A New Drug Safety Signal Detection and Triage System Integrating Sequence Symmetry Analysis and Tree-Based Scan Statistics with Longitudinal Data

Figures & data

Figure 1 Proposed signal detection and triage algorithm.

Abbreviations: ADRr, ADR-related event; CCDS, company core data sheets; CH, Cohort-related event; SRS, spontaneous reporting system; Ir, Indication-related event; PT, Protopathic bias.

Table 1 Detected Alerts of SGLT2 Inhibitor: Results from Prescription Sequence Symmetry Analysis

Clinical Classification*	Type	Marker Drug	Name	Crude SR	Adjusted SR	95% CI	Pair No.	DPP4i SSA	Corresponding Findings in TreeScan
Genitourinary-related	ADR	A07AA02	Nystatin	1.61	1.36	(1.18–1.55)	8725		Candidiasis, female pelvic inflammatory disease, inflammatory disease of cervix uteri, inflammation of vagina and vulva, vulvovaginal ulceration and inflammation, other noninflammatory disorders of vagina, disorders of prepuce, other disorders of penis
	ADR	D01AC01	Clotrimazole	1.53	1.41	(1.24–1.59)	9135
	ADR	D07AB09	Triamcinolone	1.56	1.43	(1.02–1.99)	1963
	ADR	D07CB01	Triamcinolone and antibiotics	1.34	1.23	(1.16–1.31)	46,529
	ADR	G01AA01	Nystatin	1.54	1.42	(1.27–1.59)	11,762
	ADR	G01AF01	Metronidazole	1.15	1.27	(1.05–1.54)	4544
	ADR	G01AF02	Clotrimazole	1.44	1.46	(1.28–1.67)	9835
	ADR	G01AF04	Miconazole	1.50	1.37	(1.04–1.80)	2677
	ADR	G01AF12	Fenticonazole	1.98	1.29	(1.00–1.67)	2294
	ADR	J01DC09	Cefmetazole	1.37	1.29	(1.11–1.50)	7598
	ADR	J01XD01	Metronidazole	1.36	1.24	(1.04–1.47)	5574
	ADR	J02AC01	Fluconazole	2.16	1.43	(1.19–1.72)	4431	V
	ADR	N07AB02	Bethanechol	1.47	1.22	(1.07–1.39)	11,149
	ADR	P01AB02	Tinidazole	2.09	2.29	(1.11–4.69)	440
Menopause-related	CH	G03CA57	Conjugated estrogens	1.19	1.23	(1.04–1.44)	6477		Conditions associated with female genital organs and menstrual cycle, menopausal and other perimenopausal disorders
	CH	G03XC01	Raloxifene	2.33	1.77	(1.06–2.96)	703
	CH	N06AB06	Sertraline	1.45	1.41	(1.12–1.79)	4236	V
Electrolyte, fluids and hospitalization meds	CH	A03AB02	Glycopyrronium bromide	1.80	1.54	(1.10–2.17)	1522
	CH	R03CA02	Ephedrine	1.37	1.21	(1.07–1.38)	9430
	CH	A06AD11	Lactulose	1.68	1.24	(1.09–1.42)	9516	V
	CH	B02AA01	Aminocaproic acid	1.92	2.05	(1.02–4.13)	293	V
	CH	B03XA01	Erythropoietin	8.50	3.03	(1.08–8.54)	395	V
	CH	B05AA01	Albumin	2.30	1.36	(1.08–1.71)	3947	V
	CH	B05BA01	Amino acids	2.47	1.72	(1.34–2.20)	3227	V
	CH	B05BA02	Fat emulsions	4.06	2.50	(1.45–4.32)	750	V
	CH	B05XA31	Electrolytes in combination with other drugs	26.00	12.60	(1.71–92.8)	347	V
	CH	C01CA03	Norepinephrine	2.29	1.32	(1.10–1.59)	5277	V
	CH	N02AB03	Fentanyl	7.25	2.37	(1.29–4.33)	750	V
	CH	N07AA01	Neostigmine	1.29	1.20	(1.01–1.41)	4898	V
Broad-spectrum antibiotics	CH	J01DE01	Cefepime	2.38	1.50	(1.12–2.02)	2107	V
	CH	J01DH02	Meropenem	4.54	2.05	(1.42–2.95)	1851	V
	CH	J01DH03	Ertapenem	1.56	1.24	(1.01–1.53)	3899	V
	CH	J01DH04	Doripenem	2.36	1.65	(1.00–2.72)	600	V
	CH	J01XB01	Colistin	5.10	2.14	(1.08–4.21)	536	V
	CH	J02AX05	Micafungin	9.00	5.00	(1.16–21.6)	209	V
Cancer-related	CH	A04AA02	Granisetron	2.33	1.61	(1.02–2.52)	1001
	CH	A04AA05	Palonosetron	2.58	1.72	(1.18–2.50)	1396
	CH	A04AD12	Aprepitant	2.14	1.67	(1.07–2.62)	934
	U	L01BC02	Fluorouracil	2.00	1.55	(1.02–2.35)	1095
	U	V03AF03	Calcium folinate	2.67	1.85	(1.12–3.06)	965
	CH	L02AB01	Megestrol	4.37	1.79	(1.18–2.73)	1427	V
	CH	L03AA02	Filgrastim	5.00	3.10	(1.29–7.46)	534	V
	CH	A01AB03	Chlorhexidine	3.00	11.22	(1.17–108)	3345		Periodontal diseases
Others	U	N04BA02	Levodopa and decarboxylase inhibitor	1.90	1.48	(1.11–1.97)	2483
	CH	N05AA01	Chlorpromazine	1.84	1.54	(1.09–2.17)	1645	V
	U	S01GX10	Epinastine	2.27	1.73	(1.12–2.66)	1380

Notes: *Clinical classification is expressed in either disease or medication system.

Abbreviations: ADR, known adverse drug reaction; ADRr, events related to known adverse drug reaction; CH, cohort-related; I, indication; Ir, indication-related; PT, protopathic bias; U, unknown AEs, identified as potential signals.

Figure 2 Classification of detected alerts. Numbers shown are numbers of detected alerts for each type.

Abbreviations: ADR, known adverse drug reaction; ADRr, events related to known adverse drug reaction; CH, cohort-related; I, indication; Ir, indication-related; PT, protopathic bias; U, unknown alerts identified as potential signals.

Table 2 Detected Alerts of SGLT2 Inhibitor: Results from Propensity Score-Matched TreeScan

Clinical Classification*	Type	Node†	Tree Level	ICD 10 Diagnosis	Observations	Cases	Expected	Relative Risk	LLR	p-value
Genitourinary system	ADR	B37	1	Candidiasis	2978	1932	1489	1.3	133.82	0.0001
	ADR	B373	2	Candidiasis of vulva and vagina	1678	1237	839	1.47	196.61	0.0001
	ADR	N47	1	Disorders of prepuce	1033	740	516.5	1.43	99.98	0.0001
	ADR	N471	2	Phimosis	146	109	73	1.49	18.55	0.0001
	ADR	N476	2	Balanoposthitis	678	473	339	1.4	54.44	0.0001
	ADR	N477	2	Other inflammatory diseases of prepuce	101	76	50.5	1.5	13.49	0.0005
	ADR	N48	1	Other disorders of penis	394	296	197	1.5	52.09	0.0001
	ADR	N481	2	Balanitis	74	57	37	1.54	11.41	0.0079
	ADR	N482	2	Other inflammatory disorders of penis	304	231	152	1.52	43.14	0.0001
	ADR	N4829	3	Other inflammatory disorders of penis	262	200	131	1.53	38.24	0.0001
	ADR	N76	1	Other inflammation of vagina and vulva	5152	3391	2576	1.32	262.34	0.0001
	ADR	N760	2	Acute vaginitis	2546	1671	1273	1.31	126.54	0.0001
	ADR	N761	2	Subacute and chronic vaginitis	1101	717	550.5	1.3	51.16	0.0001
	ADR	N762	2	Acute vulvitis	603	417	301.5	1.38	45.40	0.0001
	ADR	N766	2	Ulceration of vulva	140	96	70	1.37	9.89	0.0347
	ADR	N768	2	Other specified inflammation of vagina and vulva	363	238	181.5	1.31	17.88	0.0001
	ADR	N7689	3	Other specified inflammation of vagina and vulva	349	229	174.5	1.31	17.31	0.0001
	ADR	N77	1	Vulvovaginal ulceration and inflammation in diseases classified elsewhere	553	363	276.5	1.31	27.52	0.0001
	ADR	N771	2	Vaginitis, vulvitis and vulvovaginitis in diseases classified elsewhere	553	363	276.5	1.31	27.52	0.0001
	ADRr	L292	2	Pruritus vulvae	1189	836	594.5	1.41	101.00	0.0001
	ADRr	L293	2	Anogenital pruritus, unspecified	139	104	69.5	1.5	17.91	0.0001
	ADRr	N72	1	Inflammatory disease of cervix uteri	562	348	281	1.24	16.13	0.0001
	ADRr	N73	1	Other female pelvic inflammatory diseases	2038	1221	1019	1.2	40.31	0.0001
	ADRr	N739	2	Female pelvic inflammatory disease, unspecified	1593	977	796.5	1.23	41.26	0.0001
	CH	N89	1	Other noninflammatory disorders of vagina	588	369	294	1.26	19.35	0.0001
	CH	N898	2	Other specified noninflammatory disorders of vagina	527	339	263.5	1.29	21.94	0.0001
	CH	N948	2	Other specified conditions associated with female genital organs and menstrual cycle	330	214	165	1.3	14.77	0.0002
	CH	N9481	3	Vulvodynia	250	170	125	1.36	16.57	0.0001
	CH	N94810	4	Vulvar vestibulitis	250	170	125	1.36	16.57	0.0001
	CH	N95	1	Menopausal and other perimenopausal disorders	2211	1270	1105.5	1.15	24.57	0.0001
	CH	N952	2	Postmenopausal atrophic vaginitis	508	341	254	1.34	30.41	0.0001
Obesity	CH	E65	1	Localized adiposity	33	30	16.5	1.82	12.82	0.0012
	CH	E66	1	Overweight and obesity	1479	931	739.5	1.26	50.16	0.0001
	CH	E669	2	Obesity, unspecified	980	648	490	1.32	51.87	0.0001
Shoulder lesion	ADR	M75	1	Shoulder lesions	7081	3748	3540.5	1.06	12.17	0.0034
Periodontal diseases	CH	K04	1	Diseases of pulp and periapical tissues	7462	4012	3731	1.08	21.18	0.0001
	CH	K040	2	Pulpitis	3929	2159	1964.5	1.1	19.29	0.0001
	CH	K05	1	Gingivitis and periodontal diseases	23,810	12,256	11,905	1.03	10.35	0.0251

Notes: *Clinical classification is expressed in either disease or medication system. †Node is expressed in ICD10 diagnostic codes.

Abbreviations: ADR, known adverse drug reaction; ADRr, events related to known adverse drug reaction; CH, cohort-related; I, indication; Ir, indication-related; LLR, log likelihood ratio; PT, protopathic bias; RR, relative risk.