A Retrospective Chart Validation Study Evaluating the Performance of Machine Learning Algorithm (ML) to Predict the Clinical Diagnosis of Wild-type Transthyretin Amyloid Cardiomyopathy (ATTRwt-CM) and Non-amyloid Heart Failure Among Patients With Heart Failure (HF)
Conditions: ATTR-CM
Sponsor: Pfizer

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1  of 2 5  
 
N O N -I N T E R V E N TI O N A L ( NI) S T U D Y P R O T O C O L 
St u d y Inf or m ati o n  
Title  
A retr os pecti ve c hart vali dati o n st u d y 
e val uati n g t he perf or ma nce of mac hi ne 
lear ni n g al g orit h m  ( M L) t o pre dict  t he 
cli nical dia g n osis of w il d-t y pe tra nst h yreti n 
am yl oi d car di o m y o pat h y  ( A T T R wt-C M) 
a n d n o n -a m yl oi d heart fail ure  a m o n g 
patie nts wit h heart fail ure ( H F)  
Pr ot oc ol n u m ber  
B 3 4 6 1 1 1 1  
Pr ot oc ol ve rsi o n i de ntifier  
1 . 0 
D ate  
1 4 J ul y 2 0 2 3  
Rese arc h q uesti o n a n d o bjecti ves  
T he g oal of t his st u d y is t o e val uate t he 
perf or ma n ce of a A T T R wt -C M  M L 
al g orit h m t o pre dict t he cli nical dia g n osis of 
A T T R wt -C M  a m o n g H F patie nts  a gai nst 
c hart-re vie w-base d gr o u n d tr ut h wit h a 
pres pecifi e d perf or ma nce t hres h ol ds i n 
se nsiti vit y a n d s pecificit y.  
A ut h or  
 M P H 
  
 
 
 
T his  d oc u me nt  c o ntai ns c o nfi de ntial  i nf or mati o n bel o n gi n g  t o Pfizer.  E xce pt  as ot her wise  a gree d  t o i n writi n g, 
b y acce pti n g or re vie wi n g t his d oc u me nt, y o u a gree t o h ol d t his i nf or mati o n i n c o nfi de nce a n d n ot c o p y or 
discl ose  it t o ot hers  (e x ce pt w here  re q uire d b y  a p plica ble  la w) or  use  it f or u na ut h orize d  p ur p oses.  I n t he e v e nt 
of a n y act ual or s us pecte d breac h of t his o bli gati o n , Pfizer m ust be pr o m ptl y n otifie d. 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)
P P D
P P D
P P D

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 2  of 2 5  
1.  T A B L E O F C O N T E N T S  
1. T A B L E O F C O N T E N T S  .......................................................................................................2  
2. LI S T O F A B B R E VI A TI O N S  ................................................................................................4  
3. R E S P O N SI B L E P A R TI E S  ....................................................................................................7  
4. A B S T R A C T  ...........................................................................................................................9  
5. A M E N D M E N T S A N D U P D A T E S  .....................................................................................1 1  
6. MI L E S T O N E S  .....................................................................................................................1 2  
7. R A TI O N A L E A N D B A C K G R O U N D  ................................................................................1 3  
8. R E S E A R C H Q U E S TI O N A N D O BJ E C TI V E S  .................................................................1 4  
9. R E S E A R C H M E T H O D S  ....................................................................................................1 4  
9. 1. St u d y Desi g n  ...........................................................................................................1 4  
9. 2. Setti n g  ......................................................................................................................1 5  
9. 2. 1. I n cl usi o n Criteria  ........................................................................................1 5  
9. 2. 2. E xcl usi o n Criteria  .......................................................................................1 6  
9. 3. Deri ve d V aria bles  ....................................................................................................1 6  
9. 4. Data S o urces  ............................................................................................................1 6  
9. 5. St u d y size  ................................................................................................................1 7  
9. 6. Data M a n a ge me nt  ...................................................................................................1 8  
9. 7. Data A nal ysis  ..........................................................................................................1 9  
9. 7. 1. Statistical Met h o ds  ......................................................................................1 9  
9. 8. Q ualit y C o ntr ol  ........................................................................................................2 0  
9. 9. Li mitati o ns of t he Researc h Met h o ds  ......................................................................2 1  
9. 1 0. Ot her As pects  ........................................................................................................2 1  
1 0. P R O T E C TI O N O F H U M A N S U BJ E C T S  ........................................................................2 1  
1 0. 1. Patie nt I nf or mati o n  ................................................................................................2 1  
1 0. 2. Patie nt C o nse nt  ......................................................................................................2 1  
1 0. 3. I nstit uti o nal Re vie w B oar d (I R B)/I n de p e n d e nt Et hics C o m mittee (I E C)  ............2 1  
1 0. 4. Et hical C o n d uct of t he St u d y  ................................................................................2 2  
1 1. M A N A G E M E N T A N D R E P O R TI N G O F A D V E R S E E V E N T S/ A D V E R S E 
R E A C TI O N S  ......................................................................................................................2 2  
1 1. 1. Str uct ure d Data A n al ysis  .......................................................................................2 2  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 3  of 2 5  
1 2. P L A N S F O R DI S S E MI N A TI N G A N D C O M M U NI C A TI N G S T U D Y R E S U L T S ........2 2  
1 3. R E F E R E N C E S  ..................................................................................................................2 3  
1 4. LI S T O F T A B L E S  .............................................................................................................2 5  
1 5. LI S T O F FI G U R E S  ...........................................................................................................2 5  
1 6. A N N E X 1. LI S T O F S T A N D -A L O N E D O C U M E N T S  ...................................................2 5  
1 7. A N N E X 2. A D DI TI O N A L I N F O R M A TI O N  ...................................................................2 5  
 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 4  of 2 5  
2.  LI S T  O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
A E  
A d verse E v e nt  
A E M  
A d verse E v e nt M o nit ori n g  
A L  
Li g ht C hai n A m yl oi d  
A T T R  
Tra nst h yreti n A m yl oi d  
A T T R -C M  
Tra nst h yreti n A m yl oi d Car di o m y o pat h y  
A T T R wt -C M  
Wil d -t y pe Tra nst h yreti n A m yl oi d Car di o m y o pat h y  
C P T  
Cli nical Pr oce d ural Ter mi n ol o g y, F o urt h E diti o n  
Dr P H  
D oct or of P u blic Healt h  
E H R  
Electr o nic Healt hcare Rec or ds  
F A S A  
Fell o w of A m erica n Statistical Ass ociati o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F N  
False Ne gati ve  
F P  
False P ositi ve  
G P P  
G ui deli nes f or G o o d P har mac oe pi de mi ol o g y 
Practices  
G R A C E  
G o o d Rese Arc h f or C o m parati ve Effecti ve ness  
h A T T R -C M  
Here ditar y or Fa miliar Tra nst h yreti n A m yl oi d  
Car di o m y o pat h y  
H C P C S  
Healt hcare C o m m o n Pr oce d ure C o di n g S yste m  
H F  
Heart Fail ure  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 5  of 2 5  
A b bre vi ati o n  
Defi niti o n  
HI P P A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y A ct  
I C D-1 0  
I nter nati o nal Classificati o n of Diseases, T e nt h 
Re visi o n  
I C D-1 0 -C M  
I nter nati o nal Classificati o n of Diseases, T e nt h 
Re visi o n, Cli nical M o dificati o n  
I C D-1 0 -P C S  
I nter nati o nal Classificati o n of Diseases, T e nt h 
Re visi o n, Pr oce d ural Classificati o n S yste m  
I C MJ E 
I nter nati o nal C o m mittee of Me dical J o ur n al E dit ors 
I D N 
I nte grate d Deli ver y Net w or k 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
I S P E 
I nter nati o nal S ociet y f or P har mac oe pi de mi ol o g y 
I S P O R 
I nter nati o nal S ociet y f or P har mac oec o n o mics a n d 
O utc o mes Researc h  
M A  
Master of Arts  
M B A  
Master of B usi ness A d mi nistrati o n  
M D  
D oct or of Me di ci ne  
M L  
Mac hi ne Lear ni n g  
M P H  
Master of P u blic Healt h  
M S  
Master of Scie n ce  
N D C  
Nati o nal Dr u g C o de  
NI M  
N o n -i nferi orit y Mar gi n 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 6  of 2 5  
A b bre vi ati o n  
Defi niti o n  
NI S  
N o n -i nter ve nti o nal St u d y 
N L P  
Nat ural La n g u a ge Pr ocessi n g  
P har m D  
D oct or of P har m ac y  
P h D  
D oct or of P hil os o p h y  
Q C  
Q ualit y C o ntr ol  
R A  
R he u mat oi d A rt hritis 
R W E  
Real W orl d E vi de nce  
T N  
Tr ue Ne g ati ve  
T P  
Tr ue P ositi ve  
T T R  
Tra nst h yreti n  
wt A T T R -C M  
Wil d -T y pe Tra nst h yreti n A m yl oi d  Car di o m y o pat h y  
U S  
U nite d States  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 7  of 2 5  
3.  R E S P O N SI B L E P A R TI E S  
Pri nci p al I n vesti g at or of t he Pr ot oc ol  
N a me, de gree(s)  
J o b Title  
Affili ati o n  
A d dress  
Ja nice H. C h u n g, 
M P H  
Direct or, Rare 
Disease R W E 
Scie ntist, E vi de nce 
Ge nerati o n Platf or m 
R W E  
Pfizer I nc.  
6 6 H u ds o n Bl v d 
East Ne w Y or k 
Ne w Y or k 1 0 0 0 1  
 
C oll a b or at ors  
N a me, de gree(s)  
J o b Title  
Affili ati o n  
A d dress  
, Dr P H 
Pfizer I nc.  
6 6 H u ds o n Bl v d 
East Ne w Y or k 
Ne w Y or k 1 0 0 0 1  
P har m D, M B A  
Pfizer I nc.  
6 6 H u ds o n Bl v d 
East Ne w Y or k 
Ne w Y or k 1 0 0 0 1  
 P h D 
Pfizer I nc.  
5 0 0 Arc ola R d 
C olle ge ville, P A 
1 9 4 2 6  
, Phar m D,  
P h D  
Pfizer I nc.  
A v da  E ur o pa 2 0 B  
2 8 .1 0 8 Alc o be n das . 
Ma dri d   
, M S, 
F A S A  
Pfizer I nc.  
6 6 H u ds o n Bl v d 
East Ne w Y or k 
Ne w Y or k 1 0 0 0 1  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)
P P D
P P D
P P D
P P D
P P D
P P D

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 8  of 2 5  
N a me, de gree(s)  
J o b Title  
Affili ati o n  
A d dress  
 
M D, M S  
Pfizer I nc.  
6 6 H u ds o n Bl v d 
East Ne w Y or k 
Ne w Y or k 1 0 0 0 1  
 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)
P P D
P P D

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 9  of 2 5  
4.  A B S T R A C T  
Title: A retr os p ecti ve vali dati o n st u d y e val uati n g t he perf or ma nce of m ac hi ne lear ni n g ( M L) 
al g orit h m t o i de ntif y c hart-base d cli nical  dia g n osis of wil d -t y pe tra nst h yreti n a m yl oi d 
car di o m y o pat h y  (A T T R wt -C M ) a n d n o n-a m yl oi d heart fail ure a m o n g patie nts wit h heart 
fail ure ( H F) 
Versi o n 1. 0, 2 7  J ul y 2 0 2 3 
 M P H, Pfizer, I nc. 
R ati o n ale a n d b ac k gr o u n d:  T o i de ntif y s us pecte d patie nts wit h A T T R wt -C M, Pfizer 
de vel o pe d a n d assesse d a M L  m o del usi n g a lar ge, nati o nall y re pres e ntati ve data base wit h 
s u bse q ue nt perf or ma nce e val uati o n s i n m ulti ple differe nt clai m- a n d E H R -base d 
data bases .1 ,1 2 -1 5 T his m o del use d patie nt ’s m e dical clai ms  data  t o differe ntiate p ote ntial 
A T T R wt -C M patie nts fr o m t h ose w h o s uffere d fr o m ot her ca uses of H F a m o n g H F patie nts 
5 0 years of a ge or ol d er. 
 
 
. T he care pr o vi der ca n d eter mi ne if t he 
i de ntifie d patie nt re q uir e s f urt her e v al uati o n a n d/ or referral t o ot her a p pr o priate healt hcare 
pr o vi ders is nee d e d.  T his t o ol ma y facilitate earl y a n d acc urate di a g n osis of A T T R wt-C M.  
 
 
 
. 
T he  M L m o del was de v el o pe d usi n g  a n o perati n g defi niti o n of s us pici o us  A T T R wt -C M 
patie nts wit h  t he prese nce of E 8 5. 8 2, a n I C D-1 0 -C M  (I nter nati o nal Classificati o n of 
Diseases, Te nt h Re visi o n, Cli nical M o dificati o n ) dia g n osis c o de. H o we v er, t he I C D-1 0 -C M  
c o de is a n a d mi nistrati ve c o de use d f or billi n g p ur p ose . T heref ore , a n a d diti o nal cli nical 
st u d y will be re q uire d t o vali date  t hat t he M L al g orit h m ca n acc uratel y i de ntif y patie nts wit h 
cli nicall y c o nfir me d A T T R wt -C M a m o n g H F  patie nts 5 0 years of a ge or ol der .  
St u d y  o bjecti ve:  T h is st u d y ai ms t o e val uate t he perf or ma n ce of t he A T T R wt -C M M L 
m o del  t o pre dict t he cli nical dia g n osis of A T T R wt-C M a m o n g H F patie nts a gai nst c hart -
re vie w-b ase d gr o u n d tr ut h wit h a pres pecifie d perf or ma nce t hr es h ol ds i n se nsiti vit y a n d 
s pecificit y. 
St u d y desi g n:  T his is a n  o bser vati o nal, retr os pecti ve n o n -i nferi orit y st u d y wit h a st u d y 
sa m ple fr o m a lar ge nati o nal E H R  data base  i nte grate d wit h a d mi nistrati ve clai ms . 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)
P P D
C CI
C CI

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 0  of 2 5  
P o p ul ati o n: T his st u d y will i ncl u de H F patie nts ≥5 0 years ol d wit h cli nical dia g n osis of 
A T T R wt -C M or n o n -a m yl oi d  H F ascertai ne d b y c harts. Patie nts will be re q u ire d t o ha ve 
≥1 2  m o nt hs of c o nti n u o us acti vit y i n t he E H R or clai ms pri or t o t he I n d e x Date.  T here will 
be n o mi ni mal f oll o w -u p peri o d f or patie nts i n t his st u d y.  
D at a s o urce:  O pt u m’s  Electr o nic Healt h  Rec or d  a n d I nte grate d Clai ms -Cli nical data base  
t hat c o m bi nes a dj u dicate d clai ms data ( w here a vaila ble) wit h O pt u m’s E H R data, are t h e data 
s o urces f or t his st u d y. I n a d diti o n, t his st u d y will use data a v aila ble i n t he u nstr uct ure d  f or a 
s u bset of A T T R wt-C M a n d n o n -a m yl oi d heart fail ure a m o n g patie nts wit h H F  t hat ha v e 
cli nical patie nt n otes a n d ot her data t hat ca n n ot be ma p pe d i nt o t he lar ger str uct ure d 
data base.  O pt u m’s l o n git u di nal re p osit or y is deri v e d fr o m d oze ns of healt hcare pr o vi der 
or ga nizati o ns i n t he U S, t hat i ncl u de m ore t ha n 5 7 c o ntri b uti n g  s o urces a n d 1 1 1 K sites of 
care: treati n g m ore t ha n 1 0 6 milli o n patie nts recei vi n g care i n t he U S.  
S a m ple  size: Usi n g vari o us ke y w or d searc h, feasi bilit y assess me nt was perf or me d. I n t h e 
O pt u m E H R data, t here were 4 2 2 p ote ntial A T T R wt -C M rec or ds a v aila ble;  yet, bef ore 
re vie wi n g t he u nstr uct ure d n otes, o ne is u na ble t o deter mi ne t he t otal n u m b er of cli nicall y 
dia g n ose d A T T R wt -C M patie nts. Gi ve n t hat A T T R wt -C M is a rare dise ase, t he tea m will 
atte m pt t o ma xi mize t he n u m ber of p ote ntial cases b y perf or mi n g n ot e re vie w f or all 
4 2 2  c harts. Si milar n u m ber of c o ntr ol c harts will b e re vie we d t o bala n ce t he n u m ber of cases 
a n d c o ntr ols.  We esti mate t hat t he  sa m ple sizes will li kel y  pr o vi de 9 0 % p o wer t o satisf y t he 
n o n -i nferi orit y h y p ot heses. 
D at a a n al ysis : T he M L m o d el will i de ntif y patie nts wit h H F as s us pecte d A T T R wt -C M a n d 
t he re mai n der patie nts as n ot s us pecte d f or A T T R wt-C M/ n o n -a m yl oi d heart fail ure. T h e 
patie nts wit h H F will be e ntere d i n t he M L al g orit h m al o n g wit h t heir dia g n osis c o des liste d 
i n all t heir rec or ds. T h e m o del will classif y patie nts base d o n t he pres e nce a n d a bse nce of 
car diac a n d n o n -car di ac feat ures a n d cat e g orize d as s us pecte d (at-ris k) or n ot s us pecte d wit h 
A T T R wt -C M. T he m o del perf or ma nce metrics (se nsiti vit y a n d s pecificit y) will be calc ulat e d 
base d o n t he c o n c or da n ce bet wee n cas e ascertai n me nt of A T T R wt -C M usi n g dia g n ostic 
c o des wit h ascertai n me nt usi n g cli nical patie nt n otes  re vie w, t h e latter usi n g a variet y of 
criteria t o defi ne A T T R wt -C M .  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 1  of 2 5  
5.  A M E N D M E N T S A N D U P D A T E S  
N o ne . 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 2  of 2 5  
6.  MI L E S T O N E S  
Milest o ne  
Pl a n ne d d ate  
Start of data c ollecti o n  
Se pte m ber  1,  2 0 2 3  
E n d of data c ollecti o n  
Oct o ber 3 1,  2 0 2 3  
Fi nal st u d y re p ort  
N o ve m ber 3 0, 2 0 2 3  
 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 3  of 2 5  
7.  R A TI O N A L E A N D B A C K G R O U N D  
Tra nst h yreti n a m yl oi d car di o m y o pat h y ( A T T R -C M) is a rare c o n diti o n t hat is a n 
u nrec o g niz e d ca us e of heart fail ure . T he t y pical cli nical prese nt ati o n i ncl u des si g ns a n d 
s y m pt o ms of heart fail ure. T he e xisti n g nat ural hist or y data  of t he dise ase is p o or, wit h 
A T T R v -C M a n d A T T R wt -C M ha vi n g a n esti mate d me dia n s ur vi val of 2. 5 years a n d 
3. 6  years after dia g n osis res pecti vel y, a n d t y picall y res ulti n g fr o m pr o gressi ve heart fail ure or 
s u d de n deat h.2 -4 Beca use t he s y m pt o ms are heter o ge ne o us , i ncl u di n g b ot h car diac a n d n o n -
car dia c i n v ol ve me nt, t he dia g n osis of A T T R-C M, i ncl u di n g A T T R wt -C M, is ofte n dela ye d, 
or misse d. 2 ,5 Earl y dia g n osis of A T T R -C M is ke y as pr o gressi o n  w ors e ns ra pi dl y; h o we ver, 
d ia g n ostic dela y a n d mis dia g n osis of A T T R-C M is c o m m o n, wit h a re p orte d mea n ti me t o 
dia g n osis of 6. 1 years i n A T T R wt -C M. 6 C urre nt dia g n ostic t o ols i ncl u de s pec kle-tr ac ki n g 
ec h ocar di o gra p h y, car di ac ma g netic res o na nce i ma gi n g wit h c o ntrast, b o ne sci nti gra p h y, 
a n d/ or bl o o d tests f or a m yl oi d o ge nic li g ht c hai n a m yl oi d. Rece nt e x pert c o nse ns us 
rec o m me n dati o ns a n d cli nical “re d fla g” cl ues ha v e bee n esta blis he d t o hel p raise s us pici o n 
of A T T R -C M a n d ha v e b ee n classifie d i nt o car diac feat ures ( i.e., h eart fail ure, atrial 
fi brillati o n) a n d e xtracar diac feat ures (i. e., hist or y of car pal t u n nel s y n dr o me). 7 -1 1 A  
scree ni n g t o ol t hat rais es g reater cli nical a ware ness of t hese “re d fla gs ” ma y hel p raise 
s us pici o n a n d i de ntificati o n of t he A T T R wt-C M.  
I n a n eff ort t o i de ntif y s us pecte d patie nts wit h A T T R wt -C M , Pfizer de vel o pe d a n d vali date d 
a ra n d o m f orest-bas e d M L  ris k pre dicti o n m o del usi n g a lar ge, nati o nall y re prese ntati ve 
data base wit h s u bse q u e nt vali dati o n a n d perf or ma nce i n m ulti ple a d diti o nal c o h orts .1 ,1 2 -1 5his  
m o del i de ntifie d patie nt c haracteristics t hat c o ul d be use d t o differe ntiate A T T R wt -C M  fr o m 
ot her ca us es of H F a m o n g H F patie nts 5 0 years of a ge or ol der . T his m o del  s h o we d a n 
ass ociati o n bet wee n cli nical feat ures t hat w ere ass ociate d wit h A T T R wt -C M us i n g U S 
me dical clai ms. 
 
 
 
 
I n d e vel o pi n g t he M L al g orit h m, the o nl y cli nical vali dati o n c o h ort c o nfir m e d t he dia g n osis 
of s us pici o us A T T R wt -C M  patie nts i de ntifie d b y a n al g orit h m usi n g t he prese nce of a n 
I C D-1 0  (I nter nati o nal Classificati o n of Diseas es, Te nt h Re visi o n) dia g n osis c o de, E 8 5. 8 2. 
I C D-1 0  c o de is a n a d mi nistrati ve c o de use d f or billi n g p ur p ose a n d it li kel y ma y n ot be 
rea dil y use d as a g ol d sta n dar d t o c o nfir m a cli nical dia g n osis. T he prese n ce of a dia g n osis 
c o de ma y mea n t hat t he patie nt has a cli nical dia g n osis; h o we ver, it als o ofte n mea ns t hat t he 
cli nicia n ma y scree n t he patie nt f or t he diseas e, w hic h re q uires f urt her cli nical i n f or mati o n t o 
c o nfir m t he dia g n osis. Gi ve n t his, a n  a d diti o nal cli nical vali dati o n st u d y is vital  t o e ns ure t hat 
t he M L al g orit h m ca n pre dict t he ris k of cli nicall y c o nfir me d A T T R wt -C M  a m o n g patie nt s 
wit h H F.  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)
C CI

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 4  of 2 5  
8.  R E S E A R C H Q U E S TI O N A N D O B J E C TI V E S  
T his st u d y ai m s t o f urt her e val uate t h e perf or ma nce of t he A T T R wt -C M M L m o del t o 
pre dict t he cli nical dia g n osis of A T T R wt -C M a m o n g H F patie nts a g ai nst c hart -re vi e w-b ase d 
gr o u n d tr ut h wit h a pres p ecifie d perf or m a nce t hr es h ol ds i n se nsiti vit y a n d s pecificit y.  
9.  R E S E A R C H M E T H O D S  
9. 1.  St u d y D esi g n   
T his is a retr os pecti ve c o h ort st u d y. Patie nts wit h H F w h o meet i ncl usi o n a n d e xcl usi o n 
criteria will be i de ntifie d fr o m t he O pt u m  E H R  dat a base bet w ee n 0 1 J a n uar y 2 0 1 8  a n d 
3 0  A pril 2 0 2 3 . A s u bset of patie nts wit h cli nical dia g n osis of A T T R wt -C M  or n o n -a m yl oi d 
heart fail ure as certai n e d b y c harts will be i ncl u de d i n t his st u d y  (st u d y p o p ulati o n). Detail e d 
met h o d ol o g y of cli nical dia g n osis  ascertai n me nt is f o u n d i n A p pe n di x A . Patie nts will be 
i n de xe d at t heir latest heart fail ure dia g n osis or treat me nt date a n d will be re q uire d t o ha ve 
≥1 2 m o nt hs of acti vit y bef ore t h e i n de x date.  T h ere will be n o mi ni mal f oll o w -u p peri o d f or 
patie nts i n t his st u d y.   
Fi g ure 1 . St u d y Desi g n  
 
T he  M L  al g orit h m  will  calc ulate t he pre dicte d pr o ba bilit y of A T T R wt -C M  f or t hese heart 
fail ure patie nts bas e d o n t he prese n ce a n d a bse nce of  feat ur es ( de m o gra p hi cs, cli nical 
dia g n osis, etc.,) d uri n g t h e pre -i n d e x peri o d. Detaile d M L al g orit h m met h o d ol o g y ca n be 
f o u n d i n H u da et al.1 Base d  o n a pre -s pecifie d pre dicte d pr o ba bilit y t hres h ol d of 0. 5, w e will 
f urt her cl assif y t hese pati e nts as s us pecte d A T T R wt -C M  ( pre dicte d pr o ba bilit y ≥0. 5)  a n d n ot 
s us pecte d wit h A T T R wt -C M /n o n -a m yl oi d  heart fail ure  ( pre dict e d pr o ba bilit y < 0. 5) . T he 
m o del perf or ma n ce metrics (se nsiti vit y a n d s pecifi cit y) will be calc ulat e d b y cr oss -ta b ulati n g 
dia g n osis base d o n M L al g orit h m a n d dia g n osis base d o n c hart ascertai n m e nt .  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 5  of 2 5  
Fi g ure 2 . E v al u ati n g M L M o del Perf or m a nce  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 2.  Setti n g  
T his st u d y will use t he U S -base d O pt u m's dei de ntifie d E H R  data, wit h  s u p ple me ntal li n ka ge 
t o O pt u m’s I nte grate d Cl ai ms-Cli nical a dj u dicate d clai ms dataset f or t h ose  patie nts i n t he 
E H R w h o als o ha ve clai ms data a vaila ble. F or a s u bset of pati e nts i n t he E H R, data  e xist 
i ncl u di n g patie nt electr o nic cli nical n otes w hic h will all o w ma n ual cli nicia n re vie w at O pt u m 
t o c o nfir m cli nical dia g n osis of A T T R wt -C M  or n o n -a m yl oi d heart fail ure  base d o n a vaila bl e 
data t hat ali g n wit h t he Pfizer cli nicia n s pecifie d s pecificati o n . O pt u m’s r ol e, pr ocess es , a n d 
data is descri be d i n m ore detail i n  Secti o n 9. 4  a n d Secti o n 9. 6 . 
9. 2. 1.  I ncl usi on  C riteri a  
Pri m ar y A n al ysis  
T his st u d y will i ncl u de H F patie nts  ( defi ne d as h a vi n g ≥1 clai m f or H F or H F treat me nt) 
≥5 0  years ol d  wit h cli nic al dia g n osis  of  A T T R wt -C M  or n o n -a m yl oi d  H F ascertai ne d b y 
charts.  Patie nts will be re q uire d t o ha ve ≥1 2 m o nt hs of c o nti n u o us acti vit y i n t he E H R or 
clai ms pri or t o t he I n de x Date.  
Se nsiti vit y a n al ysis ( pe n di n g fe asi bilit y assess me nt) 
1.  T he earliest H F dia g n osis  or treat me nt  date as t he i n de x date  
2.  P atie nts wit h o ut H F dia g n osis or treat me nt  ( pe n di n g feasi bilit y assess me nt) 
3.  Hi g h Ris k P o p ulati o n:  
H F  p atie nts wit h cli nical dia g n osis of wt A T T R -C M 
or n o n -a m yl oi d heart fail ure ascertai ne d b y c harts  
E val uate d b y M L m o del  
Classifie d  as 
wt A T T R -C M  
 
Classifie d  as  
n o n -s us pecte d wit h 
wt A T T R -C M  
 
 
 
Perf or ma nce 
statistics 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 6  of 2 5  
•  A ge 6 5 +  
•  M ale ge n der  
•  P rese nce of car pal t u n nel s y n dr o me 
9. 2. 2.  E xcl usi o n C riteri a  
Patie nts  wit h a n y of t he f oll o wi n g dia g n oses : 
•  Li g ht c hai n ( A L) a m yl oi d osis  
•  I ntr acra nial he m orr ha ge 
•  Cere bral a m yl oi d a n gi o pat h y  
•  E n d sta ge re n al disease  
•  Bl o o d ca ncer  
9. 3.  Deri ve d V ari a bles  
V ari a ble  
R ole  
O per ati o n al  defi niti o n  
H F  
I n de x 
•  L atest  cl ai m/e nc o u nter f or H F or H F tre at me nt (see 
A p pe n dix B  f or t he c o de list) 
A T T R wt -C M  
E x p os ure  
•  C o nfir me d : Gr o u n d tr ut h a scert ai ne d by c h arts  
•  S us pecte d  A T T R wt -C M : I de ntifie d by  t he M L 
al g orit h m  ( pre dicte d pr o b a bility ≥ 0. 5) 
•  N ot  S us pecte d  wit h  A T T R wt -C M /n o n -a myl oi d he art 
f ail ure: I de ntifie d b y t he M L al g orit h m  ( pre dicte d 
pr o ba bilit y < 0. 5)  
9. 4.  D at a S o urces   
O pt u m's E H R a n d I nt e grate d Clai ms -Cli nical dataset, w hic h c o m bi nes a dj u dicate d clai ms 
data ( w here a vaila ble) wit h O pt u m's E H R data, are t he data s o urces f or t his st u d y. O p t u m 
i nte grates E H R data wit h clai ms, prescri bi n g, dis p e nsi n g, a n d practice ma na ge me nt data b y 
part neri n g directl y wit h se veral m ulti -s peci alt y me dical gr o u ps, I D Ns a n d h os pital c hai ns t o 
e xtract dat a fr o m t heir E H R a n d vari o us i nf or mati o n tec h n ol o g y s yste m s i n t he U S. B y 
n or malizi n g, vali dati n g, a n d a g gre g ati n g t he de -i d e ntifie d data, O pt u m ge n erates a 
l o n git u di nal vie w of patie nt care. 
O pt u m’s l o n git u di nal E H R re p osit or y is deri ve d fr o m d oze ns of healt hcare pr o vi der 
or ga nizati o ns i n t he U S, t hat i ncl u de m o re t ha n 5 7 c o ntri b uti n g s o urces a n d 1 1 1 K sites of 
care: treati n g m ore t ha n 1 0 6 milli o n patie nts recei vi n g care i n t he U S. T h e data is certifie d as 
de -i de ntifie d b y a n i n d e p e n de nt statistical e x pert f oll o wi n g HI P A A statistical 
de -i de ntificati o n r ules a n d mana ge d acc or di n g t o O pt u m c ust o mer data use 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 7  of 2 5  
a gree m e nt .1 ,2li nical, clai ms a n d ot her me dical a d mi nistrati ve data is o btai ne d fr o m b ot h 
I n p atie nt a n d A m b ulat or y E H Rs, practice m a na ge me nt s yste ms a n d n u mer o us ot her i nter nal 
s yste ms. I nf or mati o n is pr ocesse d, n or malize d, a n d sta n dar dize d acr oss t he c o nti n u u m of 
care fr o m b ot h ac ut e i n patie nt sta ys a n d o ut patie nt visits. O pt u m data ele me nts i ncl u de 
de m o gra p hics, me dic ati o ns prescri be d a n d a d mi nistere d, i m m u nizati o ns, aller gies, la b res ults 
(i ncl u di n g micr o bi ol o g y), vital si g ns a n d ot her o bser va ble meas ure m e nts, cli nical a n d 
i n patie nt sta y a d mi nistrati ve data a n d c ode d dia g n oses a n d pr oce d ures. I n a d diti o n, O pt u m 
uses nat ural la n g ua g e pr ocessi n g ( N L P) c o m p uti n g tec h n ol o g y t o tra nsf or m critical facts 
fr o m p h ysicia n n otes i nt o usa ble datasets. T h e N L P data pr o vi des detaile d i nf or mati o n 
re gar di n g si g ns a n d s y m pt o ms, fa mil y hist or y, disease relate d sc ores (ie, R A PI D 3 f or R A, or 
C H A D S 2 f or str o ke ris k), ge netic testi n g, me dicati o n c ha n ges, a n d p h ysici a n rati o nale 
be hi n d prescri bi n g decisi o ns t hat mi g ht ne ver be rec or de d i n t he E H R.  
Dia g n osis data, la b orat or y data, a n d s ur g ical pr oce d ure dat a f or t he st u d y p eri o d of i nterest 
will be first be o btai ne d fr o m str uct ure d dat a ( via I nter nati o nal Classificati o n of Diseases, 
Ni nt h Re visi o n/ Te nt h Re visi o n, Cli nical M o dificati o n [I C D -9 -C M/I C D -1 0 -C M], 
I nter nati o nal Classificati o n of Diseases, Ni nt h Re visi o n/ Te nt h Re visi o n, Pr oce d ure 
Classificati o n S yste m [I C D -9 - P C S/I C D -1 0 -P C S], or C urre nt Pr oce d ure T er mi n ol o g y ( C P T) 
c o des w here a p plica ble. Dr u g treat me nt d ata ma y als o be p ulle d fr o m pr escri pti o n writte n, 
me dicati o n a d mi nistrati o n, a n d pr oce d ure ta bl es w he n a p pr o priate ( via I C D -9 -C M/I C D -1 0 -
C M, Nati o nal Dr u g Ce nter [ N D C], C P T, a n d Healt hcare C o m m o n Pr oce d ure C o di n g S yste m 
[ H C P C S] c o des w here a p plica ble). I n a d diti o n, O pt u m will use data a vaila ble i n t he me dical 
rec or ds f or a s u bs et of patie nts wit h heart fail ure t hat ha ve cli nical p atie nt n otes a n d ot her 
data t hat ca n n ot b e ma p p e d i nt o t he lar ger str uct ur e d data bas e. T hese d ata ma y c o ntai n 
ver bati m me dical dat a, i ncl u di n g te xt -base d des cri pti o ns of me dical i nf or m ati o n, s uc h as 
me dical r ec or ds, p h ysicia n n otes, ne ur ol o gical sc a ns, X -ra ys, or narrati ve fi el ds i n a data bas e. 
W he n p ossi ble/a p pr o pri ate, f or vali dati o n of A T T R wt -C M or n o na m yl oi d heart fail ure 
dia g n oses a n d a n al yses of ris k fact ors a n d bac k gr o u n d e pi de mi ol o g y, la b data will als o be 
use d t o a u g me nt t he str uct ure d electr o nic healt h data.  
9. 5.  St u d y size  
T he sa m ple size f or m ula f oll o ws t he bi n o mial a p pr oac h f or bi nar y o utc o m es w here :  
N 0. 5= ( Z 1 -α  + Z 1 -β) ( p( 1-p)) 0. 5/ NI M    
 
F or 9 0 % p o w er, t he f or m ula res ults i n 7 8 i n di vi d uals f or se nsit i vit y a n d 1 2 8 i n di vi d uals f or 
s pecificit y. Usi n g vari o us ke y w or d searc h, feasi bilit y assess me nt was perf or me d . I n t he 
O pt u m E H R data, after a p pl yi n g i ncl usi o n a n d e xcl usi o n criteria i n  Secti o n 9. 2. 1  a n d 
Secti o n  9. 2. 2  , there were 4 2 2 p ote ntial A T T R wt -C M rec or ds a v aila ble; y et, bef ore 
re vie wi n g t he u nstr uct ure d n otes, o ne is u na ble t o deter mi ne t he t otal n u m b er of cli nicall y 
dia g n ose d A T T R wt -C M patie nts . Gi ve n t hat A T T R wt-C M is a rare dise ase  f or w hic h t he 
I C D-1 0 c o de h a s o nl y be e n a vaila ble rece ntl y a n d t he use of w hic h cli nicia ns are still n ot 
q uite fa miliar wit h or c o mf orta ble usi n g , t he tea m will atte m pt t o ma xi mize t he n u m ber of 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 8  of 2 5  
p ote ntial cases b y perf or mi n g n ote re vie w f or all 4 2 2 c harts. Si milar n u m ber of c o ntr ol c harts 
will be re vie we d t o b ala n ce t he n u m ber of cases a n d c o ntr ols. A n y i ncrease i n sa m ple size 
will res ult i n m ore pre cis e 9 5 % CIs.  
We esti mate t hat  t he sa m ple sizes will li kel y  pr o vi de 9 0 % p o wer t o satisf y t he n o n -i nferi orit y 
h y p ot heses liste d bel o w.  
T he n o n -i nferi orit y h y p ot heses are: 
H 0:   Se nsiti vit y ≤ 0. 8 0  
H 1 : Se nsiti vit y ≥ 0. 9 0  
a n d 
H 0:   S pe cificit y ≤ 0.7 2  
H 1 : S pecificit y  ≥ 0. 8 2  
Se nsiti vit y a n d S pecificit y esti mates were e val uat e d base d o n t he vali dati o n a n d perf or ma nce 
metrics fr o m t he ra n d o m f orest -bas e d M L ris k pre dicti o n m o del  recei ver o perati n g 
c haracteristics c ur ve  i n H u da et al.1 Se nsiti vit y is defi ne d as t he pr o ba bilit y t hat a n i n di vi d ual 
wit h t he disease i n t he p o p ulati o n will scree n p ositi ve f or diseas e b y t he al g orit h m ( Tr ue 
P ositi ves). S pecifici t y is defi ne d as t he pr o ba bilit y t hat a n i n di vi d ual wit h o ut t he disease will 
be c orrectl y i de ntifie d as n ot ha vi n g t he disease b y t he al g orit h m ( Tr ue Ne g ati ves) .  
T he dista nce fr o m H 0  t o H1  is t he n o n-i nferi orit y mar gi n ( NI M), w hic h is 0. 1 0  f or b ot h 
se nsiti vit y a n d s pecificit y.   
F or se nsiti vit y, w e wis h t o reject H 0  (i nferi orit y t o 0. 9 0) i n fa v or of H1  ( n o n-i nferi orit y t o 
0. 9 0) w hile f or s pecificit y we wis h t o reject H0  (i nferi orit y t o 0. 8 2) i n fa v or of H1  
( n o n-i nferi orit y t o 0. 8 2).  
9. 6.  D at a M a n a ge me nt  
T w o  maj or  data  s o urces f or t his st u d y are descri be d  i n greater  detail  i n vari o us  secti o ns 
t hr o u g h o ut t he pr ot oc ol. T heir c ollecti o n, retrie val, pre parati o n, a n d st ora g e are 
s u m marize d as f oll o ws: 
1.  O pt u m’s  E H R  d at a b ase:  T he  E H R  Data bas e  is a l o n git u di nall y li n ke d str uct ure d d ata  
s o urce. It has b ee n f or mall y de-i de ntifie d b y a n i n de pe n de nt statistical e x pert f oll o wi n g 
HI P A A statistical de -i de ntificati o n r ules a n d ma na ge d acc or di n g t o O pt u m c ust o mer data 
use a gree me nts .1 ,2 T he E H R i ncl u des str uct ure d fi el ds re n dere d b y N L P tec h n ol o g y , 
w herei n O pt u m data e x p erts mi ne pr o vi der n otes a n d t he n n or malize, v ali date, a n d 
i nte grate t he m i nt o t he el ectr o nic dat a base. 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 1 9  of 2 5  
I n a d diti o n t o t hese str uct ure d data, O pt u m has cli nical n otes a vaila ble fr o m s o me E H R 
s yste ms a n d ca n use te c h n ol o g y  t o searc h t he ver bati m te xt f or p hrases of i nterest a n d 
e xtract a s m all p orti o n of t h ose n otes f or re vie w a n d cli nical assess me nt. All data 
ele me nts fr o m  t his s o urce are st or e d o n  O pt u m’s  fire walle d, pass w or d -pr ot ecte d  d ata base.  
T hese  dat a ca n o nl y  be  e xtracte d b y  a p pr o ve d  O pt u m  st u d y pers o n nel  usi n g  sta n dar d a n d 
c o m merciall y a v aila ble s oft ware (e g, S A S, S Q L, P yt h o n).  
2.  O pt u m’s I nte gr ate d Cl ai ms -Cli nic al d at a b ase:  T he E H R will be s u p ple me ntall y li n ke d 
t o patie nts i n O pt u m’s  I nt e grate d Clai ms -C li nical a dj u dicate d  clai ms d ata base.  F or  a 
s u bset of t hese patie nts, electr o nic cli nical n otes will u n der g o ma n ual cli nicia n re vie w t o 
c o nfir m m y ocar ditis cases.  
F or t he v ali dati o n pr ocess usi n g t he electr o nic cli nical n otes ( w hic h will be c o n verte d t o 
dei de ntifie d str uct ur e d  data f or  a n al yses),  t he O pt u m  Nat ural  La n g ua ge  Pr o gra m mi n g  ( N L P) 
tea m will  deter mi ne if cli nical n otes are a vaila ble f or all q ualif yi n g H F p atie nts ≥5 0 years ol d 
wit h a cli nical dia g n osis of A T T R wt -C M or n o n -a m yl oi d  H F . O pt u m will perf or m a s eries of 
“e n ha n ce d searc h ” q ueri es o n t he patie nt n otes t o deter mi ne ke y ter m c o nte nt. Ne xt, t he 
O pt u m N L P tea m will use t he ke y ter ms t o e xtr act n ote s ni p pets i nt o a file f or re vie w b y t h e 
O pt u m Cli nical tea m. T hese n otes s ni p pets w ill t he n be use d t o vali date A T T R wt -C M or 
n o n -a m yl oi d H F per Pfizer cli nical tea m  s pecificati o n t hat were i de ntifie d i n t he E H R usi n g 
t he i ncl usi o n a n d e xcl usi o n criteria s pecifie d i n Secti o n 9. 2. 1  a n d Secti o n 9. 2. 2 . After 
cli nical re vie w of t he n ot es i n v ol vi n g t w o cli nicia ns fr o m O pt u m, a n d cate g orizati o n of t he 
c o nte nt f or a n al ysis, t he res ulti n g ta ble of criteria  will be creat e d. T he A T T R wt -C M (cases) 
or n o n -a m yl oi d  H F  (c o ntr ols) will t he n be classifi e d as vali date d or n ot vali date d, a n d  
rele va nt i nf or mati o n e ntere d  i nt o a s prea ds heet t hat will  ser ve as t he data  c ollecti o n  t o ol. 
Fi nall y, t he O pt u m cli nical re vie w tea m will pr o vi de t hese res ults of t he cas e vali dati o n t o t he 
Pfizer C ore St u d y Tea m s o t hat t he M L al g orit h m c o ul d be r u n usi n g  t he str uct ure d data  to  
calc ulate t h e se nsiti vit y a n d s pecificit y of  t he al g orit h m . 
Data will  be ha n dle d a n d a nal yze d usi n g P yt h o n s oft ware, Versi o n 3. 6 or l ater.  
9. 7.  D at a A n al ysis  
9. 7. 1.  St atistic al Met h o ds  
T he M L m o del  will i de ntif y patie nts wit h H F as s us pecte d A T T R wt -C M  a n d t he re mai n der 
patie nts as n ot s us pecte d f or A T T R wt -C M / n o n-a m yl oi d H F . T he patie nts wit h H F will be 
e ntere d i n t he M L al g orit h m al o n g wit h t heir dia g n osis  c o des liste d i n all t heir rec or ds. T he 
m o del will classif y patie nts base d o n t he pres e nce a n d a bse nce of car di o m y o pat h y feat ur es 
a n d cate g orize d as s us pecte d (at -ris k) or not s us pecte d wit h A T T R wt -C M . T he m o del 
perf or ma n ce metrics (se nsiti vit y a n d s pecificit y) will be calc ulate d b y cr oss -ta b ulati n g 
bet wee n dia g n osis bas e d o n M L al g orit h m a n d dia g n osis base d o n c hart ascertai n me nt.  
T he a nal yses f or n o ni nferi orit y of se nsiti vit y a n d s pecificit y are strai g htf or war d. T he 
calc ulati o ns f or t hes e me as ures are s h o w n b el o w.  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 2 0  of 2 5  
T a ble  1 . 
Se nsiti vit y a n d S pecificit y  
M L cl assific ati o n  
C o h ort ( Ascert ai ne d b y C h arts ) 
 
A T T R wt -C M  
N o n -a m yl oi d H F  
 
+  
Tr ue P ositi ve ( T P)  
False P ositi ve ( F P)  
T P + F P  
- 
False Ne gati ve ( F N)  
Tr ue Ne g ati ve ( T N)  
T N + F N  
 
T P + F N  
T N + F P  
 
 
Se nsiti vit y = T P / ( T P + F N)  
S pecificit y = T N / ( T N + F P)  
We w o ul d t he n calc ulate t he o ne -si de d 9 5 % c o nfi de nce i nter val ( CI) f or se nsiti vit y, 
ass u mi n g 9 0 % p o wer:  
9 5 % CI = se nsiti vit y − 1. 6 4 5( S E  se nsiti vit y) 
w here S E  se nsiti vit y = s q uare r o ot [se nsiti vit y –  ( 1-se nsiti vit y)]/ n se nsiti vit y) 
T he 9 5 % CI f or s e nsiti vit y m ust e q ual or e xcee d a c ut  p oi nt ( C P) val ue bet w ee n 0. 8 0  a n d 0. 90  
w here:  
C P = 0. 9 0 - NI M  Z 1 - β / ( Z 1 -α + Z 1 -β)  
W he n α = 0. 0 5 a n d p o w er = 0. 9 0    we reject i nferi orit y f or all val ues ≥ C P = 0. 8 5 6 1 . 
Si milarl y , f or s pecificit y, we reject i nferi orit y f or all val ues ≥ C P =  0. 7 7 6 1 .  
9. 8.  Q u alit y C o ntr ol  
All c o des a n d/ or c o d e al g orit h ms will be re vie we d b y t he cli nical lea d fr o m Pfizer, as w ell as 
t he pr ot oc ol a ut h ors. T he st u d y tea m will be res p o nsi ble f or u p h ol di n g hi g h le vels of q ualit y 
c o ntr ol t hr o u g h o ut t he data a nal ysis a n d re p orti n g pr ocesses. Q ualit y c o ntr ol ( Q C) c hec ks 
will be perf or me d o n all P yt h o n  pr o gra m mi n g, data ta bles, a n d re p orts ge n erate d i n t he 
c o urse of t his r esearc h. Q C fi n di n gs a n d d oc u me ntati o n of re me dial acti o n will be 
mai ntai ne d. St ora ge of pr o gra m mi n g, data, a n d re p orts will be carri e d o ut per sta n dar d 
pr oce d ures . 
I n t he v ali dati o n  st u d y, after t he O pt u m  N L P  tea m creat es  ke y  ter m ta gs f or use  i n t he s ni p pet 
re vie w f or t he t w o O pt u m cli nicia ns w h o will re vie w patie nt n otes wit h t hese ke y ter ms 
me nti o ne d, t he t w o cli nicia ns  will  rec or d t heir fi n di n gs fr o m t he n otes  re gar di n g w het her  t he 
n otes  s u p p ort a A T T R wt -C M  or n o n -a m yl oi d  H F . T hese res ults will be pr o vi de d t o t he Pfizer 
st u d y tea m f or re vi e w a n d a n y clarifi cati o ns or q uesti o ns will be ma na ge d bet wee n t he t w o 
gr o u ps u ntil res ol ve d.  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 2 1  of 2 5  
9. 9.  Li mit ati o ns  of t he R ese arc h M et h o ds  
T here are s o me i m p orta nt li mitati o ns t o c o nsi der f or t his st u d y:   
•  Patie nts ma y ha ve recei v e d healt h care o utsi de of t he net w or k of pr o vi ders a n d 
healt hcare or ga nizati o ns t hat c o ntri b ute t o t he O pt u m data bases, or pri or t o ha vi n g t he 
i n de x dia g n osis a n d we ma y n ot be a ble t o e x cl u de t he p ossi bilit y t hat a patie nt was 
dia g n ose d wit h H F, as w ell as ot her ris k fact ors, pri or t o e ntr y i nt o a healt h care 
s yste m w here O pt u m has E H R access. 
•  T his st u d y utilizes E H R data t hat ha ve i n h ere nt li mitati o ns s uc h as t he p ossi bilit y f or 
e ntr y err ors a n d missi n g i nf or mati o n w hic h c o ul d l ea d t o e xtre m e or i nc orrect val ues. 
As a res ult, t here is a p ote ntial f or bias d ue t o a l ac k of q ualit y c o ntr ol a n d 
c o nsiste nc y f or d ata c ollecti o n a n d re p orti n g wit hi n t he data base. St u d y sa m ples 
o btai ne d fr o m E H R data a nal yses are n ot ra n d o ml y selecte d a n d u n o bs er ve d fact ors 
ma y i ntr o d uce bias i n s u bject selecti o n.  
9. 1 0.  Ot her A s pects 
N ot a p plica ble . 
1 0.  P R O T E C TI O N O F H U M A N S U B J E C T S  
All parties will e ns ure t h e pr otecti o n of p atie nt pers o nal data a n d will n ot i ncl u de patie nt 
na mes o n a n y s p o ns or f or ms , re p orts, p u blicati o ns, or i n a n y ot her discl os ur es, e xce pt w h ere 
re q uire d b y la ws. I n case of data tra nsfer, Pfizer will mai ntai n hi g h sta n dar ds of 
c o nfi de ntialit y a n d pr ote cti o n of patie nt pers o nal data.  
1 0. 1.  P atie nt Inf or m ati o n  
T his st u d y i n v ol ves data t ha t e xist i n a n o n y mize d str uct ure d f or m at a n d c o ntai n n o patie nt 
pers o nal i nf or mati o n . 
1 0. 2.  P atie nt C o nse nt  
As t his st u d y i n v ol ves a n o n y mize d str uct ure d d ata, w hic h acc or di n g t o a p plica ble le gal 
re q uire me nts d o n ot c o nt ai n data s u bject t o pri vac y la ws, o btai ni n g i nf or me d c o nse nt fr o m 
patie nts b y Pfizer is n ot r e q uire d.  
1 0. 3.  I nstit uti o n al R e vie w B o ar d (I R B)/I n de pe n de nt E t hics C o m mittee (I E C)  
T here is n o re q uire me nt f or re vie w si nc e t his st u d y o nl y uses c o m merciall y a vaila ble de -
i de ntifie d sec o n dar y data s o urces a n d is c o nsi d ere d e xe m pt fr o m t he re q uir e me nts f or 
“ h u ma n s u bjects res earc h ” i n t he U S.  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 2 2  of 2 5  
1 0. 4.  Et hic al C o n d uct of t he S t u d y 
T he st u d y will be c o n d ucte d i n acc or da nce wit h le gal a n d re g ulat or y re q uir e me nts, as well as 
wit h scie ntific p ur p ose , v al ue a n d ri g or a n d f oll o w ge nerall y acce pte d res earc h practices 
descri be d i n i n G ui deli nes f or G o o d P har mac oe pi de mi ol o g y Practices ( G P P) iss ue d b y t he 
I nter nati o nal S ociet y f or P har mac oe pi de mi ol o g y (I S P E), G o o d Practices f or O utc o mes 
Researc h iss u e d b y t he I nter nati o nal S ociet y f or P har mac o ec o n o mics a n d O utc o mes 
Researc h (I S P O R), a n d t he G R A C E ( G o o d Rese Arc h f or C o m parati ve Effecti ve ness) 
P ri nci ples. 
1 1.  M A N A G E M E N T A N D R E P O R TI N G O F A D V E R S E E V E N T S/ A D V E R S E 
R E A C TI O N S  
1 1. 1.  Str uct ure d D at a A n al ysis  
T his  st u d y i n v ol ves data  t hat e xist  as str uct ur e d dat a  b y  t he ti me of  st u d y start. I n t hes e data  
s o urces, it is n ot p ossi ble t o li n k (ie, i de ntif y a p ote ntial ass ociati o n bet wee n) a partic ul ar 
pr o d uct a n d me dic al e ve nt f or a n y i n di vi d ual. T h us, t he mi ni m u m criteria f or re p orti n g a n 
A E (ie, i de ntifia ble p atie nt, i de ntifia ble re p orter, a s us pect pr o d uct, a n d e ve nt) ca n n ot be met.  
1 2.  P L A N S F O R DI S S E MI N A TI N G A N D C O M M U NI C A TI N G S T U D Y R E S U L T S  
O ne or m ore a bstracts ma y be de v el o pe d a n d s u b mitte d t o rele va nt scie ntific c o nfere n ce(s) 
a n d o ne or m ore ma n uscri pts ma y be de vel o pe d a n d s u b mitte d t o rele va nt peer -re vie we d 
me dical j o ur nals. A ut h ors hi p will f oll o w t he g ui d eli nes pr o p ose d b y t he I nter nati o nal 
C o m mittee of Me dical J o ur nal E dit ors (I C MJ E; w w w.ic mje. or g). All a ut h ors s h o ul d meet t he 
criteria f or a ut h ors hi p, a n d all pe o ple w h o meet t h e criteri a s h o ul d be a ut h ors. A n y p ote ntial 
c o nflicts of i nterest will be discl ose d.  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 2 3  of 2 5  
1 3.  R E F E R E N C E S  
1.  
H u da A, Casta ñ o A, Ni y o gi A, et al. A mac hi ne l ear ni n g m o del f or i d e ntif yi n g patie nts 
at ris k f or wil d -t y pe tra nst h yreti n a m yl oi d car di o m y o pat h y. N at C o m m u n . 
2 0 2 1; 1 2( 1): 2 7 2 5. d oi: 1 0. 1 0 3 8/s 4 1 4 6 7 -0 2 1 -2 2 8 7 6 -9 . 
2.  
Ma urer M S, B o k hari S, Da m y T, e t al. E x pert c o nse ns us rec o m me n d ati o ns f or t he 
s us pici o n a n d dia g n osis of tra nst h yreti n car diac a m yl oi d osis. Circ Heart Fail. 
2 0 1 9; 1 2( 9):e 0 0 6 0 7 5.  
3.  
Gr o ga n M, Sc ott C G, K yle R A, et al. Nat ur al hist or y of wil d -t y pe tra nst h yreti n car di ac 
a m yl oi d osis a n d ris k s tratificati o n usi n g a n o vel sta gi n g s yste m. J A m C oll Car di ol. 
2 0 1 6; 6 8( 1 0): 1 0 1 4 -1 0 2 0. d oi: 1 0. 1 0 1 6/j.jacc. 2 0 1 6. 0 6. 0 3 3  
4.  
Gill m ore J D, Da m y T, F o nta na M, et al. A ne w sta gi n g s yste m f or car diac tra nst h yreti n 
a m yl oi d osis. E ur Heart J. 2 0 1 8; 3 9( 3 0): 2 7 9 9 -2 8 0 6. d oi: 1 0. 1 0 9 3/e ur heartj/e h x 5 8 9  
5.  
D or bala S, A n d o Y, B o k hari S, et al. 
A S N C/ A H A/ A S E/ E A N M/ H F S A/I S A/ S C M R/ S N M MI e x pert c o ns e ns us 
rec o m me n dati o ns f or m ulti m o dalit y i ma gi n g i n car diac a m yl oi d osis: part 2 of 2-
dia g n ostic criteria a n d a p pr o priate utilizati o n. J N ucl Car di ol. 2 0 2 0; 2 7( 2): 6 5 9– 6 7 3.  
6.  
R oze n ba u m M H, Lar ge S, B ha m bri R, Ste wart M, W hela n J, va n D o or ne waar d A, 
Das g u pta N, Masri A, Nati vi -Nic ola u J. I m p act of Dela ye d Di a g n osis a n d Mis dia g n osis 
f or Patie nts wit h Tra nst h yreti n A m yl oi d Car di o m y o pat h y ( A T T R-C M): A Tar gete d 
Literat ure Re vie w. Car di ol T her. 2 0 2 1 J u n; 1 0( 1): 1 4 1 -1 5 9.  
7.  
Kittles o n M M, R u ber g F L, A m bar de k ar A V, Bra n na ga n T H, C he n g R K, Clar ke J O, 
De m ber L M, Fra nt z J G, Hers h ber ger R E, Ma urer M S, Nati vi -Nic ola u J, Sa nc h ora wala 
V, S hei k h F H. 2 0 2 3 A C C E x pert C o nse ns us De cisi o n Pat h wa y o n C o m pre he nsi ve 
M ulti disci pli nar y Care f or t he Patie nt Wit h Car diac A m yl oi d osis: A Re p ort of t he 
A merica n C olle ge of Car di ol o g y S ol uti o n Set O versi g ht C o m mittee. J A m C oll Car di ol. 
2 0 2 3 Mar 2 1; 8 1( 1 1): 1 0 7 6 -1 1 2 6.  
8.  
Witteles R M, B o k hari S, Da m y  T, et al. Scree ni n g f or tra nst h yreti n a m yl oi d 
car di o m y o pat h y i n e ver y da y practice. J A C C Heart Fail. 2 0 1 9; 7( 8): 7 0 9– 7 1 6.  
9.  
Nati vi -Nic ola u J N, K ara m C, K hella S, Ma urer M S. Scree ni n g f or A T T R a m yl oi d osis 
i n t he cli nic: o verla p pi n g dis or ders, mis dia g n osis, a n d m ulti or ga n a ware ness. Heart Fail 
Re v 2 0 2 2; 2 7( 3): 7 8 5 -7 9 3. htt ps:// d oi. or g/ 1 0. 1 0 0 7/s 1 0 7 4 1 -0 2 1 -1 0 0 8 0 -2.  
1 0.  Ma urer M S, Elli ott P, C o me nz o R, Se mi gra n M, Ra pezzi C. A d dressi n g c o m m o n 
q uesti o ns e nc o u ntere d i n t he dia g n osis a n d ma na g e me nt of car diac a m yl oi d osis. 
Cir c ulati o n 2 0 1 7; 1 3 5( 1 4): 1 3 5 7 -1 3 7 7.  
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 2 4  of 2 5  
1 1.  Ra pezzi C, L ore nzi ni M, L o n g hi S, et al. Car diac a m yl oi d osis: t he great prete n der. 
Heart Fail Re v 2 0 1 5; 2 0( 2): 1 1 7 -1 2 4. htt ps:// d oi. or g/ 1 0. 1 0 0 7/s 1 0 7 4 1 -0 1 5 -9 4 8 0 -0.  
1 2.  Br u n o M, S heer R, Ree d C, Sc he part A, Ra d hi ka N, a n d Si m m o ns,  J D. Cli nical 
c haracteristics a n d h ealt h care res o urce use of pati e nts at ris k f or wil d -t y pe tra nst h yreti n 
a m yl oi d car di o m y o pat h y i de ntifie d b y mac hi ne lear ni n g m o del. J o ur nal of Ma na ge d 
Care a n d S pecialt y P har mac y. 2 0 2 3; 2 9( 5): 5 3 0 -5 4 0. d oi: 1 0. 1 8 5 5 3/j mc p. 2 0 2 3. 2 9. 5. 5 3 0.  
1 3.  Heit ner S, El ma n M, Masri A, A p hi n ya na p h o n gs Y, Re ye nt o vic h A, Ate ya M, E mir B, 
F o wler R, Mills J R, N ole n K D, S o h n A, H u da A, Casta n o A, Br u n o M. Perf or ma nce 
e val uati o n of a ma c hi ne l ear ni n g m o del f or s yste m atic i de ntificati o n of wil d -t y pe 
tra nst h yreti n a m yl oi d car di o m y o pat h y at t w o aca d e mic me dical ce nters. H eart Fail ure 
S ociet y of A merica - 2 4t h A n n ual Scie ntific Meeti n g. 2 0 2 0.  
1 4.  Heit ner S, El ma n M, Masri A, A p hi n ya na p h o n gs Y, Re ye nt o vic h A, Ate ya M, E mir B, 
F o wler R, Mills J R, N ole n K D, S o h n A, H u da A, Casta n o A, Br u n o M. Perf or ma nce 
e val uati o n of a ma c hi ne l ear ni n g m o del f or s yste m atic i de ntificati o n of wil d -t y pe 
tra nst h yreti n a m yl oi d car di o m y o pat h y at t w o aca d e mic me dical ce nters. H eart Fail ure 
S ociet y of A merica - 2 4t h A n n ual Scie ntific Mee ti n g. 2 0 2 0. 
1 5.  Heit ner S, El ma n M, Masri A, A p hi n ya na p h o n gs Y, Re ye nt o vic h A, Ate ya M, E mir B, 
F o wler R, Mills J R, N ole n K D, S o h n A, H u da A, Casta n o A, Br u n o M. Perf or ma nce 
e val uati o n of a ma c hi ne l ear ni n g m o del f or s yste m atic i de ntificati o n of wil d -t y pe 
tra nst h yreti n a m yl oi d car di o m y o pat h y at t w o aca d e mic me dical ce nters. H eart Fail ure 
S ociet y of A merica - 2 4t h A n n ual Scie ntific Meeti n g. 2 0 2 0.  
1 6.  Real -W orl d Data: Assessi n g Electr o nic Healt h Rec or ds a n d Me di cal Clai ms Data T o 
S u p p ort Re g ulat or y Decisi o n Ma ki n g f o r Dr u g a n d Bi ol o gical Pr o d ucts G ui da nce f or 
I n d ustr y. 
1 7.  G ui da nce f or I n d ustr y a n d F D A Staff B est Practices f or C o n d ucti n g a n d Re p orti n g 
P har mac oe pi de mi ol o gic Safet y St u dies Usi n g Electr o nic Healt hcare Data . 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

B 3 4 6 1 1 1 1  
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Versi o n 1. 0,  2 7  J ul y 2 0 2 3  
 
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy  Pr ot oc ol  Te m pl ate  F or  Sec o n d ary  D at a  C ollecti o n  St u dy  
0 1 -J u n -2 0 2 2  
Pa ge 2 5  of 2 5  
1 4.  LI S T O F T A B L E S  
Ta ble  1 . 
Se nsiti vit y a n d S pecificit y  
1 5.  LI S T O F FI G U R E S  
Fi g ure 1 . 
St u d y Desi g n  
Fi g ure 2 . 
E val uati n g M L M o del Perf or ma nce  
1 6.  A N N E X 1. LI S T O F S T A N D -A L O N E  D O C U M E N T S  
A p pe n di x A. C h art R e vie w S pecific ati o n  
D o u ble clic k o n t he ic o n t o vie w t he c hart s pecificati o n: 
C h art R e vi e w 
S p ecifi c ati o n
 
A p pe n di x B. C o de L ists U se d i n Ide ntific ati o n of C ase a n d C o ntr ols  
D o u ble Clic k o n t he ic o n t o vie w t he c o de lists: 
C o d e List f or C as e 
a n d C o ntr ol I d e ntifi c ati o n
 
1 7.  A N N E X 2 . A D DI TI O N A L I N F O R M A TI O N 
N ot A p plica ble . 
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)

D o c u m e nt A p pr o v al R e c or d
D o c u m e nt N a m e:
D o c u m e nt Titl e:
Si g n e d B y:
D at e( G M T)
Si g ni n g C a p a cit y
0 9 0 1 7 7 e 1 9 e 7 1f c 6 d\ A p pr o v e d\ A p pr o v e d O n: 3 0- A u g- 2 0 2 3 2 0: 4 4 ( G M T)
P P D