity) of inception cohort studies
1b Individual inception cohort study with > 80% follow-up
1c all patients died before the Rx became available, but some now
survive on it; or when some patients died before the Rx became
available, but none now die on it.
2a SR (with homogeneity) of either retrospective cohort studies or
untreated control groups in RCTs
2b Retrospective cohort study or follow-up of untreated control
patients in an RCT
2c "Outcomes" Research
3a
3b
4 Case-series (and poor quality prognostic cohort studies)
5 Expert opinion without explicit critical appraisal, or based on
physiology, bench research or "first principles”
Clinical epidemiological study of the comparison
between resin core and metal core
cumulative survival rate (%) sample (number)
Observati
Reference on period
(year) Resin core Metal core Resin core Metal core (yrs.)

Creugers NH
et al (2005) 96±2 96±2 150 127 5
Jung RE et
al (2007) 93.5 90.2 31 41 8.6
Coronal dentin Coronal dentin Coronal dentin
Fokkinga WA Coronal dentin (+)/(-): (+)/(-): (+)/(-):
et al (2008) (+)/(-): 84/85 17
71/84 57/93 54/64
1. Due to short observation period, observation was potentially aborted
before trouble of build-up material was occurred
2. Due to low sample size (=lack of statistical power), no significant
difference was potentially detected between both treatment
3. Due to variety of cementation, it’s doubtful whether the results was
referred from the difference of build-up material
 Core chart
(original medical record regarding build-up procedure)
Remaining coronal dentin
4-grade assessment in core chart
Root stump, remaining 1/5, 2/5, 3/5
In this study, we categorized
Root stump →Coronal dentin (-)
Remaining 1/5, 2/5, 3/5
→Coronal dentin (+)

Core margin
Core margin Positional
relation
between
Crown margin these
margins
 Flow of survey
Sampling period Observation period
April 1st 1988 December 31st 1991 November 16th
Build-up procedure 2004
• Dentist of our clinic (n=46) Check the omission of chart
(clinical experience (<5 years/ >5 years: 6/40) (patient ID, patient name ， build-
up material)
• Decision of build-up material was depend
on each dentist

Core chart Medical record

Cor Check
e ch
art against one
another

One examiner performed prior all procedure

All procedures had been performed twice, and check the
adequacy of data collection
 Assessment criteria of survive/failure
Start of observation Final tracking date
Functional period
April 1988 ～ December 1991 November 16th
Describe in core chart 2004
Date of receiving build-up
Tx. Survive
Failure
For some reasons,
1. Drop-out build-up
material
2. Remove build-up
material
3. Tooth extraction

Date of final visit

Survive Disable to tracking
1. Disable to visit due to
moving, death, etc
2. Before final tracking
 Subjects
Inclusion criteria
Consecutive series of patients who received build-up treatment at Fix Prosthodontic
clinic, Okayama University dental hospital between April 1988 and December 1991.
The patients whose core chart was stored.

Resin core Total Metal core

804 patients 1024 patients 220 patients
(1767 teeth) （ 2274 teeth ） (407 teeth)

Exclusion criteria
・ Omission the information on core chart (patients ID, patients name)
・ Mismatch the contents between core chart and medical record
10 23
patients patients

Resin core Final subjects Metal core

794 patients 991 patients 197 patients
(1752 teeth) （ 2124 teeth ） (372 teeth)
 A 15-years cumulative survival rate of
resin core and metal core
Kaplan-Meier Analysis
100
cumulative survival rate (%)

80
78.7%

60
55.4%
40

20 Resin core (n=1752)

Metal core (n=372) P ＜ .0001
0
0 5 10 15
Follow-up period (years)
Log rank test
 Considering Internal Validity
Does Metal core really have a poor result?

 Multiple comparison among groups, baseline

data should be matched in detail.
 Core trouble such as caries and tooth
extraction can be influenced by the patients’
plaque control ability.
 In case of large tooth defect, metal core
trended to be chosed. Severity of coronal
tooth defect would have a major impact on
the results.
 Number of remaining teeth between
metal and resin core
It seemed to be no large group difference in risk of tooth
loss due to other reasons
30
Number of remaining teeth

25
20

15
10
Resin core (n=1752)
5
Metal core (n=372)
0
0 5 10 15
Follow-up period (years)
 Cumulative survival rate from the
remaining coronal dentin
Is confounding factor the choose metal core or
remaining coronal dentin?
100
cumulative survival rate (%)

80

60

40

20 Presence of coronal dentin (n=764)

Absence of coronal dentin (n=289) P ＜ .0001
0
0 5 10 15
Follow-up period (years)
Ｌ og rank test
 Risk factors and these detail for
failure of core restoration
（ check of statistical power ）

Number of teeth
Build-up material (metal core/resin core) 187 / 866
Gender （ male/female ） 272 / 781
Coronal dentin （ absent/present ） 289 / 764
Core margin （ below crown
191 / 862
location margin/normal ）
Root canal from （ straight/funnel ） 906 / 147
Tooth location （ maxilla/mandible ） 620 / 433
Tooth type （ anterior/posterior ） 353 / 700
DMFT （ mean ± S.D. ） 20.0±5.6
 Risk factor analysis for prognosis of Core
Restoration
Cox’s proportional hazard model
Relative risk 95% Cl P-value

Gender （ male/female ） 2.433 [0.282-0.598] ＜ .0001

Coronal dentin （ absent/present ） 1.828 [1.192-2.806] .0057
Type of core （ cast metal/resin ） 1.729 [1.096-2.730] .0186
Age at installation 1.017 [1.001-1.034] .0380
Tooth location （ mandible/maxilla ）1.206 [0.824-1.765] .3358
Core margin location (below crown margin
/normal) 1.224 [0.762-1.966] .4041
Tooth type （ anterior/posterior ）1.068 [0.714-1.598] .7486
DMFT 1.003 [0.971-1.036] .8507
Root canal form （ straight/funnel ） 0.958 [0.572-1.604] .8712
 Meaningful Difference?
 Standardized Effect Size:
 St. ES = Effect size before and after
treatment /variability of baseline data (SD)
 St. ES = <0.2 low
 St. ES = 0.2 < 0.5 acceptable
range
 St. ES = 0.5 < 0.8 high
 St. ES = 0.8< extremely high
 Impact-based Interpretation
 Meaningful difference for the patients?
Fusion of clinical epidemiological
research and basic research
Interaction between Clinical specialist course and
General course

Basic Clinical
Research Research
Basic Clinical
Reseach Research

Epidemiology
Epidemiology

Fusion of biological aspect and clinical epidemiological aspect

Strategic research with specific purpose
 Let’s try it anyway !!!
Collaborators of this presentation

 Nawachi K.  Sonoyama  Kimura A.

 Nawachi K. W.  Mine A.
 Uehara J.  Arakawa H.
 Matsuka Y.
 Kojima S.  Minakuchi H.
 Yatani H.
 Mizushima T.  Maekawa K.
 Okamoto S.  Yamashita A.
 Kanyama M.
 Suzuki H.  Hara ES
 Terada S.
 Hikasa  Glenn T.
Okayama University Graduate School ofT.
Med., Dent. and Pharmaceutical Sciences
Clark*
Department of Oral Rehabilitation and Regenerative Medicine
*University of Southern California, School of Dentistry