Tokyo Twin Cohort Project 　 (ToTCoP) :Its Beginning and Related Issues to be Considered

Juko Ando, Ph.D. (Keio University), Chief researcher

Koichi Nonaka ( Wako University), co-researcherKoichi Nonaka ( Wako University), co-researcherNoriko Kato (National Institute of Public Health), co-researcher

Syuichi Ooki ( Ishikawa Prefectural Nursing University), co-researcher

What are we going to study?

Primary Aim: to clarify effects of genetic and shared/non-shared environmental factors on the early-stage of human development in terms of temperament, motor skills, cognitive-linguistic abilities, and other behavioral traits.

ToTCoP cohort: Longitudinal follow-up by questionnaires to new born twin population in Tokyo metropolitan area

Subcohorts (subsets of ToTCoP cohort): # Observation and Interview at home # Optical Topography (OT) at laboratory …..

Coverage Area of ToTCoP

• Tokyo Area = Tokyo Met. +Kanagawa +Chiba +Saitama (Pref.s)

Tokyo

KanagawaChiba

Saitama

Yokohama

TokyoNarita

N of twin pairs born in Tokyo Area

0

200

400

600

800

1000

1200

1400

1999 2000 2001 2002

TokyoKanagawaChibaSaitam

2970

3031

2889

3339

About 3000 pairs of twins are expected to be born

per year within our research area

Ideal

Realistic?

In Japan, there is no population (electronic) registry available to researchers.

Population-based Twin Cohort 5-year Follow-up from Infancy

The Basic Resident Registration (BRR) (Open to Public Reading)

BRR: Is it useful to twin study?

BRR: reflecting the whole population in each area

Possible source for complete recruiting (no sampling, no selection biases)

BRR: printed on a family-basis with the information on name, sex, birthdate

Possible source for identifying twins by the members with the same birthdates

We may have the necessary information

… except for research fund

Recently, the order of the list has been randomized in order to hide the family constitution. This has made our research impossible in the future!! We

have to give up new recruitment from BRR.

BRR: Its practical limitation as a source of the population list

BRR: Transcription by hand is necessary for each district

We cannot obtain the list for the whole area at once, giving different time-frame of recruiting for different district

BRR: New born babies are not registered instantly, usually with a time-lag of 3 months or more

Youngest subjects are usually at age 6 months or more, thus on-going information on the first half year of life is hardly obtained

Actually quasi-population-based newborn recruiting with a different time frame for each district

ward city village town total

Tokyo 23 26 1 3 53

Kanagawa 25 17 1 17 60

Chiba 6 32 5 39 82

Saitama 10 39 4 41 94

Total 64 114 11 100 289

N of local governments

• 13 well-trained assistants are transcribing the data in EACH municipal office.

Information transcribed from BBR

• name• residential address• date of birth• sex

• Expected twins, triplets, quadruplet, quintuplet

= individuals with same address and same date of birth

Schedule2004/11 2005/4 2006/4 2007/4 2008/4 2009/4 10

48m24mHome interview

12m 36m

Full-scale Questionnaires18m 24m9m 12m 15m 30m 36m 42m 48m 54m

DNA(all)OT(NIRS), EEG

Brain Imaging (OT)

Building twin address list from BRR

Subcohorts

ToTCoP Cohort

Pilot(9-14m)

Registry/CohortSep↓

Main(3-14m) Entry

Address list transcribed from BRR

Pilot

Announcement

Request to Entry

Full-scale Questionnaire

(9-14 m.o.)

Main

Announcement

Request to Entry

Full-scale Questionnaires

(9, 12, 15, 18, 24, 30, 36, … -14 m.o.)

Subcohorts

At Home

At Laboratory

…

merged

Pilot study (from mid March,2005)Sending Fliers

to 311 families with 9-14 month-old twins

Entry 178 (57.9%)

Sending Entry Sheets309 (April 1)

2 moved

zygositybirth/current weight

milk/food intakesleeping regularity

etc…

Sending Full-scale Questionnaire, IC

Full-scale Questionnaire122 (39.5%)

Response to Request to Entry (Pilot)

0

10

20

30

40

50

60

70

-20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300

Days from First Request to Entry

Acc

umul

ativ

e R

etur

ned

Ent

ry S

heet

(%

)

Announcement

First Request to Entry

2nd RtoE

3rd RtoE

Re-announcement4th RtoE

Response to Request to Entry

0

10

20

30

40

50

60

70

-20 0 20 40 60 80 100 120 140

Days from 1st RtoE

Acc

umul

ativ

e R

etur

ned

Ent

ry S

heet

(%

)

Pilot Entry Apr 2005

Announcement & RtoE

Main Entry(1) Sep 2005

Main Entry(2) Nov 2005

Pilot late-comers Nov 2005

Announcement

1sT Request to Entry3rd RtoE

2nd R toE

Main study (from Sep,2005)Sending Fliers

to 1001(Sep) & 310(Nov) families with 3-14 month-old twins

Entry 658 (50.1 (55.6)%)

Sending Entry Sheets1313

zygosity0,3,9 mo.

weight, length, chest, head,milk intake

sleeping regularitysocial behavior,etc…

Full-scale Questionnairesfor 9, 12, 15, 18, 24, 30, 36,.. month-old

Modified according to the results of

Pilot study

.. about to start this month

Response to Full-scale Study (Pilot)

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

0 50 100 150 200 250 300

Days

Cum

ulat

ive

Pro

port

ion

of R

etur

ned

Que

stio

nnai

re (

%)

to Entry population

To Registered population

Date for sending request

Dates of sending questionnaresaccording to birthdate of the twins

c.a. 45% to the registered mother population

almost 80% to the populationgiving consent to Entry

Present Statistics of ToTCoP cohortas of 13 J an 2006

DB Req Entry %Oct-05 3 1 1 1 100.0Sep-05 4 2 0 0 0.0Aug-05 5 19 6 3 50.0 15.8J ul -05 6 27 8 4 50.0 14.8J un-05 7 46 21 10 47.6 21.7May-05 8 69 40 17 42.5 24.6Apr-05 9 67 50 29 58.0 43.3Mar-05 10 96 79 54 68.4 56.3Feb-05 11 109 85 49 57.6 45.0J an-05 12 125 101 53 52.5 42.4Dec-04 13 175 145 84 57.9 48.0Nov-04 14 178 160 69 43.1 38.8Oct-04 15 183 172 100 58.1 54.6Sep-04 16 176 160 82 51.3 46.6Aug-04 17 185 147 83 56.5 44.9J ul -04 18 218 152 87 57.2 39.9J un-04 19 229 207 84 40.6 36.7May-04 20 182 169 75 44.4 41.2Apr-04 21 205 178 82 46.1 40.0Mar-04 22 205 184 75 40.8 36.6Feb-04 23 218 194 84 43.3 38.5J an-04 24 202 185 70 37.8 34.7

Total 2917 2444 1195 48.9 41.0

Main3(2006J an)

Pilot(2005Mar)

Main1(2005Sep)

Pilot(latecomer)(2005Nov)

Main2(2005Nov)

Birthdate

Request dates Age inmonth

Total (pairs) % toDB

What are the Research Questions?

# Full-scale questionnaires are now being made and brushed up.

# Procedures for subcohort studies are now preliminarily on-going.

# The followings are the present research frame.

Measures

DENVER Ⅱ=behavioral development,IBQ-R/ECBQR/CBQ=Rothbart’s temperament Scales PTCI=Preschool Temperament & Character Inventory 、BISQ=Brief Infant Sleep Questionnaire CBCL=Child Behavior Check List 、 MAI=Maternal Attachment Instrument, EES=Evaluation of Environment Stimulus SDS=Self-Rating Depression Scale PSI=Parental Stress Inventory

month 9 mo 12 mo 15 mo 18 mo 24 mo 30 mo 36 mo 42 mo 48 mo 54 mo

PhysiquesStressful Life Events

○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Zygosity ○ ○Laterality ○ ○ ○ ○ ○ ○

Motor Development DenverII DenverIITemperament IBQ-R ECBQ PTCI CBQ PTCI

Autisitic SymptomsSocial Behavior

M-CHAT YaleScreener

M-CHAT YaleScreener

M-CHAT

Sleeping Behavior BISQ BISQConduct Disorder CBCL CBCL CBCL

Nutrition ○ ○ ○Cognition Bayley Bayley Bayley WISC-R

Triad Interaction ○ ○ ○ ○ ○Language ○ ○

Attachment MAI MAICultural/ Educational

Environment○ ○ ○ ○

Parental Behavior ○ ○ ○ ○ ○Home Environment EES EES

Twin Situation ○ ○ ○ ○ ○Depressive Symptom SDS SDS SDS SDS SDS

Parental Stress PSI PSIMarital Love ○ ○

Social Support ○ ○ ○ ○ ○ ○

Subcohorts

# Observation and Interview at home

# Optical Topography (OT) at laboratory

Triad of ToTCoP

Bythe twins

Central concern to the

researchers

Forthe twins

Incentive to parents of the young twins

Of the twins Much concern to

parents and twins themselves

# Only twins are necessary.

# Appropriate proportion of MZ and DZ for the method?

Representativeness of underlying population is

NOT necessary.

# Burden of too many items in the questionnaires may inhibit continuous entry.

# “HZ issue” was checked at the pilot study.

Bythe twins

Central concern to the

researchers

TWIN STUDY METHOD by comparing MZ and DZ twins, NOT singletons

Twin A Twin B

Question 1 Question 1

Question 2 Question 2

Question 3 Question 3

Question 4 Question 4

Twin A Twin B

Question 1 Question 1

Question 2 Question 2

Question 3 Question 3

Question 4 Question 4

LOW contrast between co-twins HIGH contrast between co-twins

H Z

Ofthe twins

Much concern to parents and twins

themselves

# ToTCoP does not have original comparative singleton families.

# Representativeness of underlying population is NECESSARY for adequate estimation of the status-quo of the whole twin families.

# Response proportion is critical. 40-60% is enough?

Parents are interested in Being TWINS, compared with being a SINGLETON

# ToTCoP does not have enough resources to help directly each family.

# But, we have to give information as much as possible to facilitate healthy growing of the twins.

# This is not for science, but for the welfare of the families. What if we give information to change parental behaviors?

# It is ethically necessary, if we should lose scientific objectivity.

Forthe twins

Incentive to parents of the young twins Parents are quite busy in rearing twin babies for

the first few years, with the nuclear families tending to be isolated from appropriate information or official help

Feedback to Participants

• Periodical Newsletters (3 issues per year)• Hint cards on rearing twin children (mail)• Web page information (only in Japanese)• Introduction to circles for twin’s parents• Individual feedback assessment on

physics (specific to twins) and other psychological and environmental indices.

• Information exchange meeting for the participants

Informed Consent and Ethical Issues

• Written IC is obtained at the 1st full-scale questionnaire.

• Participants to other subcohort programs are requested to give IC for each program.

• ToTCoP program and other subcohort programs are to be assessed beforehands at the institutional ethical committee.

Data management

• Participant’s basic information transcribed from BRR is maintained with ID number by FileMaker Pro installed on an off-line PC.

• Data from questionnaires are entered as a text file with ID number, and shared within the ToTCoP researchers by Web disk.

• Data handling specific to twin data is the critical issue to be considered A.S.A.P.

# Asian population has, in general, an advantage of a higher relative proportion of MZ twins for more accurate estimation of genetic/environmental contribution.

# ToTCoP should make every effort to keep higher participating proportion in order to take the advantage of its population-based origin, as well as to obtain longitudinal follow-up data as much as possible for its research questions on human early development.

Finally …