Risteys · CREST

Endpoint definition steps	FinnGen
Phenotype data	520210
1. Apply sex-specific rule None	520210
2. Check conditions None	520210
3. Check pre-conditions, main-only, mode, registry filters Registry filters: Hospital discharge: ICD-10 — M34.1 Cause of death: ICD-10 — M34.1 2 out of 7 registries used, show all original rules.	533
4. Check minimum number of events None	533
5. Include endpoints None	533
6. Filter based on genotype QC (FinnGen only)	533

Summary Statistics

↥

-FinRegistry-

Key figures

	All	Female	Male
Number of individuals
Whole population	2272	1946	313
Only index persons	2112	1834	278
Unadjusted period prevalence (%)
Whole population	0.05	0.06	0.01
Only index persons	0.06	0.07	0.01
Median age at first event (years)
Whole population	58.34	58.28	59.14
Only index persons	57.94	57.80	58.89

-FinnGen-

Key figures

	All	Female	Male
Number of individuals	533	467	66
Unadjusted period prevalence (%)	0.14	0.16	0.03
Median age at first event (years)	56.74	56.79	56.38

-FinRegistry-

Age distribution of first events

-FinnGen-

Age distribution of first events

-FinRegistry-

Year distribution of first events

-FinnGen-

Year distribution of first events

-FinRegistry-

Cumulative Incidence Function

-FinnGen-

Cumulative Incidence Function

No data

CodeWAS (R11)

↥

CodeWAS is a tool for exploring the associations between an endpoint and all of the medical codes and drug codes.

This is a new tool, please reach out using the contact form for feedback and improvement ideas.

First, a cohort is built by matching controls to the endpoint cases using year of birth and sex. Then, a Fisher test is done for all the medical codes and drug codes between the cases and controls of this cohort. Codes are reported in the table below if they have −log₁₀(p-value) ≥ 6.

Matched cohort

Matched cases
479: Matched controls
4788

Code

Vocabulary

Description

Odds Ratio

-log₁₀(p)

N matched cases

N matched controls

M34.1

ICD-10 Finland

CR(E)ST syndrome

+∞

323.0

479

202

Kela drug reimbursment

Connective tissue diseases, rheumatoid arthritis and comparable disease

23.3

186.8

313

358

C08CA05

ATC

nifedipine; systemic

34.9

180.5

244

138

P01BA02

ATC

hydroxychloroquine; oral

21.0

165.0

277

293

M34.9

ICD-10 Finland

Systemic sclerosis, unspecified

447.3

136.1

130

I73.0

ICD-10 Finland

Raynaud syndrome

61.8

122.1

141

L04AX03

ATC

methotrexate; systemic (immunosuppressants)

10.3

87.9

198

306

XX9XE

NOMESCO Finland

Other ultrasound examination

54.3

81.1

NK4XE

NOMESCO Finland

Joint ultrasound examination not elsewhere classified

10.6

68.6

145

188

M34.0

ICD-10 Finland

Progressive systemic sclerosis

734.2

66.6

XPX04

NOMESCO Finland

Angioscopy

114.9

64.8

M35.9

ICD-10 Finland

Systemic involvement of connective tissue, unspecified

41.5

64.1

ND2AA

NOMESCO Finland

Hand and fingers X-ray examination

8.1

60.6

153

262

UJD10

NOMESCO Finland

Esophagoscopy, gastroscopy and duodenoscopy

4.8

54.5

258

938

FM1EE

NOMESCO Finland

Extensive structural and functional ultrasound examination of heart

5.2

52.2

202

586

XPX99

NOMESCO Finland

Other diagnostic examination of periferal vessel

11.1

50.1

100

111

L04AA06

ATC

mycophenolic acid; systemic

29.9

48.3

GD1DD

NOMESCO Finland

High resolution CT examination of lungs

10.5

47.2

113

GD1AA

NOMESCO Finland

Thorax X-ray examination

3.9

43.8

305

1475

XQ841

NOMESCO Finland

Examination of dermatosis with microscope

241.6

43.7

ZXD30

NOMESCO Finland

Difficulties in perfomrming procedure

11.2

41.7

QC6S1

NOMESCO Finland

Photography of skin or subcutaneous tissue in hand

217.7

39.5

M35.0

ICD-10 Finland

Sicca syndrome [Sjögren]

13.3

34.2

GD1ED

NOMESCO Finland

Extensive high resolution CT examination of lungs

11.1

32.0

XG410

NOMESCO Finland

Flow-volume spirometry

10.1

30.8

L88

ICPC

Rheumatoid/seropositive arthritis

8.3

30.3

K21.0

ICD-10 Finland

Gastro-oesophageal reflux disease with oesophagitis

4.9

30.0

108

267

L04AX01

ATC

azathioprine; systemic

8.1

29.9

M35.1

ICD-10 Finland

Other overlap syndromes

53.7

29.8

G04BE03

ATC

sildenafil; oral

60.8

29.5

H02AB06

ATC

prednisolone; systemic

2.8

26.0

289

1674

TNX10

NOMESCO Finland

Arthrocentesis, unspecified region, unspecified region

5.0

25.4

207

XG470

NOMESCO Finland

Measurement of diffusion capastity of the lungs

12.3

25.2

M34.8

ICD-10 Finland

Other forms of systemic sclerosis

263.2

24.9

L94.0

ICD-10 Finland

Localized scleroderma [morphea]

36.7

24.6

C08CA02

ATC

felodipine; oral

4.4

21.9

223

ND2DA

NOMESCO Finland

Bilateral hand X-ray examination

10.0

21.8

NH3EA

NOMESCO Finland

Feet X-ray examination with load

9.2

20.4

NH3AA

NOMESCO Finland

Foot and toes X-ray examination

3.8

20.4

288

K74.3

ICD-10 Finland

Primary biliary cirrhosis

30.4

19.8

C08CA01

ATC

amlodipine; oral

2.5

19.4

212

1147

NF1AE

NOMESCO Finland

Hip joint ultrasound examination

8.1

19.4

A12AX

ATC

Calcium, combinations with vitamin D and/or other drugs

2.5

19.2

234

1340

TFC00

NOMESCO Finland

Catheterisation of right atrium or ventricle

19.7

18.9

NK6QA

NOMESCO Finland

Measurement of bone density from tow or more locations with X-ray

4.2

18.8

206

M34

ICD-10 Finland

Systemic sclerosis

197.4

18.7

ZY020

NOMESCO Finland

Telephone, letter or other consultation without direct patient contact

4.6

17.7

155

J84.9

ICD-10 Finland

Interstitial pulmonary disease, unspecified

12.7

17.6

FM1AE

NOMESCO Finland

Standard cardiac ultrasound examination

3.0

17.5

115

453

ND2BA

NOMESCO Finland

Hand and fingers extensive X-ray examination

8.8

16.8

R06.0

ICD-10 Finland

Dyspnoea

2.5

16.6

161

802

S01XA20

ATC

artificial tears and other indifferent preparations; ophthalmic

2.2

15.9

257

1635

J84.1

ICD-10 Finland

Other interstitial pulmonary diseases with fibrosis

12.3

15.8

C02KX01

ATC

bosentan; oral

165.2

15.6

A05AA02

ATC

ursodeoxycholic acid; oral

9.9

15.2

NH3DA

NOMESCO Finland

Bilateral foot X-ray examination

6.8

15.1

K44.9

ICD-10 Finland

Diaphragmatic hernia without obstruction or gangrene

3.7

15.0

214

M01CC01

ATC

penicillamine; oral

58.6

14.9

I27.2

ICD-10 Finland

Other secondary pulmonary hypertension

26.0

14.8

H04.10

ICD-10 Finland

Dry eye syndrome

3.2

14.1

278

SBA10

NOMESCO Finland

Measurement of excretion of saliva

14.1

13.9

E0000UV

ATC

2.1

13.8

231

1460

C02KX04

ATC

macitentan; oral

+∞

13.6

R4120

NOMESCO Finland

Occupational therapy

3.8

13.5

171

L04AD01

ATC

ciclosporin; systemic

9.5

13.4

K22.4

ICD-10 Finland

Dyskinesia of oesophagus

19.7

13.0

RT172

NOMESCO Finland

51.5

12.9

L01BA01

ATC

methotrexate; systemic (folic acid analog.)

4.4

12.8

116

XQ860

NOMESCO Finland

Laser Doppler measurement/scan of capillary perfusion

+∞

12.6

R91

ICD-10 Finland

Abnormal findings on diagnostic imaging of lung

3.3

12.1

210

EB1HA

NOMESCO Finland

Panorama tomography of teeth and jaws or similar X-ray examination

2.0

11.9

223

1450

GD1AD

NOMESCO Finland

Thorax CT examination

5.1

11.7

RT160

NOMESCO Finland

66.6

11.7

TGC00

NOMESCO Finland

Bronchial lavation

7.0

11.6

7101A

ICD-9 Finland

Diffuse diseases of connective tissue, Systemic sclerosis[SCLERODERMA]

+∞

11.5

K62.3

ICD-10 Finland

Rectal prolapse

10.4

11.1

WZA10

NOMESCO Finland

Long statement of health and health related matters

10.4

11.1

D06BX01

ATC

metronidazole; topical

2.7

11.1

344

NHQ40

NOMESCO Finland

Amputation of toe

13.3

10.7

L03.0

ICD-10 Finland

Cellulitis of finger and toe

3.5

10.7

154

L04AA01

ATC

[U] ciclosporin; systemic

10.4

10.6

TQX10

NOMESCO Finland

Biopsy of skin and subcutaneous tissue

2.9

10.5

245

I27.8

ICD-10 Finland

Other specified pulmonary heart diseases

+∞

10.5

XG412

NOMESCO Finland

Flow-volume spirometry with bronchospasmolysis

3.7

10.3

131

I70.2

ICD-10 Finland

Atherosclerosis of arteries of extremities

3.7

10.2

127

J01FF01

ATC

clindamycin; systemic

2.0

10.1

161

967

Z03.5

ICD-10 Finland

Observation for other suspected cardiovascular diseases

3.2

10.0

180

Z01.8

ICD-10 Finland

Other specified special examinations

2.1

9.8

127

700

A02BC02

ATC

pantoprazole; systemic

1.9

9.8

340

2688

J18.9

ICD-10 Finland

Pneumonia, unspecified

2.2

9.7

112

587

I27.0

ICD-10 Finland

Primary pulmonary hypertension

56.2

9.7

J99.1*M34.8

ICD-10 Finland

Respiratory disorders in systemic: sclerosis

102.0

9.4

K22.7

ICD-10 Finland

Barrett oesophagus

11.0

9.4

J84.8

ICD-10 Finland

Other specified interstitial pulmonary diseases

11.8

9.1

R13

ICD-10 Finland

Dysphagia

3.1

9.0

164

NDR20

NOMESCO Finland

Incomplete excision of soft tissue tumour of wrist or hand

9.7

8.8

M32.9

ICD-10 Finland

Systemic lupus erythematosus, unspecified

9.7

8.8

A02BC01

ATC

omeprazole; systemic

1.9

8.6

149

911

RT274

NOMESCO Finland

16.6

8.6

K22.1

ICD-10 Finland

Ulcer of oesophagus

8.1

8.4

RT272

NOMESCO Finland

11.0

8.3

C02DE02

ATC

11.0

8.3

L97

ICD-10 Finland

Ulcer of lower limb, not elsewhere classified

4.4

8.2

UJF32

NOMESCO Finland

Coloscopy

1.9

8.1

141

860

R15

ICD-10 Finland

Faecal incontinence

4.3

8.1

A10BA02

ATC

metformin; oral

0.4

8.1

797

NH3BA

NOMESCO Finland

Foot and toes extensive X-ray examination

3.7

7.9

PF1AT

NOMESCO Finland

Intravascular dilatation of arteries of knee, lower leg and ankle (PTA)

13.3

7.9

ZX120

NOMESCO Finland

Intravenous

2.6

7.9

247

QDB10

NOMESCO Finland

Major dressing of wound of skin of lower limb

3.7

7.8

SPAT1263

SPAT

Sampling

1.8

7.8

211

1486

NG1AE

NOMESCO Finland

Knee joint ultrasound exmination

9.6

7.8

NA1BA

NOMESCO Finland

Cervical spine extensive X-ray examination without contrast

9.6

7.8

SPAT1249

SPAT

Treatment-related counselling outside office

1.8

7.7

204

1424

TNX00

NOMESCO Finland

Puncture and needle biopsy of soft tissue, unspecified region

5.3

7.6

XJC02

NOMESCO Finland

Mesurement of oesophageal pressure and pressure profile of lower oesophageal sphincter

12.1

7.6

D50.9

ICD-10 Finland

Iron deficiency anaemia, unspecified

2.8

7.6

183

FM1DE

NOMESCO Finland

Doppler ultrasound examination of heart

2.7

7.5

210

A02BC05

ATC

esomeprazole; systemic

1.7

7.5

221

1596

SBB00

NOMESCO Finland

Fotograf of mouth and teeth

4.1

7.4

M31.4

ICD-10 Finland

Aortic arch syndrome [Takayasu]

+∞

7.3

UJF30

NOMESCO Finland

Ileoscopy through colon

2.4

7.2

273

J01AA04

ATC

lymecycline; systemic

2.2

7.2

387

RT231

NOMESCO Finland

30.5

7.2

RT310

NOMESCO Finland

20.4

7.2

I87.2

ICD-10 Finland

Venous insufficiency (chronic)(peripheral)

2.3

7.2

297

NC1AA

NOMESCO Finland

Elbow X-ray examination without contrast

4.0

7.1

M81.9

ICD-10 Finland

Osteoporosis, unspecified

3.5

7.1

QCE10

NOMESCO Finland

Excision of other lesion extending through all layers of skin in upper limb

5.1

7.1

C08DB01

ATC

diltiazem; oral

3.5

7.0

TPH04

NOMESCO Finland

Cathetrisation of vein

1.9

7.0

107

622

A02BC03

ATC

lansoprazole; oral

1.8

7.0

156

1028

RT271

NOMESCO Finland

14.0

6.9

K57.3

ICD-10 Finland

Diverticular disease of large intestine without perforation or abscess

2.0

6.9

538

ZXE13

NOMESCO Finland

Procedure duration 90 to 119 minutes

4.0

6.9

SAA03

NOMESCO Finland

Extended examination of mouth

1.7

6.9

189

1326

M05BX04

ATC

denosumab; parenteral

3.0

6.8

139

L98.4

ICD-10 Finland

Chronic ulcer of skin, not elsewhere classified

5.5

6.8

SPAT1312

SPAT

General health counselling

1.8

6.8

155

1026

K08.1

ICD-10 Finland

Loss of teeth due to accident, extraction or local periodontal disease

2.3

6.8

295

K74.5

ICD-10 Finland

Biliary cirrhosis, unspecified

40.6

6.8

NGQ20

NOMESCO Finland

Amputation of lower leg

40.6

6.8

XCW99

NOMESCO Finland

Other investigative procedure of eye

2.3

6.7

298

JN3AE

NOMESCO Finland

Abdominal ultrasound examination

2.2

6.7

349

SPAT1255

SPAT

Intravenous administration of medicine

3.1

6.7

119

M35.8

ICD-10 Finland

Other specified systemic involvement of connective tissue

22.9

6.7

NDQ20

NOMESCO Finland

Amputation of finger

22.9

6.7

K76.9

ICD-10 Finland

Liver disease, unspecified

6.6

6.7

S09

ICPC

Infected finger/toe

4.2

6.7

JN1AE

NOMESCO Finland

Ultrasound examination of upper part of abdomen

2.3

6.6

267

H02AB07

ATC

prednisone; oral

2.1

6.6

432

SPAT1148

SPAT

Treatment of chronic ulcer or burn

2.2

6.5

336

WZB00

NOMESCO Finland

Telephone receipt or other advice

1.7

6.5

148

977

JJ2AT

NOMESCO Finland

Biopsy of liver with ultrasound guidance

4.4

6.5

J01MA12

ATC

levofloxacin; systemic

2.0

6.5

474

ADA20

NOMESCO Finland

Thoracal sympathectomy

70.8

6.4

QDB05

NOMESCO Finland

Revision of wound of skin of lower limb

5.0

6.4

EBA10

NOMESCO Finland

Surgical removal of tooth

2.5

6.4

214

J01AA07

ATC

tetracycline; systemic

2.0

6.4

451

PD4AC

NOMESCO Finland

Arterigography of lower extremity with X-ray

9.4

6.3

M05.8

ICD-10 Finland

Other seropositive rheumatoid arthritis

2.8

6.3

153

B01AC27

ATC

selexipag; oral

+∞

6.3

G73.7*M34.8

ICD-10 Finland

Myopathy in scleroderma

+∞

6.3

383

Kela drug reimbursment

Selexipag

+∞

6.3

RT171

NOMESCO Finland

27.1

6.2

SAA01

NOMESCO Finland

Simple examination of mouth

1.7

6.2

340

2847

L95

ICPC

Osteoporosis

3.3

6.1

NA3AA

NOMESCO Finland

Lumbar spine X-ray examination without contrast

2.3

6.1

262

FB1BD

NOMESCO Finland

Extensive CT examination of arteria pulmonalis

2.5

6.0

189

Mortality – FinRegistry

↥

Association

Association between endpoint CREST and mortality.

Females

Parameter	HR [95% CI]	p-value
CREST	2.418 [2.09, 2.8]	< 0.001
Birth year	0.992 [0.98, 1.0]	0.062

During the follow-up period (1.1.1998 — 31.12.2019), 370 out of 1714 females with CREST died.

Males

Parameter	HR [95% CI]	p-value
CREST	2.657 [1.86, 3.8]	< 0.001
Birth year	0.986 [0.98, 1.0]	0.004

During the follow-up period (1.1.1998 — 31.12.2019), 88 out of 263 males with CREST died.

Mortality risk

Mortality risk for people of age

years, who have CREST.

N-year risk	Females	Males
1	0.263%	0.492%
5	1.279%	3.229%
10	3.077%	7.7%
15	6.036%	14.045%
20	10.835%	23.099%

Relationships between endpoints

↥

Index endpoint: CREST – CR(E)ST syndrome

GWS hits: -

Endpoint

Case Overlap

Survival Analysis

Genetic Correlations

Genetic Signals

N (Jaccard index)

HR [CI]

Extremity

rg [CI]

Extremity

Hits

Coloc Hits

FinRegistry

FinnGen

FinRegistry

FinnGen

Loading data

NAME	CREST
CONTROL_EXCLUDE
CONTROL_PRECONDITIONS
CONTROL_CONDITIONS
SEX
INCLUDE
PRE_CONDITIONS
CONDITIONS
OUTPAT_ICD
OUTPAT_OPER
HD_MAINONLY
HD_ICD_10_ATC
HD_ICD_10	M341
HD_ICD_9	$!$	The FinnGen clinical team has checked and no code can be used for this rule.
HD_ICD_8	$!$	The FinnGen clinical team has checked and no code can be used for this rule.
HD_ICD_10_EXCL
HD_ICD_9_EXCL
HD_ICD_8_EXCL
COD_MAINONLY
COD_ICD_10	M341
COD_ICD_9	$!$	The FinnGen clinical team has checked and no code can be used for this rule.
COD_ICD_8	$!$	The FinnGen clinical team has checked and no code can be used for this rule.
COD_ICD_10_EXCL
COD_ICD_9_EXCL
COD_ICD_8_EXCL
OPER_NOM
OPER_HL
OPER_HP1
OPER_HP2
KELA_REIMB
KELA_REIMB_ICD
KELA_ATC_NEEDOTHER
KELA_ATC
KELA_VNRO_NEEDOTHER
KELA_VNRO
CANC_TOPO
CANC_TOPO_EXCL
CANC_MORPH
CANC_MORPH_EXCL
CANC_BEHAV

CR(E)ST syndrome

Endpoint definition

Endpoint definition steps

FinnGen

Phenotype data

1. Apply sex-specific rule

2. Check conditions

3. Check pre-conditions, main-only, mode, registry filters

4. Check minimum number of events

5. Include endpoints

6. Filter based on genotype QC (FinnGen only)

Similar endpoints

Case counts by codes

Summary Statistics

-FinRegistry-

Key figures

-FinnGen-

Key figures

-FinRegistry-

Age distribution of first events

-FinnGen-

Age distribution of first events

-FinRegistry-

Year distribution of first events

-FinnGen-

Year distribution of first events

-FinRegistry-

Cumulative Incidence Function

-FinnGen-

Cumulative Incidence Function

CodeWAS (R11)

Matched cohort

Mortality – FinRegistry

Association

Females

Males

Mortality risk

Relationships between endpoints