Science - USA (2022-04-08)

Perezet al.,Science 376 , eabf1970 (2022) 8 April 2022 7 of 13

AB

Thrombocytopenia

Renal involvement

Tup

Bup

anti-Smith

SLADAI

Low complement

Panup

Myeup

Combined

Leukopenia

Lymphopenia

Discoid rash

Malar rash

Photosensitivity

Myedown

Neurological involvement

anti-dsDNA

Serositis

Pandown

Mucosal Ulcers

Arthritis

anti-phospholipid

IFITM3 Myeup

ISG15 Panup

HLA-C Panup

MT2APanup

LY6E Panup

S100A11 Myeup

IFI27 Panup

IFI6 Panup

TYROBPMyeup

TYMPMyeup

MNDAMyeup

JUNB Bup

IFITM2 Panup

TCL1ABup

PSME2 Panup

LGALS1 Myeup

IFI44LPanup

VPREB3 Bup

IFITM1 Myeup

TIMP1 Myeup

PSMB9 Panup

LGALS2 Myeup

TNFSF10 Myeup

TNFSF13B Myeup

Tup

Bup

Panup

Myeup

Myedown

Pandown

Tup

Bup

Panup

Myeup

Myedown

Pandown

C

anti-Smith

Mucosal Ulcers Thrombocytopenia

Mean AUC = 0.70 0.09

True positive rate

1.0

1.5

0.0 Odds ratio

RNASE2PLD4

STRADBNPDC1

VPREB3RTKN2

RP11-1399P15.1LGALS3BP

IFI27

anti-dsDNA

Mean AUC = 0.66 0.00

Odds ratio

FKBP5ARRDC3

SAMD3CELA1

AK5APOBEC3A

MDS2ZDHHC1

BHLHE40TSHZ2

Mean AUC = 0.69 0.08

True positive rate

1.0

1.5

0.0

Mean AUC = 0.680.01

Odds ratio

IL1BNR4A1

G0S2FRG1B

PATL2ARHGAP24

RP5-887A10.1CA11

SDR42E2PTCH2

Odds ratio

LILRA3GPR183

VMO1KIF22

LINC00649PTCH2

LGALS9ODF3B

ICAM4PTGER4

Lorem ipsum

0.0 0.5 1.0 0.0 0.5 1.0

01 2 01 2

(^02012)
D
Odds ratio
0 1 2
Differentially
expressed in:
True positive rate
Case control OOS
ROC AUC: 0.84
1.0
0.8
0.6
0.4
0.2
0.0
0.0 0.5 1.0
VRK2
AC016629.8
TCL1A
STRADB
MS4A6A
GBP3
TNFSF13B
FOS
EIF3L
PITPNC1
DNAJB1
SDR42E2
CTD-2035E11.3
MDS2
PRMT10
E
Molecular PC1
Molecular PC2
CTL
Training Set
SLE
Molecular Clusters
Low High
Molecular Clusters
F

• 10
  5
  0
  Low
  Training Set
  Low: 1.8, High: 4.0
  False positive rate False positive rate False positive rate
  High
  SLEDAI
  H
  Log
  T cell abundance 10
  Log 10 module expression
  anti-dsDNAanti-Smith
  Renal involvementDiscoid rash
  LymphopeniaMalar rash
  PhotosensitivityLeukopenia
  Low complementArthritis
  Neurological involvementSerositis
  Thrombocytopeniaanti-phospholipid
  Mucosal Ulcers
  0 2 4
  Odds ratio
  Test Set
  given high group membershipOdds of clinical feature
  Up-Pan R= -0.55
  Asian R= -0.52, European R= -0.57
  IFITM3 Myeup
  ISG15 Panup
  HLA-C Panup
  MT2APanup
  LY6E Panup
  S100A11 Myeup
  IFI27 Panup
  IFI6 Panup
  TYROBPMyeup
  TYMPMyeup
  MNDAMyeup
  JUNB Bup
  IFITM2 Panup
  TCL1ABup
  PSME2 Panup
  LGALS1 Myeup
  IFI44LPanup
  VPREB3 Bup
  IFITM1 Myeup
  TIMP1 Myeup
  PSMB9 Panup
  LGALS2 Myeup
  TNFSF10 Myeup
  TNFSF13B Myeup
  CTL Low High
  G
  Molecular PC1
  Test set
  Molecular PC2
  SLE Low High
  European
  Asian
  Correlation
  0 1
  Fig. 4. Prediction of disease status and molecular stratification of SLE.
  (A) Correlation between log 10 (expression of Panup)(xaxis) and log 10 (abundance
  of CD4Naïvecells) in processing batch 4 cases only. (B) Correlation matrix
  between average expression of each of six gene modules and clinical features.
  (CandD) Receiver operating curve for out-of-sample (OOS) prediction of case-
  control status (C) and individual clinical variables (D) using a logistic regression
  model trained on 302 expression features. Inset depicts the most important
  molecular features inferred by the model, colored by the module to which each
  feature belongs. (E) Principal components analysis of training set based on
  302 expression features. Green, control; red, case. Heatmap shows the top
  25 most correlated expression features to molecular principal component PC1.
  Expression was binned and averaged across 24 equal steps across molecular
  PC1. K-means clustering of samples based on principal components yielded
  two molecular subphenotypes (Low, High). (F) Distribution of SLEDAI scores
  (yaxis) for each molecular subphenotype (xaxis) in the training cases. *P< 0.05
  (Wilcoxon rank-sum test). (G) Projection of OOS test set onto molecular PC1
  and PC2 and colored by case-control status (left) and molecular cluster membership
  (right). Heatmap shows the top 25 most correlated expression features to
  molecular PC1 in the test set. (H) Odds ratio of having a clinical feature given
  membership in the High molecular cluster versus the Low molecular cluster.
  RESEARCH | RESEARCH ARTICLE