Canada France National Institute National Institute of

1

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)


Setagaya

National Center for Child Health and Development

Okura, Setagaya-ku, Tokyo

Laboratory

Hospital


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


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


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


System of Healthcare Policy

Conventional Plan Do Achievement

unknown

Plan Do

Check (Evaluation/

Monitoring)

Action (for

improvement)

Current healthcare policy


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


Plan Do

Check (evaluation/monitoring)Action (forimprovement)

Plan Do)

Check (evaluation/monitoring)Action (for improvement)

Plan Do

Check (evaluation/monitoring)Action (forimprovement)

Continuous Improvement


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


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.


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.


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)


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.


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


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


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,


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.


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


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


Change in Free Thyroxine (FT4) Concentrations in Neonates


Changes in Thyrotropin (TSH) Concentrationsin Neonates


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.


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


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

↓↓↓↓


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


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


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



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.


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


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


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




● 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


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


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







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


Course of so-called “Transient Infantile Hyper-TSH-emia” (Left) and Course of

“Mild Cretinism” (Right)

5 5


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







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


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


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


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.







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.


Annette Grüters, Department of Pediatrics, Charite University Hospital,

Humboldt University, Berlin, Germany (Kyoto, Nov. 2003)


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


Role of thyroperoxidase (TPO)

Follicular lumen Follicle cell


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%


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






7


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


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


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


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


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 - )


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.


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


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


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


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


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


Overall Accuracy Assurance of Screening

CountryPrefectural and city governments/government designated cities

Legal basisArticles 5 and 13 of Maternal and

Child Health Law


(outsourcing)


(in municipality)

Central surveillance organization

Outside accuracy management

National Center for Child

Health and Development

Notification, 1977

Abolishment, 2000 Outline of each municipality


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


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


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


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


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)


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.


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


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.


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

Documents

Canada France National Institute National Institute of