• ---------------· --·

COl'fFIDE~TL ~

r ollov,.-in~ i::, ar~ uncate on th~ prc::eeG.L.!gs rutc 11namgs so iar of tDe firsr phase cf this proposeci nvc phased sr;.1dy. : have used the original protocol as outlL.TJ.e for :ris unciate.

criLeria~

3om :n , i•. : ··~ c.:r :ater.

,. ~.:,remau.rr~ anc:. seve:e pre:naru:-e :ru1crer:. ?rematu.~i:r:.~ '\vas defined as birthweight o: ...

C . .,...:;"'-=-~ ">C: i;ir. ;.,.w.,.; an~ ,...,-~ -!"""'" .-...,ar : nor; c ,..,- '"'"'"' tn· -.:>r_ ..... _.X r~on'.Dl- f"T,f',..._: we~~'."-- y.,i ~--·.&.I.J. ..... _ ~ .... -•-·-• _..,:._J. .. v ... -v ... · Ll.& ... ...... \.. ... :: '-"• ,._..,....,., 1o ....,.._ -- -- _..,-

ider.tiiiec Lnese cnua.rer.l oy :he IC.D9 ::oae ;c:·.

se~ ·:c avoic.. 1nciudinz cn11Gre:: enre:iie~ irl the P.1 .. lVIC) tha~ did no: use the s~rvi~es. ?oiic

:~'n· ,_:, ~~ , _ _.: .. -,. ,._-,: .~:--., ·\..\··ho 1~-1 ~r.'.,· r ..... ,..,., _,_ ..... .- ...-. ,_:J.r. ~ .. r"' 1 _...... _. -· . ..... ! a.... ... ~>...1.,_.~_ -_u.~..,::.--•lli.-:!..~. occllr:'et (including

Q Childrer. ti1a: re~~2.1r1ec: lor:ge:- tl:2.:: l C ccys i~ tfle bini: !iosnitz.l or \\'ere hosDitalized

c:.:29IOC

Case definition:

-----------·----

N..--~ _.....".,....-- n~ n--- • s...­T'O I ' . ' '! . '"''\. ' '"'' ;... - . :- .'-' ..... ...... / - ..._.,- '-''-.....I.a. - - .1..'-. ... """'"'-'-,J....J· .... ..l....-

A case v.·as defmed as a.""!y cn.i1d t.J.a1: was diagnoseci \Vith one of the neurologic or renal

conditions, iis1ed iiJ. t!:e a1u1ex. ?'\ o dislinc-tion was made on whether a diagnosis was

ITiacie in the ~iinic or D.cspital setting.

Exnosure assessmenr:

1=onfcunde:-s ::nd Effect: 1\Iodiffet·s:

. - ..... year ~:.r1c. r!1Cnlh or

·\1/e used propo~iorrc.l. hazard5 ::iode}s fo: all :-isk analyses. s:ratifieC. b:·- site~ year and

-· . . . . . . - -monLt.l o! otr:!'l fulG. aG. .. iUSiec. :Lor g-==ce:-.

. ,.. ·- .. ~ :ne GG~e o: :~:s: 0.1ag:1osl~

. . .. .. . . anc 1r~;ar1:11e cereorc:.: pa1sy.

c: ':29/:JC

Ya::;c; .. T'e~ in t.."le firs: \.'e~r o_flife. ''S"' oft..T.-..-.a~iti" B va",..inel simiic.r to the gen • ..t.J. - ......... "- ..... - .L ·-}:J .... .... - \..-........ .' -

By l:.mi1ing IO tr..i~ group, v.re imencied to avoid the bias by. indication problen

"tO less ex;:iosu.re (-\ .. accination) i~ :be group ai higher risk of disease anci tl1u~. 1(

•• - • • • • 4 • • • ,, ... - •

.:. ~ some cnagnoses are oner.1 maa.e u: me C!.liDC sertmg:- vve 1nczua.ea a11 rour ~

aciciitional analyses c.::: auusm, s:ee::: msorGe:-s, spe:::ific deveiopmemal a..."1C: sue

peri:12..tal cond.i~ior~s~ '.\~e also did "L~e anal)'ses ior the categor:"· c.: neurologic

6ev·:lopme~:~l disorders llild the sneech dela:' for .:U.L infants.

~cie:1~1fy 2a r:~a_;.::mill.!.l :ru.rnDe~ of exposure c2.-regories \\·ith large enough n'!.Li"lbe

2.i-:d -.:om-carabie size. \1./e ~hen use=:l the. low·est caiegor;' as re!-eren: .. ~: l mo;

Jnl·~· able :o ide:1ti~·· !\VO caLe2ones ror :~e rare ciisorde:.s or three :atego:ies -

::or.L':'lon diso~C.e:-5. -~~: truee mon~s \Ve 1aen11I1ec. fi\'e :a:ego~es fo:- ;ncs~ di·

~amnie Size :md ?ower:

. --.. ezs: ,:--.;_~ :r:~..:-:1:-e:-....

• • ' • • ...l ,~. • • ' • ' ' "1 . . . . 1 . 1

aeveiopmen:a; msoru.er~. >'i e cilC not exclUae em crer: \\1th congemta or pennmai

disorciers :::s :l:is would reduce :he nu.."Tiber of cases to below 50 .

. :\: ~or:.:tl C·: c.ge ~ \\;e found a?~':?.. oi· Q .89 (0.62~ 1.28) Jnd 1.42 (0.62~ _j .:S) IO~ eXDCSt!.Te

-JT.--12.5 a::d > 1:~5 ~g, respecti·ve!:·~ ;viili 0 pg as refere:.:t.

:\t three :nontn.s: see graph :5

For all fo u:;:- :C. "'?vi Os:

? or autism 2.nd the of deve!onmental delavs, the relative risks fcuEd ._,;e:·e .. . .. .. . .. sligb.tl~.r altered: see graph :7. For the other disorde::s ·-vith signi:ficam .. ;mmoers ct

:::as:~s in the :'-.VD acided hlv10s (sl=-e:;J msoraers, sneecn disorders, epilepsy), :ne resultS

:-o:- me -e::n:e catego.-;.· o~"neurobgic deveioomental delays none o~-t..i)e ex:Josw.r;: groups

• <;:'' ~ u j.

ro:- me suogrou; :nciucieci ir~ t:,e :..~ove 3J.1aJyses (see grapr~ ! 9~.

Di~cussior.:

a:e gi·ve::-1 i::-1 tl!e s~cond a..1d :iii:-,:. ::::10ntl:. In aciciition= the i1ighes! proponion of children

:n ~;ur col-:or~ e>:~eeded t.':ie EP~~~ :~-~.tits at one a1d three. months cfage (see SDJdy

prctoccll). \Y~1~reas the expos:.2:-e ::.: ~1.re~ nionth~ of a2e ~s related to late: exnosure

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>Jumoe:- of corr.u.-nor; cases ir. some disorder-s

__ l 2990 ,-6-6---~~0---,.._--~:~3--

""0Qf. - ... ~\,.. 3070 314C 3l539

3070 59 15

3140 158 20

31539 i 330 . i

?or c):her disorjcrS:- :he trend C·f±e :1sk \Vith incieasing exposure 'tO L,hjmerosal \VaS

(re~al or uncleaL· ·._ sonmambuiis:-~1, :nixed en1c tiona..l

~i~t\.LIJG.nces 2··-~ c~rcbr=.l pc.isy). For epileps:; we f01.md a signi:ficam drop of the risk

;:irl~er ciiagno~.:d co~'lUlsio:ls i;1 :hese c:-!iicirea to bette~ llrldcrs~&~d this rlnding.

l o ~:·\ta1uate :;oteni.:ai conrouna1ng b;· heaitl1 care use (to icienLify poientic..l sick :hildrer1

. . . . .. . .. . . . . ..... . . J.Ur110e:- :;,: nosFrta~ ~1c ~~1n1c cra::nose~. ::ne m~-x1mum 1engic c: nospr:aJ sta;· pre:ea1ng

.. .. . - ,.. . . , . . ~r: :j1e rreque::::: C!s:~DULlOC o: an:-· o: tnes=.. sugges:1ng tna: tne calegones are

:orr~Da:ao1= 1~ te:-r:;s c: pre-exist1:;~ illnesses o: health :are see~Lanf Defiavjor of tfle

anC.: ?olic. v:ith o::- without tne Hepmitis E

Tbe freouencY ciistrib~Iiorl o: these l •

differed fo-: the }oyv·esL exposur= cs:egor:y! but ,~;as similar above 25 ;J.g a: three n1onths

•··

s

vaccin~. :himerosa2 ::-ee ·vac::ines~ cQmbinatior: vac:ine or"""F~b a..T'!d DT? or sim~

tiJ::ir.g cf the vaccinstion.s. We. plai1 w repea! t.~e a.'1alyses snatified oy one of tr

mec~u.re~ c:t~alth care S"'"'i:.inc behavior ar1<:i u.,..,,_-w-daieness cf irn..rrn.w."lizations. ......... :::: -

.~.s fo:- o!ema:ure childre::. we fo1md no associated risk of neurologic de·\relonm{

Oe biased. \\11e:: including all nrematl.rre cm1aren. irresDeCti\'e oftheir biiw.1vvei·

of !hi.-:nerosai aocve the 25 ug level at tJrree momh£. s~

an a·,:oid::.nce of vaccina:ion in the mos-r severe group (which is aiso more 1ikely

'-A.·'her2 inciuci::::; the ch.iLir-en f:om all HMOs, we noticed ~:hm the increased risk ........, • '! • "':'

.i. ne ~vo aocea 1

. . - . . anem10n cencn msorae:. ::c:

-:-ne c12:·ve :0:- au:is77 .. siightJ:,· differs as most added eXJ:·OSed cases are founci in

nigl1es~ e:·:posu:e categcne~ . ' • ' - .- ' T • • ' -. ~s r::e:monec. oerore, ro::- :ne otne:- c;sor::ters tne n

- . .... - . . . \v~:. rot:nc :c:- ::.:.e Jroac. categorieS o: 3..J.JY o:- sueCl!lC a.e,.-eloomenta~ ce1ays.

• 1 • ~ • .. • • , . •

:nc.:~ tn1r;1erosa~ exuoscre 1s nnKec Io 1n::

,.

o:. '2910(

~irni!ations:

• \\"e have Emiied ocr a;1alyses to a iist of potential outcomes based on prior

k.I1cwiedge of adve:-se conditions fou11c in ir.Ja."1ts exposed to high doses of

meu~yLTLe::ur:-··. \\7e CfuJnOI ~ule out other disorders potentiall:~ related to exnosure 10

ew.1y·ime::1.Lry.

• ..,1/ e '"'·ere aOle ~c e"'laluaie onl~..- relati,:ely se··.-·ere conditions that come :o me.:iical

attemior.. a...r1d nat possibl:'' more suiJtle effects that would require neuropsychological

Iesting.

• -::-ne srud:• ·.;..·as "J..ncie:powered fo:- some conditions, pa:.-r.iculariy me re!:lal cmcomes.

c Some :nisciassiii:alior~ errors nay ha\'e oc.:.th-;ea 1n toe exnosure assessmen: :~_some

va.cc~!'lanons. pa.:-:ic'..liari:-· Li}e ::1eonara He:;B dose may not nave ·oeen reponed':.

• ...... ,.. . ar~rer~:n:~a!e ·oe:v,.reer. 3ingie ciose L~imerosa: ~ee Hit, ,,.ac:.ines

...,..... . . . .. ne ana1yses were oone assummg

:orne from singi: icse--via.ls diC. no: subs:a.'1Iiali:: alte:- the results.

:;sr1 consumct;or ..

(')-u.

a(:t!ve :omponen: ir: tGe vac:ines. =.x-nosure to 1hime:osal from vac::1nes 1s invariaOly

11" vv~ reiieC entirel~.- or .. autoca::::. no: c8n:ro~ ct~aiit; ·. a~.sumec.

r , .- .. . ' • . . , . ~

cr t:1= cu:-rer.: :InGirlgs ~r~ou~r1 :~.::: c.bs:r2:TlCJns or case-control stEG)·~ \\'~ J=·ropose to ~ . . runs:Iornr.:g o: cohorts

.. ·

:c

< '( H'-lFfDFNTI!\L (

(

· -r~~:;;~~~:~:~;.;~~~~~;~,;~;~;;;-.-~~~~~== :~.~=-==:=· =:i~=-~~~r:\;_~il~~~-~;~~2:=~ · ~­. ·rr:~r-T~~?~:~~!:~;~~~·,, "~~~~~~~~:---·--··---- ··~·: ----·· -- ···--····;1~nr~;-·-=.--·;:;;;t~r;. ::~::: ·· ·

'~ l i (i~~;ttl,l~;'n'~'· ~~r t'lltnlim•s ~;p('clti~~ to i ·~ii _ ~ .. ~:1__{0-.~?~_2-:?_\L_ ---------TRY (r~~j~~-,l?!~)=-~--~~--.11' I ~ M~scry <l!ld '."""'PP_ine~;s di~:onl•·t X I 2.~R ~-!:~;, 5.5:~) _ \ .. 1'-!o ca.•;es

· .ll I H I M 1 ::c!~l. l'lll< II ltlllid d 1~;1111 h:lltn·:; ~i \ ~~-:! ~! ~(_)~] ({-~ ! .'l-: -. ! .'! :.; ( 0: :~ ~~ ~~--- >-1}_ ________ ?.

:'110 /dtt-nlionck!i(:iiSy ISR 0_9(i((Ui5,l.'ll) 2.14(0.~9.4.62) .11 ~ ~ ~il":c\l~c tH:ly~: i1; t.kv~iop111Cill I '!1.'i i _()(, (ii.-92~ f':t2)'"-- --- ())() (ff.~f~( J.t;) ____ ---l i -~. 1i) iT )cv~~~-~P•~ ,;.,,,:ti ~p(·crh cklny f! \ j i. i i ((P}\-T:J 1)- ----- ----().'l~() "((i'.4iCfj0) _______ _

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Graph ; : Reiative risk .,. 9E % c: of Deveiopmentai neurologic cisorders after aiffsrent

e;;:posure levsis ofthimerosal at 3 months of age, NCK &GHC

~ -----------------------------------------------------------------------------

-' - i ... . .. ! ~ i , --- ---~---- ---- i---------T =.J:-~~---- ---f --; ;.---- -F;--- -1--:;~

I l ~~ - -- -~~--------------------------------------------------------------

25 UQ 37.5 ug 50 ug 52.5 U';

(ii=:27\. ir1=30~ rr-;=328) Cn=485; (n=~i2) :;;.!mUiativ;; r,;;;;'::ury exccsure (a no· numbe"; Of axposed ~SeS (n))

~ 52..5 u«; :n=52:·.

Graon :::: Reiatlve risi< .... 95 % C/ of Rena: disorders after differen~ exposure ieveis of thimerosal at 3 months of ag;. NSK &GHC

r-·.,.,.'

< 37.5 u:: \:--:=~." :7.E. u~ {:;=28_'· 5C, u; ;~=3C E2.5 ug {r·=~2~' > 62.~ u; (n=~5· Curr,~.native :nei::ur-y expe:st..::-e :\a:;:i rrumoer of exposeci cz.ses (n})

Ccmoir.e:i2.xl~ 2.'29/0C

Graph 3: Relative r:s~: -. 95 % c: of .Autism after different exposure ieve!s of thimerosal at :3 months of age, NCK &GHC

10 r------------------------------------------------------------,

" . ...... j

< 37.5 ug (n=5·. 37.5 ug (n=16i S2.5 ug (n=6) > 62.5 ug 1n=16)

Cumuiative mercury exposure (and numb&r of exposed cases(n))

Graph 4: Relative risK ..;- 95 % ::;: of Stammerinc after different exposure !eve!s of thimerosai at 3 months of age, NCK &GHC

~00 ------------------------------------------------------------------------

1G - · · • ·- • ·- ·- • ·- • · • • •

' e ; ~ .5.!. -~

-;, ..

::umu•ative mercur:· excosure itlnc numue!" of exposed cases~n)'

Grapr~ :: Relative ~is>:- 95% C' c~ Somr.ar.bt.:i:srr a,. :1ich: te!"rors c;fter differen: exposure ievets of thimerosal a~:; months of age. NCV. &8HC

' ---------------------------------------------------------

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Graoh e: Relative ;isi< - 9f. % C! of Soe~ifi:: deiays in deveiogment after differen: expcsUie leveis c: thimercsai at 3 months of ag€, NCK &GHC

3

25 ug .37.5 ug :=. t:; 32.: ~-: :r:= · :: (n=2 i) \n=2'34) ;_: ... .=:.~33'; {;,=! ~: _;

Gt.!n~·-; _. .>·:9 ~ercurf e;-_;:c:·.l::-e {and numb-er cf ?.!q:csed casss(;:;}~

;cttve risk.; .. -~-

>52.: c~

:rT8rent ·:=xposure i·.2- --fs ct th!merc~;: at 3 months -=-~ .. 2ge, NCK_&GHC

~ .,.--------

Ul

! i .. :---------------- ·-~--- · ·-- ·------ ------ ·- · -~- ------- · --i- ·· -· ·-- -- -~--- ·- ·- ·---·r· -· · ; 1.0: i .. 1::. t --. I ~ ~ . . ...

{ - ' -G--------------------------------------------------------------

0 u;

Grapn 1~: Relative risk~ 95 ~C.- C. cf Unsn.:~1flec o~i2V 1n d~ve,oomen: after difteren: exposuie ieve!s o7 thimerosal a:: montns of age. N=r~ &GHC

~-----------------------------------------------------------------

..:. ..... - ............ - ... --.--- ... -- .. ., .. ----.-.--.---------.--- ........ -----

···-·······r··························-·-····-····r···

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25 us 37.5ur > 62.5 C£ lr~=-:~·: (r~=s;.·.

ClltTl~:iative m.Srcl!r".-·; e~p~suie (anG number of exposeC cases:n}:

•··

2.·'29/CJC

Grapr! -:.::: R.etative risK..;. 9S % c: of infan;:ile cerbra! oaisv after different exoosure ievets of

thimercsai at 3 months of age, NCK &GHC

:o ~----------------------------------------------------------------------

... """!, • ~-.. .;.;.'

9 i,: . ~-

.. -1

i?: i

I

-i i !

0.66

...

62.5 ug (;'1=6) > 62.5 ug (r:=9)

Curr~uiative mercury exposure (and :'1L~~i1ber ci expos-~d cc.ses {n))

Gr~~~ ~3: Relative iL-.'-~ oo1- 95 ~-'a c: ::·~· ;;_:J!i~osv after c:;ffsrent expc:~ ... ~:e le'o~eis of

thif71.;3;csa! at 3 mo~ths ot age: NCK ~ .. :;Hr:;

. J .,.------------

~ z-.: :.JQ 1n= "'.7· ~~.5. U9 ;n::3 :C U9 n=2-5·· E:.5 U£ (fi=~2' > 6:.~ :.J£: \n=:2·. :umutctiv~E- ~er=~ry e::::oosure :a:-1::: numoei c:= exoosed ~cses tn};

Grapr. "'s..;: R.eiative hs~~- ~ es CJc =: o7 Unsos~i'?ie·t K~cne'.' a~ urete; d:zorcie:- afte7 differen~ exoosure· ieveis o~ thimsicsa• a:~, months o~ age. t~::~-: &GH:

10 ------------------------------------------------------------------------------

.,. -

C.~

2!29/0C:

Graph"!=: Reiative risk- 95 ~-~ Cl of Deveicpmente! n9urcjocic disorders amono orematures 1>1500 cj after different exposure ievels of thimerosal at 3 months or age

3 ~--~------------------------------------------------------

~ ::. -:------- . ------ .... --. --- . ----.--.---. ---- ... --.- . -.--. i- . -----.----- ·j·- .. --- ~

~ - • I i ! -- ! ! c :;:

-- J.se .:. o.s I o.s2 I o.sE * - -

~ ---------------------------------------------------------------------< 37.5 u~ '27.5 u~ 50 ug 52.5 uc; > 62 .. 5 u~

Cumulative mercury e~posure

Graph 16: Relative risk- 95 % Cf cf Autism after different exposure levels vf thimerosal at 3 months of age for all HMOs

~Q -------------------------------------------------------------------

.~

-c.·

::umwative rnercur:· e;;oosure :anc number of exooseo ;;.c:ses 1r.);

G:aoh ~7: Re:ative rist·.-'- 95 ~~ c: of ~eveiopmenra! neu;ologic disorder; afte~ difte;ent exposu:-e levels of thimerosal a~ 3 months of age fo:- all HMOs

.s

- i t J ...

~ '·- --

8 ~------------------------------------------------------------------------0 u~ (r:=28j

62.:; u; (r=32)

Cumu:ative mercury sxposur-= :anC r·a~moe:- c:: e~oosed cases tn},

> 62.: up \ n=5se.:.

Graph ~ 2: Relative risK..;. 95 % c; of Develoomental neurologic djso;ders after differer.t e~posure levels of thimerosai at 3 months of age tor ALL kids, all HMOs

i

§; ·~~ ............ r,.., ___ ..::;:p I ~.05 T 1.04 ,., • .. 02 T' 0' Iii

~~~~~1~--~~-----~~---~~ ~ 1 ... E 1 • ~esz ~-,;:l i T o.74 •' o.a2 - -

0 ug (n=56)

~2.5 !..!g 25 ug (n=59)

37.5 ug (n=021)

50 ug

~.11=845)

62.5 ug (n=364)

Cumulative mercury exposure (and number of exposed cases (n))

> 62.5 ug (n=928)

Giapn 1~: Reiative risk""' 9S% c: of Develoomental speech disorder after different exposure !eveis of thimerosal at 3 monihs of age for A:..L. .i<ids. all HMOs

' ~--------------------------------------------------------

.::: : -.-.-- ... -- .... -.-.--.-.-.--------- ... -------------.----- -~.--------- ---.-------~ .. ---¢ T ~ .. ~.~ ; ~.3: ~ ~ ....,.. i .. ...,=

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::umulativE mercury exocsure (ana numoe~ :::f exnosec cases m):

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Thimer-osal VSD srmiv- F ollow-uo on conference csll 03/02/2000 . .

Tni s rep or: Slli"'TI!TI2..i.-:zes acidi"tional anal;,'ses • c1c as a result of fne men:.- suggestions re:ervec dUJ.-ing the r:;e~1ioned conference call.

As the out·:ome "ne:1.rologi~ developmental disorder~" see::ns tc nrovicie a reasonable .... ... . . ,... ,... , . ·. -- . - '

sU:.~a.-:y or all rmpo~L outcomes ~1n 1erms o~ samp1e SIZe)~ l nave restrlcte~ tn.e fo11o\-;.ing anal) .. ses :o tf.t.is ca[egor:' of outcomes.

~J.Jso fer sa:.i.ce of reducing the :1umber of a.:.YJ.al)'Se~, J.Ild :o keep the results easie:- 10 • - .. • .... 1 • ' - • • ... 1nte:pret, l na~ve ~Jsea. me C!.lrnwatlve e:(pos~e at tr1ree months as a conL1nuous ·,·~!a.Cie. Tr:is also resc'l':es the problem of which reierence category :o caoose.

;_~ :\djus:rr.te:· .. --c for age

e Data frcr~:: :~CK be:-cre :995

• Control c.1=.gr:oses

,.._., . . .... --·· . • ... nrrnercsa.i cor!":e::: o: ::::- vac::::lJ.;.es

. ...., . C!ose :ro:- :J.e"8b ll"~

-~,.-,0"' rr-·0~ """:/Q"'; ~-,rl,"l1"::~;"".;:: .! a.J..,::""' ..II. ... .!_. I . • ~ ......- .O..o. V'f "'-'- _,_. •

d.cse from 10/92 :;nv-:ari: ..

• .... • - ~ • - .. -. • • - • - - • • ""* 1: tne au1o:-n.atec cs.tc Stlgges!ec w1a: c.. cr.:JlC.. C9DLln110U.:S!:~· enro11ec. 1r: ~he :!.!"s: :v,ro :'e~s. had had or-j:\"· ~\:/c doses of I-le;:ati:i~ f, by tl-1e 2.g~ 2f:. years. Du: all the fGt:: :;:-? 2~d rtiD fuJd. three polio vac:inc.tiorr~.

......... . ~ . . . . . . . ll"llS 2rpi)rcacn s~1gges--ceu G12.: :ne o1nn aose ,,~··as not

registered in 3.8·:,-·o ~-~u 16.5::;/C aL ~~CK a:-ri GtlC :-especti·vcly :~-.. ltemati\··ely, I l-Jok~d a: chilGren conti!:uou.s:l;: enrolled in the .-

Il:"5~

~-i:Jse of Hc~~E. by s1:\: :7lOnti1s~ bwt '\Vere c::: s:f-!ed.ule for U~? ~ 1-lib 2:..:1~ Poiio (at least ~v.;o o: eacn.::. f~.'::ordiri~ to tl:is a.Ja~~·'sis~ 4.::: ~~ ai:.C : '7.9~,c~ o~ .. -~irt~l ~ose,: are :nisse:: a: NCl·: ~~d ;JrtC respe~:r~/e!:~-. =.:\ .. e:- :ne ;'ea:-s 'L'le:-e !S {;. s:eaa:~· Lunro•v"errler:: a: ~~::I~: fron-_ S .9'!-·G

~IC...KG3.'::S/OC F:..es~ons~.ac~

._...., -.-- -.... ..,._ ... ~ · •.

tc ~-3~-~~ ~'Dereas a! GHC, t.~ere is ar! imprcveme:rr 3.J.~e: an ln.It1a.L dec!me (: :.s~ .. C~ .:.: .. ~~·0 .. ::5.9~ .... 0~ 15.6~/C anci l3.6q;o fo:· ~9:?.. '93~ ~94, ~95 ~ ~1d '96 respe:~ively).

. , 1 - .,. • - , ' .,( ,1 1 • ., •• 1.nese c;:.ta are comparao.e to nnamgs m Jonn lV!Ul oo.y·s pc.per on cata qua.llty. , · · · 1 · 1 hi · a~ ~c , b • , · .. 1 - · _;,..Jtnougn :r:ese ra::es are re atrve y · gn at ri , tz1ey pro- a01y nave ntt e enec: on L':e

t...'-.J.merosal anaiysis as only 1.:.5 ].lg of ethylmercury to the cumulative dose is ad.:ieci for . -- -eacu nepD ,·acc1ne.

Socic;-ec~norn.ic s1arus

= iinkeC. tile r:1es :c- 1990 ce:r:.sus G.ata orr blocks of homes. . men ass1gnea race an c. 1·-,..ome •c t~c ~;,:~c.r~ "'- a-~c~ .. r.:nC' •c nrru' :~·.., '"~<' T;....,. mos+ ""r""V"'ie-.-L ;.,., the;- ~1'oci· l""' ..,. •T .l.l..- • ,., ........,..., v.J.;..J.~ -.~.~ ""' '-'.1-.-....,.,: • · v...-. w.-J rtw..;J i..6.J.-... ~ !--' ..., .Q.J. .LJ. ~ ...... L.l. I..J ~ .'-"•.:;.•

60% was white. 30~'o black, 5 ~-c asian etc, I woulci call the cr...iid white). :Joi.."'lg 1.h.i~:­oomined me follovf.,.,g distri.omion of race anc mcome;

• Race:

Hisuan.ic 6.9~/0 .~.~.siaJ1 6.5~/Q

. - . . -~2:Cl\·~e .~nenca:.-:

... - . . . . . .,. -~·early· .:JOl!Sen.o:c. 1nccme: Und.e: :s !C.: 6.8 S-~.

- 2L I::

monL.'1s.;. ?Jt.1ougrc there. was 2. siign: inc::-ease o: expcsure. a."TTcng wr...i1es a:."'lc ..:l..si2.r.s ;:2\·re:-age :-lg expcsme a:~ mont.~s 5C :.:~ anc 4~ ~g "\'£. 46 ug anC 4~ ~g c...~ong Dla~}~s

. . . . .... . . . . - . an.c. an. 1:1:rease:. :nance o: :ne cru-::o~e lli7.ton~ \\:'lute£ .. stra~lilcc:uor: o;:

:-ace O:."' 1nco:ne . -....-. . :. .. 1~· P ... r\ .. est1r::aie~.

. ... ~ •. \ . ~ . . . Lt:m:;er -:-:'-Vel~ C1Di::J. '\"1S1L3

u: tne . ' moc.e_ .. cnecJ:.Jn;

. . .. cne:1: t:u.:

P,espor.s:.Co:

.....

•

~I) ··-' ! '-...

1·-~ (-~ ~~"\.;~-:: ~~ r-:--· ·-:- ':" '-· ..... /' - - .: ; ..;._ ... 4 -

formally for ever:"' srrarurr_. ?-~s an altenati\'e I did suOanal)'Ses for u~e ciiffe:en! :'w~ea.rs o: age at wrjc.h a child was ng.ht censored because of eithe: diagncs1s or stopped enrollment. For all ages this glYes: RR 1.006 (1.004, 1.010) Under 1 year: 1.006 (0.985, 1.027) 1 -2 vears: l.01 0 (1.000, 1.020) 2-3 years: 1.007 (0.999, 1.014) 3-4 years: 1.009 (0.999, 1.019) > 4 years: 1.002 (0.990~ 1.0 14)

TI1e!"e anoe~s to oe a dedine in the R...~ fu~er 4 ye2l"S of age, but a rather cons~t RR before that .

. j,.s a.T1 alternative 10 the PH model, I also ran a logistic regression modeL ic."'lcluding gende:-. site, year a.11d month ofbirth as covariates, e:;..'"Posure measure and om:::ome as m the ?H mode:, irnposL."'lg a lT'inimum age of cominuous enrollment for non-cases (imposing t:.'1e s2.rr1e minimal age of diagnosis on cases removed too many o: men: c.nci ··ne mor. ... : wow·-' ..,("1- .......... v .. -cr">· ~- .!. ....!-J. . ~ ~J.U~ ...,.'-"'i..i. ''-'J.~---·

Tne RP .... u.1.us o~o~air1eC v.·~ :.007 (1.002. :. 0 ~ l": ro:- no :Tinirn<L time o:· e:::rrollmen:

l.008 (l.OO: .. :.c:~:·~ fo~ minimal ~years of emollmen:

conciucie lG.c.: u,::: ::10ae~ aoes :lO': . . ... propornonamy ~Slli"TIDtlOI: :s vane..

The NC?.: g::ou::. i.: cw....-:-enti·v ::1e:.Kl;.~g ~o~ ~ sar!:nie ci" th= ~2..ses of suee::-_ C1SC:-J.e: ~;:DS:

3:539> on :he ·:iat~. o: ... dicgnosis.

ex:Jcs~e ~1c 2. !C:-

\Vfli:!: one y-.,.·ou1C. :10:: expe:: ~ relatio~sni~ rG eXJ.s::

diffe:-er:: exnosure categones are .- . ana:nea. '....J:-aDr:.

:..Ki.t(C3.-'28/0(

-

•

7. Comparison to number of vaccines, aluminum

The purpose ofthese analyses would be to differentiate between the effect of thimerosal and the vaccines themselves. Unfortunately (nearly) all vaccines in our analysis were either thimerosal containing (DTP, DTaP HepB and Hib) or thimerosal free (polio). Any analysis ofthe number of vaccines or aluminum as an exposure variable would show a correlation to the thimerosal analysis and not be helpful in the distinction. I ran anhyses with the number ofHib, DTP, HepB and polio vaccines as exposure and found a relationship ofthe risk to the number ofDTP and Hib vaccines received at three momhs, which was to be expected. I also found a relationship :o the age at which the first F~ib vaccine was given (the Imer the vaccine given, the le:s chance ofncarologic developmental delay), which was also to be expected. Surprisingly, I did not fmu his for DTP. To easily differentiate bc~\vecn the effect ofthirnero::..J and vaccine, ve would m . to compare a group that received thimerosal free vaccine to thimerosal ·-Ontaining \; .:me, which leads to point 8. The closest we have come to such a comparison was by comparing the group that received 1he DTP-Hib combination vaccine (contaL"liflg 25 pg of mercury) to the group that received the DTP and Hib separately ( ~ach 25 pg of mercury). This comparison showed no significant relation to the outcome neurologic developmental delay.

8. Thimerosal content of Hib vaccines:

The FDA is currentiy matching the lot numbers to information on the exact or mean thimerosal content for all vaccines used in the two HMOs.

- ,. LKLK03/28/00 Response.doc 4

.. ~ , .. \ ....... ';",. n __,"" , ......... T • -- : 1. j : "-1 ;- J - !-. ''\ i i .~. ~ -··· .... ... . . - .;. _ __,~ ~ . ' ......... __

Graph 1. Relative risk+ 95 % confidence intervals of after different exposure levels o·f thimerosal at 3 months of age for some additional conditions

Unspecified conjunctivitis

1.5T-----------------------------------------------------~

.:.: r_:.2 T 1::::±:::±.15 1.21 ~. 11 ~.21 I ~ .~·~-1 .. ~~ .!. - :: -y l1.18 z1 ·1--~ ----~--~~~~--~--------~~~--~----------~--~---~ -E C)

~

0 ug (n=366)

'i2.5 ug (n=52·8)

25 ug 37.5 ug 50 ug (n=GO:) (n=6069) (n=5388) Cumu;ative mercurf exj)osure

Non :; 9ecific non-1:=fectious Gas-f: ._-enteritis

1.5 . --------

62.5 ~g (n=i2 ~7)

> 62.5 ug (n=2494)

~. I -1· 1.14 ±-1.1 11 f111 j: ! . _ ~--· ..... _·---.~! .. 1 .o:. I

]1~~r--~~-~~=~~------~--~~--~r~------~1~1.~0~ ~ i ~ I

0.5 ~--------------------------------------------------------~ 0 ug

(n=522)

12.5 ug (n=72'1)

Unspecified injury

25 ug 37.5 ug 50 ug ln=815) (r.=8171' (n=7924) Cumulative mercury exposure

62.5 ug (n=1775)

> 62.5 ug (n=3090)

2~------------------------------------------------------------

0.5~--------------------------------------------------------~ 0 ug (n=82) 12.5 ug

(n=52)

,.·

LKLK03/28/00

25 ug

(n=\22) 37.5 ug

(n=652)

50 ug

(n=1199)

Cumulative mercury exposure

Response.doc

62..5 ug (n=612)

> 62.5 ug {n=€50)

5

~··---~

.. . "\--

Thin1erosal v-sD stud'l ..

Phase I

Update

2/29/00

Thomas \~ erstraeter:, F'"obert Davis, Frank DeStefano