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2008JICA training course (2008.12.8) at SCIPH1
JICA: Support for the Establishment of a Neonatal Screening System for
Middle East Region, FY2008
(2008.12.08) Sapporo City Institute of Public Health
Neonatal Screening Program - Establishment, Evaluation, and Follow-up Survey -
HARADA Shohei, M.D., Ph.D.
Head of the Division of Clinical Practice Policy,
Department of Health Policy,
National Research Institute for Child Health and Development
Neonatal Screening Research and Development Center of
Japan Public Health Association (JPHA)
2008JICA training course (2008.12.8) at SCIPH2
Setagaya
National Center for Child Health and Development
Okura, Setagaya-ku, Tokyo
Laboratory
Hospital
National Center for Child Health and Development
Major problems� Incidence of pediatric intractable
diseases per year: 20,000� Number of deaths during the perinatal
period per year: approximately 5,000� Number of accidental deaths in minors
per year: 1,400
Role�Role of medical policy
• Promotion of clinical research
• Correction of medical disparities (training of personnel, information transmission)
• Policy recommendation
U.S.National Institute of Child Health and Human Development (NICHD)
U.K.National
Collaborating Centre for Women and Children’s
Health (NCCWCH)
日赤病院
General Perinatal
Maternal and Child Medical
Center
Overseas network
Role of National Center for Child Health and Development
LaosNational Maternal and Child Health Center (NMCHC)
CanadaInstitute of Human
Development, Child and Youth Health (IHDCYH)
FranceCentre national de la recherche scientifique (CNRS)
Others
National/public
hospitals
University hospitals
Medical device
companies
Research institutions
incl. universities
JaCHRI
Japan Pediatric Society
Japan Society of Obstetrics and Gynecology
Network with prefectural and city governments
Medical cluster
Patient groupsPatient support
groups
Pharmaceutical companies
Law� Maternal and Child
Health Law� Mother's body
protection law
Domestic network
JICA Training Course2008JICA training course (2008.12.8) at SCIPH4
Correction of Disparities between Child Health and Development and the Center for Advanced Pioneering Medical Practice
Correction of Disparities between Child Health and Development and the Center for Advanced Pioneering Medical Practice
National Center for Child Health and Development
Standardization of infertility
and habitual abortion/obstetrical medicine
Central institution: JaCHRI
Central institution: General Perinatal Maternal and Child Medical Center
Standardizatio
n of
evidence-based
pediatric m
edicine
Network for pediatric clinical studies/trialsNetwork for
pediatric medicine
Promotion of obstetrical emergency medical services
Safe and smooth pediatric medical care
(pedi atr i c e
mergency medi cal c
are, pedi atr i c
ment al
prac
ti ce, et c. )
Fetal therapy/medical transplantation/gene and
cell remedies/regenerative m
edicine
Establishing a center for advanced pioneering medicine
Network for perinatal medicine
Network for obstetrical clinical
studies
2008JICA training course (2008.12.8) at SCIPH5
Hospital Laboratory
Domestic research
institutionsOverseas research
institutions
Academic societies Company
Clinical research group
Coordinating committee for research/project
Research ProjectPromoting Committee・Stem cell
・Gene therapy
Ethical committeeEthical review board
for research of human ES cell
Ethical review board for gene therapy Obtainment of public
research feeRelocation of researchers
LaboratoryPromoting system for research projects
2008JICA training course (2008.12.8) at SCIPH6
System of Healthcare Policy
Conventional Plan Do Achievement
unknown
Plan Do
Check (Evaluation/
Monitoring)
Action (for
improvement)
Current healthcare policy
2008JICA training course (2008.12.8) at SCIPH7
Surveillance LoopMonitoring System
ScreeningScreening
Event
Action
For quality For quality
improvementimprovement
Accumulation/Accumulation/
registrationregistration
Data
Information
Information Information
supplysupply
Laboratory
Healthcare
system
Surveillance
centre
Follow-up survey
Reporting
Recommendation of
improvement
Feedback,
recommendations
Data analyses
Analysis,
interpretation
Central Surveillance
Organization
2008JICA training course (2008.12.8) at SCIPH8
Plan Do
Check (evaluation/monitoring)Action (forimprovement)
Plan Do)
Check (evaluation/monitoring)Action (for improvement)
Plan Do
Check (evaluation/monitoring)Action (forimprovement)
Continuous Improvement
2008JICA training course (2008.12.8) at SCIPH9
Disease
management
Primary prophylaxis
・Vaccination
・Environmental hygiene
Secondary prophylaxis
・Early detection/early intervention
・Screening
Third prophylaxis
・Prevention of complications
Prophylaxis
・Prophylaxis
・Treatment
・Rehabilitation
・Pain relief (care)
2
2008JICA training course (2008.12.8) at SCIPH10
Target Diseases for Mass Screening
1. The natural course of the disease is well known.
2. Life prognosis is poor or severe sequela may remain without early treatment.
3. Good results can be obtained by early treatment.
4. There are almost no false-negative cases and very
few false-positive cases.
A screening test method exists.
5. The disease shows a certain incidence, and a good cost-benefit ratio can be expected.
2008JICA training course (2008.12.8) at SCIPH11
Wilson JMG, Jungner G. Principles and Practice of
Screening for Disease. WHO Chronicle 1968;22(11):473.
1. The condition sought should be an important health problem.
2. There must be an accepted and effective treatment for patients with the
disease, that must be more effective at preventing morbidity when initiated
in the early, asymptomatic stage than when begun in the later, symptomatic
stages.
3. Facilities for diagnosis and treatment should be available.
4. There must be an appropriate, acceptable, and reasonably accurate screening
test.
5. The natural history of the condition, including development from latent to
manifest disease, should be adequately understood.
6. The cost of case-finding (including diagnosis and treatment of patients
diagnosed) should be economically balanced in relation to possible
expenditure on medical care as a whole.
2008JICA training course (2008.12.8) at SCIPH12
History of Neonatal Screening (1)
1934 Detection of phenylketonuria (PKU) (Folling, Norway)
1953 Publication of the treatment method of PKU by low-phenylalanine milk (Bickel, Germany)
1958 Development of the bacterial inhibition assay (BIA) for measurement of blood phenylalanine (Guthrie, U.S.)
1961 Start of mass screening using dried blood filter paper (filter paper blood) (Guthrie) →Guthrie method
1965 Urinary PKU screening (Okayama)
2008JICA training course (2008.12.8) at SCIPH13
BIA method (Bacterial Inhibition Assay)
A test method that visually compare the circle of
growth of a standard specimen and a specimen to be measured on agar medium containing a certain
type of bacterium and an inhibitor of an amino
acid necessary for the growth of the bacterium.
2008JICA training course (2008.12.8) at SCIPH14
Robert Guthrie
(1916-1995)
The Founder of
The Neonatal
Screening
At the Second
Meeting of the
International
Society for
Neonatal Screening
On September 1993
In Lille, France
2008JICA training course (2008.12.8) at SCIPH15
History of Neonatal Screening (2)
1967 Research group for PKU screening by the medical aid of the Ministry of Health and Welfare (Japan)
1973 Start of the research association for metabolic abnormality screening (Japan)
1974 Mass screening for cretinism by measuring thyroxine in filter paper blood (Dussault, Canada)
1975 Development of the measurement method of thyroid stimulation hormone (TSH) on filter paper blood (Irie, Naruse)
1976 Research group for the “early detection of congenital hypothyroidism” concerning pediatric chronic diseases (endocrine secretion/metabolism/blood) by the Ministry of Health and Welfare
2008JICA training course (2008.12.8) at SCIPH16
Jean-H Dussault (1941-2003)Founder of mass screening for cretinism by
measurement of thyroxine (T4) in filter paper blood
(Quebec, Canada)
Jean Dussault died on March 23, 2003, in his 62nd
year of life, thus ending a remarkable career filled
with outstanding scientific achievements. Jean
Dussault’s earliest scientific contribution in late
1972, was the development of a new blood test for
congenital hypothyroidism.
In 1974, he became director of the
Screening Program for Congenital
hypothyroidism; Quebec Network for
Genetic Disease.
He was, for example, nominated for the
Nobel prize of Medicine in 1982 at 42
yrs of age,
2008JICA training course (2008.12.8) at SCIPH17
Expansion of mass screening for cretinism in Japan
(Upper) Pilot screening in Sapporo City, Kanto, Kansai, and Kyushu
(Middle) In October 1979, start of nationwide screening in accordance with the notification by the Ministry of Health and Welfare
(Lower) Since TSH measurement was made by RIA, expansion of screening was slow even after 1 year.
2008JICA training course (2008.12.8) at SCIPH18
Cretinism before Mass Screening
– The incidence of cretinism diagnosed and treated based on clinical symptoms, excluding iodine deficiency disease, was approximately 1: 6,000.
– Approximately 10% was diagnosed by 1 month after birth, 35% within 3 months, 70% by 1 year, and approximately 100% by 3 to 4 years.
– The rate of intelligence quotient of 85 or higher was 78% in patients diagnosed by 3 months, 19% by 3 to 6 months, and 0% after 7 months.
F.Delange, Horm Res 1997; 48: 51-61
3
2008JICA training course (2008.12.8) at SCIPH19
Normal infants
PatientsTN
TP
FN FP
Cut-off Value
TN : True Negative FP : False Positive TN + FP = Normal Infants
TP : True Positive FN : False Negative TP + FN = Patients
2008JICA training course (2008.12.8) at SCIPH20
Change in Free Thyroxine (FT4) Concentrations in Neonates
2008JICA training course (2008.12.8) at SCIPH21
Changes in Thyrotropin (TSH) Concentrationsin Neonates
2008JICA training course (2008.12.8) at SCIPH22
Cut-off levels of TSH in neonatal screening for
congenital hypothyroidism (CH) in Japan
1. Protocol for pilot screening (1975-)
Pilot studies; Osaka, Tokyo, Hokkaido, etc.
2. Audit of pilot screening (The Research Project
Team (RPT) on the Screening of CH granted by the
Ministry of Health and Welfare)
3. Protocol for nationwide screening (1979.4-)
Abnormal high value of the first specimen:
50 µµµµU/ml of bloodCut-off level of the second blood sampling:
20 µµµµU/ml of blood4. Survey of screening results in each region
5. Standardization of protocol for screening
(by RPT, 1995-)2008JICA training course (2008.12.8) at SCIPH23
Reference Values of Mass Screening for Cretinism in Japan
To perform detailed tests immediately if the TSH concentration in the initial filter paper blood sample is abnormally high (> 50 mU/L).
In case of “high values,” a second blood sampling (re-blood sampling) should be performed. In this case, the values are approximately 20 mU/L.
Report by the research group of the Ministry of Health and Welfare in 1980 when screening was started.
2008JICA training course (2008.12.8) at SCIPH24
Structure (Standard ) of Screening in Japan
Notification of results
Prefectural and city governments/government designated cities
Implementation guideline for tests of congenital metabolism
abnormality, etc.
Laboratory for screening
Pregnant women, families
Medical institution for detailed tests
Enlightening and publicizing of the necessity of receiving tests through maternal and child health handbook and mothers’ classes
Request for tests
Liaison council for screening
Consultantphysician
Filter paper blood
Medical institution for blood sampling
Request for detailed tests
Informationsupply
Publicizing the screening system
2008JICA training course (2008.12.8) at SCIPH25
Cretinism (CH) found in 959 of 3,823,814 neonates = 1: 3,987
TSH > 50 in the filter paper blood sample
(detailed test immediately = 943)
TSH = 30 to 50 (detailed tests after re-blood sampling) = 16
When estimating from the Paris statistics,
CH in 16 of 4,980 neonates (0.13%) after re-blood sampling 2008JICA training course (2008.12.8) at SCIPH26
Relationship between TSH and T4 in the initial filter paper blood samples for cretinism
detected in early-stage screening in Hokkaido (1981 to 1985). Ectopic thyroid and synthesis
disturbances cannot be limited to hypo T4-emia, and TSH shows only mildly to moderately
high values.
TBG deficiency
↓↓↓↓
2008JICA training course (2008.12.8) at SCIPH27
What We Learned from Mass Screening for CretinismFindings obtained after the start of screening and improvement
in screening based upon the findings
●Change in the reference value (cut-off value) of TSH●Change in the dose of Thyradin-S●New clinical state: Transient hypothyroidism
Mild cretinism●Handling of premature babies●Problem of iodine-containing disinfectants●False negative cases not detected with screening
4
2008JICA training course (2008.12.8) at SCIPH28
Normal infants
PatientsTN
TP
FN FP
Cut-off Value
TN: True Negative FP: False Positive TN + FP = Normal Infants
TP: True Positive FN: False Negative TP + FN = Patients
2008JICA training course (2008.12.8) at SCIPH29
Numbers of False-positives and True-positives
500500
100100
5050
1010
55
11
10 20 30 40 50 100 (TSH μU/ml of blood)
FalseFalse--positivespositives
TrueTrue--positivespositives
Cutoff for urgent medical
examination
Cutoff for recall
Between 1989 and 1994 in Hokkaido
2008JICA training course (2008.12.8) at SCIPH30
2008JICA training course (2008.12.8) at SCIPH31
Standardization of Cut-off Level of TSH in First Dried Blood
Specimen on Neonatal Screening for Congenital
Hypothyroidism in JapanChanges in the reference values of TSH requiring immediatedetailed tests
1981
1991
1994
None 80 50 40 30 30 >
66 66 2626 44 88 33
55 4 2020 66 1212 66
2211 1515 1111 1717 77
Cut-off level of TSH (μμμμU/ml of blood)
The figures above are the numbers of laboratories.
2008JICA training course (2008.12.8) at SCIPH32
Sampling of Filter Paper Blood and Reference Values of TSH
� Blood filter paper collected within 4-7 days after birth
� By primary TSH screening
� The value of TSH is shown as a whole blood indication (mU/L of blood)
� Cut-off level of serum TSH = 1.6 times that of the whole blood value
1. TSH>15-30 in 1st sample: Urgent medical examination
2. TSH>10 in 1st sample: Request for 2nd sample (re-blood sampling)
3. TSH>10 in 2nd sample: Medical examination after re-blood sampling
2008JICA training course (2008.12.8) at SCIPH33
Birth Prevalence of Congenital
Hypothyroidism in Europe before and
after Screening Programmes
45.416.4Denmark
23.816Netherlands
38.5
1 in 2 598
14.5
1 in 6 897
Sweden
AfterBefore Country
Rate per
100 000
2008JICA training course (2008.12.8) at SCIPH34
Estimated Frequency of Cretinism Detection (CH) by
CRMSource A = National follow-up survey by Boshi-Aiiku-kai Maternal and Child Health Center
Source B = Opinions about specified chronic diseases in children (FY2001)
1 in 2,2063,26625.9%7,204,685Total
1 in 2,20853638.5%1,184,3021999
1 in 1,53478229.3%1,199,1831998
1 in 2,19754426.7%1,194,5101997
1 in 2,90341624.1%1,206,5511996
1 in 2,30951417.5%1,187,0671995
1 in 2,44250517.5%1,233,0721994
Incidence of
CH
Number of
CH
Missing
data
Number of
neonates
FY
2008JICA training course (2008.12.8) at SCIPH35
What We Learned from Mass Screening for CretinismFindings obtained after the start of screening and improvement
in screening based upon the findings
● Change in the reference value (cut-off value) of TSH● Change in the dose of Thyradin-S● New clinical state: Transient hypothyroidism
Mild cretinism● Handling of premature babies● Problem of iodine-containing disinfectants● False negative cases not detected on screening
2008JICA training course (2008.12.8) at SCIPH36
Diseases Presenting Hyper TSH-emiaGuideline Preparation Committee for Mass Screening for
Cretinism, 1998
1. Primary (thyroid) cretinism
I. Thyroid dysplasia
i. Thyroid deficiency or hypoplasia
ii. Ectopic
II. Synthesis disturbance of thyroid hormone
i. Defective iodine concentration
ii.Damage of organizing iodine
iii. Damage of deiodination of iodotyrosine
iv. Synthesis disturbance of thyroglobulin and iodothyronine
1. Coupling defect of iodotyrosine
2. Defect of thyroglobulin
3. Structural abnormality of thyroglobulin
III. Localization (iodine deficiency)
IV. Chronic thyroiditis: IPEX Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked
V. TSH-refractory
i. Part of pseudohypoparathyroidism
ii.Abnormal TSH receptor gene
VI. Iodine exposure
VII. By transplacental materials
i. Radioactive iodine
ii.Antithyroid agent
iii. Inorganic iodine
iv. Inhibiting antibody of TSH receptor
2. Symptoms of inappropriate secretion of TSH
I. TSH producing adenoma
II. Resistance to thyroid hormone
3. Infantile transient hyper TSH-emia
4. Existence of an intervention material to TSH measurement system (anti-TSH antibody, anti-mouse IgG antibody (HAMA), etc.)
5
2008JICA training course (2008.12.8) at SCIPH37
Severity of Transient Thyroid Dysfunction in Neonates by
Etiology
781792527
12
10
11
25
4
8
3
5
1
3
5
1
1
4
2
0
0
2
0
2
3
0
0
2
0
4
6
11
0
2
1
1
11
1
0
11
0
2
0
2
Excessive iodine
Fetography
Iodine-containingdisinfectant
Anti-thyroid agent
Low-birth-weight baby
Others
Down syndrome
Severe asphyxia
Pneumothorax
Others
Sub-
total
FPHigh
TSH
M-THTH
2008JICA training course (2008.12.8) at SCIPH38
What We Learned from Mass Screening for CretinismFindings obtained after the start of screening and improvement
in screening based upon the findings
● Change in the reference value (cut-off value) of TSH● Change in the dose of Thyradin-S● New clinical state: Transient hypothyroidism
Mild cretinism● Handling of premature babies● Problem of iodine-containing disinfectants● False negative cases not detected on screening
2008JICA training course (2008.12.8) at SCIPH39
Classification of Congenital Hypothyroidism by Site of Lesion/Clinical
State(Japanese Journal of Pediatric Medicine 34 Extra Edition, 626-634, 2002)
Central
Hypothyroidism
Transient
hypo-T4-emiaVariousNormal to
mildly high
LowMild to
severe
Central
Mild cretinism
Persistent
hyper-TSH-emia
Transient
hyper-TSH-emia
False positive
Excessive
response
Mildly to
moderately
high
Low or
normalMild
(latent)
Primary
CretinismTransient
HypothyroidismExcessive
response
Abnormally
high
LowSevere
(manifest-
ing)
Primary
Duration of the
clinical state
Permanent
Duration of the
clinical state
Transient
TRH testSerum TSHSerum
T4
SeveritySite of
lesion
2008JICA training course (2008.12.8) at SCIPH40
Course of so-called “Transient Infantile Hyper-TSH-emia” (Left) and Course of
“Mild Cretinism” (Right)
5 5
2008JICA training course (2008.12.8) at SCIPH41
Concept of Mild Hypothyroidism(=Mild Cretinism)
•Mild congenital hypothyroidism (mild cases)
• Compensated congenital hypothyroidism
• Alemzadeh R et al.: Is there compensated hypothyroidism in infancy? (compensated case) Pediatrics 1992;90:207-211
• Borderline congenital hypothyroidism
• Daliva AL et al.: Three-year follow-up of borderline congenital hypothyroidism. (borderline case) J Pediatr 2000;136:53-56
• Atypical congenital hypothyroidism
• Mandel S et al.: Atypical hypothyroidism and the very low birth-weight infant. (atypical case) Thyroid 2000;10:693-695
2008JICA training course (2008.12.8) at SCIPH42
What We Learned from Mass Screening for CretinismFindings obtained after the start of screening and improvement
in screening based upon the findings
● Change in the reference value (cut-off value) of TSH● Change in the dose of Thyradin-S● New clinical state: Transient hypothyroidism
Mild cretinism● Handling of premature babies● Problem of iodine-containing disinfectants● False negative cases not detected on screening
2008JICA training course (2008.12.8) at SCIPH43
Atypical CH and the VLBW Infant
●Tests were conducted on 311,282 infants born in Massachusetts from January 1, 1993 to December 31, 1996.
●118 infants were found to have typical hypothyroidism
● 98 had normal birthweight (NBW, > or = 2,500 g)
● 9 had low birthweight (LBW, 1,501-2,499 g)
● 11 had very low birthweight (VLBW, < or = 1,500 g)
●Atypical hypothyroidism and the incidence of CH
● 4 had NBW, 1:3051
● 4 had LBW, 1:1589
– 10 had VLBW, 1:153 (suspected transient hypothyroidism))
•Atypical hypothyroidism in the VLBW category
–48% of cases in this weight category
–56% of all cases of atypical hypothyroidism
2008JICA training course (2008.12.8) at SCIPH44
100100
5050
00
(%)(%)
00 77 1414 2121 2828 35(day)35(day)Age of specimen collection in low-birth
weight infants in Hokkaido
1990-92
(n=1,710)
1985 (n=589)
1987: Recommendation of repeating blood sampling twice for low-birth weight infants weighing 2,000 g or less
2008JICA training course (2008.12.8) at SCIPH45
Results of neonatal screening for congenital
hypothyroidism in four groups based on birth
weight (1990-92, in Hokkaido)C.H.: Congenital hypothyroidism, T.H.: Transient hypothyroidism
31521401,223108,380Total
21481231,170106,6702,001-
10
(32.3%)
4
(7.7%)
17
(12.1%)
53
(4.3%)
1,710
(1.6%)
Subtotal
(/Total)
315161,0781,500-2,000
134144161,000-1,499
60823216- 999
No. of
T.H.
No. of
C.H.
No. of
med.exam.
No. of
recalled
No. of
screened
Birth
weight (g)
6
2008JICA training course (2008.12.8) at SCIPH46
Monitoring of the Performance of Laboratories for Screening
Recommendation of Repeating Blood Sampling in Premature Babies Twice
� In 28 of 35 laboratories (80%), repeat blood sampling twice was recommended.
� Even if blood sampling twice was recommended, the recovery rate varied, namely, 68 to 100%, and there was room for improvement.
� There were many laboratories where the distribution of the days after birth at the time of sampling from premature babies could not be confirmed.
2008JICA training course (2008.12.8) at SCIPH47
What We Learned from Mass Screening for CretinismFindings obtained after the start of screening and improvement
in screening based upon the findings
● Change in the reference value (cut-off value) of TSH● Change in the dose of Thyradin-S● New clinical state: Transient hypothyroidism
Mild cretinism● Handling of premature babies● Problem of iodine-containing disinfectants● False negative cases not detected on screening
2008JICA training course (2008.12.8) at SCIPH48
A. Gruters et al. : Incidence of iodine contamination in neonatal
transient hyperthyrotropinemia. Eur J Pediatr 140: 299-300, 1983
Those who had shown
transient increases in TSH in
the neonatal period and a
urinary iodine concentration
exceeding the normal value
in reference cases, 16 µµµµg/ml: 76.8%
(95.4% of the reference cases
were within the range.)
Iodine-containing
disinfectants used in the
Dept. of obstetrics was the
cause.
2008JICA training course (2008.12.8) at SCIPH49
Annette Grüters, Department of Pediatrics, Charite University Hospital,
Humboldt University, Berlin, Germany (Kyoto, Nov. 2003)
2008JICA training course (2008.12.8) at SCIPH50
Umbilical cord, umbilical region
Iodine-containing
disinfectantMother’s vagina, vulva
Thyroid in neonates
Transplacental
Maternal milk
Transient increase in TSH in filter paper blood
Wolff-Chaikoff
effect
Increase in
urinary iodine
levels
Normalization of TSH in filter paper bloodDecrease in urinary
iodine levels
Transient disturbance of thyroid hormone synthesis due to excessive iodine
2008JICA training course (2008.12.8) at SCIPH51
Role of thyroperoxidase (TPO)
Follicular lumen Follicle cell
2008JICA training course (2008.12.8) at SCIPH52
Change in TSH values in filter paper blood before and after
limitation of the use of iodine-containing disinfectants
in Hokkaido in general
10 to 15 mU/L group: From 0.956% to 0.564%
15 to 30 mU/L group: From 0.278% to 0.103%
2008JICA training course (2008.12.8) at SCIPH53
Why Is too High False-positive Rate (High Re-blood
Sampling Rate) Unfavorable?
(In the Case of Cretinism)
• Decrease in the efficiency of screening • • • Deterioration of the cost-
benefit ratio
• Delay in detailed tests and early treatment of true-positive patients • • •
Because the reference value to select the cases for detailed test will be set
high.
• Missed cases of cretinism to be detected by a mild increase in SH
concentration in filter paper blood • • • The cut-off value for re-blood
sampling of the initial specimen will be set high.
• Harmful effect of accustomed “blood sampling again” • • •
Laboratory for screening: Lack of tension
Institution for delivery: Confusion concerning detailed tests and re-
bloodsampling
• Psychological effects on families • • • Bad effects on the relationship
between mother and child, worsening of maternity blues
2008JICA training course (2008.12.8) at SCIPH54
What We Learned from Mass Screening for CretinismFindings obtained after the start of screening and improvement
in screening based upon the findings
● Change in the reference value (cut-off value) of TSH● Change in the dose of Thyradin-S● New clinical state: Transient hypothyroidism
Mild cretinism● Handling of premature babies● Problem of iodine-containing disinfectants● False negative cases not detected on screening
7
2008JICA training course (2008.12.8) at SCIPH55
Infants with Congenital
Hypothyroidism Undetected by
Neonatal Screening
� Central CH could not be detected by
primary TSH screening
� Biological variants
– Delayed TSH elevation
– Mild CH (Normal T4, Elevated TSH)
� Error in screening
– Sample collection
– Sample processing
– Reporting and treating2008JICA training course (2008.12.8) at SCIPH56
Infants with Congenital Hypothyroidism Undetected
by Neonatal Screening in Japan (1992-2000.2)
Summary of False-negative Cases in Japan
141141535Total
100001Very mild
000101Processing
000033High cutoff
200103Collection
111121227Delayed TSH
rise
n.d.PHPAplasiaEctopiaDyshorm.No. of
missed
Etiology
2008JICA training course (2008.12.8) at SCIPH57
Requirements for continuing mass screening
for congenital hypothyroidism (cretinism)
• Early detection/early treatment
– Start of treatment within 2 weeks after birth
– Improvement in QOL during the whole life cycle
• Good cost/benefit ratio (low harmful effects)
– False-positive rate: Approximately 0.5%
– Protection of false-negative cases or mix-up of specimens
2008JICA training course (2008.12.8) at SCIPH58
How to Assure the Following
Requirements• Early detection/early treatment
– Start of treatment within 2 weeks after birth
– Improvement in QOL during the whole life cycle
• Good cost/benefit ratio (low harmful effects)
– False-positive rate: Approximately 0.5%
– Protection of false-negative cases or mix-up of specimens
� Long-term follow-up system for positive patients
� System to figure out false-negatives
� Investigation of the cause of false-positives/
preventive measures
Accuracy assurance of the complete screeningSurveillance loop
2008JICA training course (2008.12.8) at SCIPH59
Surveillance LoopMonitoring System
ScreeningScreening
Event
Action
For quality For quality
improvementimprovement
Laboratory
Healthcare
system
Surveillance
centre
Follow-up survey
Reporting
Recommendation of improvement
Feedback, recommendations
Data analyses
Analysis,
interpretation
Central Surveillance
Organization
Accumulation/Accumulation/
registrationregistration
Data
Information
Information Information
supplysupply2008JICA training course (2008.12.8) at SCIPH60
Follow-up Survey System in Conventional Neonatal
Screening (Early Phase)
• Congenital metabolism abnormalities (1977 - ) • • •
Boshi-Aiiku-kai Maternal and Child Health Center (information on special milk)
• Congenital hypothyroidism (1979 - ) • • •Activity of the research group of the Ministry of Health and Welfare; until the 8th national follow-up survey (cases until 1987)
Registration of approximately 100 cases annually• Congenital adrenal hyperplasia (1989 - ) • • •
Case registration by the activity of the research group of the
Ministry of Health and Welfare
2008JICA training course (2008.12.8) at SCIPH61
Follow-up Survey System in Conventional Neonatal
Screening (Later Phase)
• Congenital metabolism abnormality (1977 - ) • • •
Boshi-Aiiku-kai Maternal and Child Health Center
(information on special milk)
• Congenital hypothyroidism (1994 - ) • • •
Boshi-Aiiku-kai Maternal and Child Health Center
At first, approximately 160 cases annually
• Congenital adrenal hyperplasia (1992 - ) • • •
Activity of the research group of the Ministry of Health,
Labour and Welfare Approximately 60% probabililty
Boshi-Aiiku-kai Maternal and Child Health Center (1994 - )
2008JICA training course (2008.12.8) at SCIPH62
Follow-up Survey System at Boshi-Aiiku-kai
Maternal and Child Health Center
• 2-step method
– List of positive patients on screening from laboratories for screening • • • More than 50% did not cooperate in the fiscal year 2001.
– Distribution of the follow-up survey form to each physician in charge and collection of the forms
– Collection of more than 90% of the forms in case of congenital metabolism abnormality
– Extremely increased administrative tasks after addition of cretinism
• Regional alliance method
– Ask the liaison council for screening in the municipality
– Approximately 40% of the follow-up survey in the internal municipality was not performed.
2008JICA training course (2008.12.8) at SCIPH63
Change in the Term of DiagnosisA:Cretinism, B:Transient hypothyroidism,
C:Transient hyper TSH-emia, D: Cretinism suspected, E; Normal
31405381419883201153
838508032541E
16225845111D
5090150800C
3265083130B
13050569621151A
EDCBAPhysician in charge
Correction
8
2008JICA training course (2008.12.8) at SCIPH64
Main body: Prefectural and city governments, government-designated
cities
- Change in the laboratories to be entrusted/private contracted
laboratories due to general revenue
Laboratories • • • Internal accuracy management, committee of
technicians
Training by Boshi-Aiiku-kai Maternal and Child Health Center
Monitoring system at each local government
• • • Local council
• • • Consultant physicians
Japanese Society for Mass-screening, The Japanese Society of
Pediatric Endocrinology, Japanese Society for Inherited Metabolic
Diseases, Japan Association of Obstetricians and Gynecologists
(Research Group of the Ministry of Health, Labour and Welfare)
Outside accuracy management • • •
Screening Accuracy Management Center (Japan Public Health Association)
System to Maintain Neonatal Screening
2008JICA training course (2008.12.8) at SCIPH65
Problems with a Change in Test Laboratories
Accuracy management before tests
Cooperation with obstetrical institutions
Accuracy management at test laboratories
Cut-off value suitable for the actual situation in the area
Accuracy management after tests
Establishment of a follow-up survey system
(consultant physicians, local council meeting)
Days after birth at the time of blood sampling, recommendationof blood sampling in premature babies, survey for disinfectants
Setting of the proper cut-off value, figuring out false-negatives
2008JICA training course (2008.12.8) at SCIPH66
Problems of the Change in Test Laboratories
Accuracy management before tests
Cooperation with obstetrical institutions
Accuracy management at test laboratories
Cut-off value suitable for the actual situation in the area
Accuracy management after tests
Establishment of the follow-up survey system
(consultant physicians, local council meeting)
Days after birth at the time of blood sampling, recommendation
of blood sampling in premature babies, survey of disinfectants
Setting of a proper cut-off value, figuring out false-negatives
2008JICA training course (2008.12.8) at SCIPH67
Clinical Laboratory vs ScreeningLaboratory tests at general medicalinstitutions
Screening
Physician Patient
Feedback
Clinical symptoms or physical findings
Clinical
diagnosis
Overall evaluation of
clinical diagnosis and
test results
Results
Re-examination is possible if there is any error with the laboratory tests
Specimen
Measure-
ment
Neonates
Filter paper
specimen
Feedback
Measurement
Abnormal
Accuracy Accuracy
assuranceassurance
No Feedback
Normal
False negative
True negative
2008JICA training course (2008.12.8) at SCIPH68
Overall Accuracy Assurance of Screening
CountryPrefectural and city governments/government designated cities
Legal basisArticles 5 and 13 of Maternal and
Child Health Law
Laboratory for screening
(outsourcing)
Laboratory for screening
(in municipality)
Central surveillance organization
Outside accuracy management
National Center for Child
Health and Development
Notification, 1977
Abolishment, 2000 Outline of each municipality
2008JICA training course (2008.12.8) at SCIPH69
Next Generation System to Maintain Neonatal Screening
Main body: Prefectural and city governments, government-designated cities
- Change in the laboratories to be entrusted/private contracted laboratories
due to general revenue
Laboratories • • • Internal accuracy management, Committee of technicians (academic societies), training at Maternal and Child Health Center
Local councils in municipality
• • • Consultant physicians
Japanese Society for Mass-screening, The Japanese Society of Pediatric Endocrinology,
Japanese Society for Inherited Metabolic Diseases, Japan Pediatric Society, etc.
Outside accuracy management • • • Japan Public Health Association Accuracy Management Center
Overall “Accuracy assurance” of screeningCentral follow-up survey control system
Department of Health Policy,
National Research Institute for Child Health and Development
2008JICA training course (2008.12.8) at SCIPH70
System to Distribute Information to Local Governments and
Test Laboratories
Japanese Society for Mass-screening
MHLW
Screening accuracy
management center
Committee of technicians
Research Group of MHLW
Local
governmentTest laboratory
Basic training
Accuracy management
committee
Training by Aiiku-kai
2008JICA training course (2008.12.8) at SCIPH71
Long-term Follow-up of Positive Patients in
Neonatal Mass Screening
Local governmentTest laboratory for
screening
Dept. of Obstetrics(Medical institution for blood sampling)
Medical institution
for detailed tests
National Center for Child
Health and Development
1. Consignment
4. Report
2. Blood sampling
3. Report of results
5. Request for detailed tests
6. Notification of results
7. Introduction of patients
• Primary survey by the center
• Data of positive patients from the local government
• Secondary survey by the center
• Answers from medical institutions
Disclosure of results
• MHLW
• Academic societies
• Research group
• Home page
2008JICA training course (2008.12.8) at SCIPH72
Guidelines for the Retention, Storage, and Use of Residual Dried Blood Spot
Samples after Neonatal Screening Analysis: Statement of the Council of Regional
Networks for Genetic Services.
Therrell BL, Hannon WH, Pass KA,et al.
Biochem Mol Med. 1996 Apr; 57(2): 116-24.
These guidelines provide scientific information for policy development by state health departments considering appropriate use of neonatal screening specimens after screening tests are finished. Information was collected, debated, and formulated into a policy statement by the Newborn Screening Committee of the Council of Regional Networks for Genetic Services (CORN), a federally funded national consortium of representatives from 10 regional genetics networks.
Neonatal screening programs vary widely in approaches and policies concerning residual dried blood spot samples (DBS) collected for neonatal screening. Recognition of the epidemiological utility of DBS samples for HIV seroprevalence surveys and a growing interest in DBSs for DNA analysis has intensified consideration of issues regarding retention, storage, and use of residual DBS samples. Potentially these samples provide a genetic material “bank” for all neonates nationwide. Their values as a resource for other uses has already been recognized by scientists, administrators, and judicial officials.
Programs should promulgate rules for retention and use of residual neonatal screening.
DBS samples based on scientifically valid information. Banking of neonatal samples as sources of genetic material should be considered in light of potential benefit or harm to society.
9
2008JICA training course (2008.12.8) at SCIPH73
Pass博士の写真(ろ紙)
Dr. Kenneth Pass in the Wadsworth Center, New York State Department of Health, Albany
At the storage of positive specimens (photo taken in May 2005)
2008JICA training course (2008.12.8) at SCIPH74
Storage and Use of Residual Dried Blood Spots
from State Neonatal Screening Programs
Olney RS, Moore CA, Ojodu JA, Lindegren ML, Hannon WH.
J Pediatr. 2006 May; 148(5): 618-22
OBJECTIVES: To provide current data for policy discussions and to assess future needs among neonatal screening programs regarding the storage and use of residual dried blood spots (DBS) in the United States.
STUDY DESIGN: An electronic questionnaire was administered to U.S. state health department laboratory directors in 2003.
RESULTS: Responses were received from 49 of the 50 states.
Approximately half of them stored residual DBS for more than 6 months, 57% did not have a written policy that determines how residual DBS can or cannot be used, and 16% informed parents that DBS might be retained. Residual DBS were used by 74% of respondents for evaluation of neonatal screening tests, by 52% for clinical or forensic testing, and by 28% for epidemiologic studies. Use of DBS was reported more frequently by states with extended storage. When asked if they might participate in an anonymous multistate epidemiologic study by contributing unlinked DBS, 41% responded affirmatively. CONCLUSIONS: More states have used residual DBS for evaluating neonatal screening tests than for epidemiologic studies. There is potential interest among states in using unlinked DBS for multistate studies and a need for written policies addressing all uses of residual DBS.
2008JICA training course (2008.12.8) at SCIPH75
Helsinki Declaration and Human-derived
Materials/Information
• Helsinki Declaration by World Medical Association
• 1964 (Initial stage of institution) Recommendations guiding
medical doctors in clinical research
• 1975 (Revised in Tokyo) Recommendations guiding medical
doctors in biomedical research involving human subjects
• 1983 The term “medical doctor” was changed to “physician.”
• 2000 Revised Ethical principles for medical research
involving human subjects
– Article 1 Medical research involving human subjects includes
research on identifiable human material or identifiable data
– Article 22 Requesting informed consent limited to studies on human
subjects
2008JICA training course (2008.12.8) at SCIPH76
Protecting Genetic Materials and Genetic Information: A
Case Study of Guthrie Cards in Victoria.
Lawson C, Smith R.: J Law Med. 2001 Nov;9(2):215-32
Genomic Interactions Group, Research School of Biological Science, Australian National University, Canberra.
The authors are privileged to have received correspondence about a dispute over the ongoing storage of genetic material (as Guthrie Cards) in Victoria (case that Mrs. Thompson, a woman from Victoria, Australia requested the return of the filter paper of her daughter after a PKU test). The correspondence details the confusion over the roles of the government and the private sector service provider concerning the storage, use and destruction of these stored genetic materials collected as part of a government public health program (confusion about the existence of responsibilities for storage/use/destruction of genetic materials collected by the government in the project as the healthcare policy). The purpose of publishing this account is to highlight the present inadequacies in current practices and the ongoing potential for a crisis in the management of collected genetic materials by a lack of appropriate regulation, transparency and accountability. The article suggests measures to remedy some of the existing inadequacies in contractual arrangements and recommends that the government retain ownership and control of both the genetic materials and the derived information to ensure some accountability in the present legal environment.
2008JICA training course (2008.12.8) at SCIPH77
Society where children and families can live safely and comfortably
Extremely low birthrate
Children are country’s treasures.
Children are the future.
Financial
deteriorationLower societyAbuse
Collapsing
community
Country
MHLWLocal government
Professionals of
Healthcare/welfare
Fostering a healthy next generation
Role of each player
Advocacy (as a spokesperson for children)2008JICA training course (2008.12.8) at SCIPH78
Fostering a healthy next generation
DB of pediatric chronic diseasesDB of child healthcare and development/diseases
CountryMHLW
Local governmentProfessionals of Healthcare/welfare
Role of each playerAdvocacy (as a spokesperson for children)
Policy recommendation/promotion of child medical healthand development/promotion of research
Accumulation of evidence
Follow-up survey/registration ofpediatric clinical diseases
Participation of pediatricians, etc.
Healthcare administration
Preparation of healthcarepolicy
Recommendation of policy
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