eFigure 1. Inclusion/exclusion criteria and sample size for analytic cohort
A1
eFigure 2. Covariate prevalence difference stratified by antipsychotic-type, comparing medical events to non-events during 180-day follow-up
A2
eTable 1. Characteristics of FGA and SGA users in the 180 days prior to antipsychotic initiation
among FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New
Jersey and Pennsylvania from 1994 to 2005.
SGA
FGA
Difference
N=17,137
(100%)
N=9,060
(100%)
(%)
Demographics
Age, mean (SD)
82.5
(7.5)
81.9
(7.7)
-0.6
13945
81.4
7197
79.4
-2.0
White
15632
91.2
8125
89.7
-1.5
Black
1190
6.9
779
8.6
1.7
Other
315
1.8
156
1.7
-0.1
January - March
4162
24.3
2227
24.6
0.3
April - June
4436
25.9
2051
22.6
-3.3
July - September
4277
25.0
2433
26.9
1.9
October - December
4262
24.9
2349
25.9
1.0
# Physician visits, mean (SD)
4.0
(4.0)
3.8
(3.7)
-0.2
# Hospitalizations, mean (SD)
0.4
(0.6)
0.5
(0.6)
0.1
# Total Medications, mean (SD)
8.2
(5.1)
6.9
(4.6)
-1.3
# Psychotropic medications, mean (SD)
1.1
(1.1)
0.8
(1.0)
-0.3
# Infection-related visits, mean (SD)
0.1
(0.5)
0.1
(0.5)
0.0
# Hospitalizations ≥ 3 days, mean (SD)
0.2
(0.5)
0.2
(0.5)
0.0
Female
Race
Date of antipsychotic initiation
Health Services / Medication Use
A3
eTable 1. Characteristics of FGA and SGA users in the 180 days prior to antipsychotic initiation
among FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New
Jersey and Pennsylvania from 1994 to 2005.
SGA
FGA
Difference
N=17,137
(100%)
N=9,060
(100%)
(%)
Cardiovascular Disease
Angina
59
0.3
44
0.5
0.2
Atrial fibrillation
597
3.5
400
4.4
0.9
Intracranial hemorrhage
168
1.0
123
1.4
0.4
Ischemic stroke
190
1.1
311
3.4
2.3
Other cerebrovascular disease
2686
15.7
1608
17.7
2.0
Cardiac arrhythmia
4660
27.2
2594
28.6
1.4
Coronary artery disease
2295
13.4
1581
17.5
4.1
Congestive heart failure
3818
22.3
2386
26.3
4.0
38
0.2
28
0.3
0.1
826
4.8
200
2.2
-2.6
Hypertension
9482
55.3
4388
48.4
-6.9
Myocardial infarction
1083
6.3
670
7.4
1.1
Peripheral vascular disease
1741
10.2
605
6.7
-3.5
741
4.3
558
6.2
1.9
Angiotensin II receptor blocker
4854
28.3
2387
26.3
-2.0
Antiarrhythmia
1314
7.7
769
8.5
0.8
DVT/PEa
Hyperlipidemia
Valvular heart disease
Cardiovascular Medications
A4
eTable 1. Characteristics of FGA and SGA users in the 180 days prior to antipsychotic initiation
among FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New
Jersey and Pennsylvania from 1994 to 2005.
SGA
FGA
Difference
N=17,137
(100%)
N=9,060
(100%)
(%)
Anticoagulant
3580
20.9
1423
15.7
-5.2
Beta blocker
5467
31.9
2156
23.8
-8.1
Calcium channel blocker
5332
31.1
2897
32.0
0.9
Diuretic
3362
19.6
1411
15.6
-4.0
Statin
3420
20.0
697
7.7
-12.3
ADHD
202
1.2
63
0.7
-0.5
Anxiety
2676
15.6
1082
11.9
-3.7
Dementia
9283
54.2
3815
42.1
-12.1
Delirium
1894
11.1
1004
11.1
0.0
Depressive illness
5347
31.2
2387
26.3
-4.9
Manic-depressive illness
1252
7.3
475
5.2
-2.1
Drug abuse/dependence
138
0.8
67
0.7
-0.1
Alcohol abuse/dependence
317
1.8
105
1.2
-0.6
Other psychiatric disorder
1859
10.8
1128
12.5
1.7
Antidepressant Rx
7450
43.5
2401
26.5
-17.0
Anticonvulsant Rx
2089
12.2
695
7.7
-4.5
Psychiatric Disorder
Psychiatric Medications
A5
eTable 1. Characteristics of FGA and SGA users in the 180 days prior to antipsychotic initiation
among FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New
Jersey and Pennsylvania from 1994 to 2005.
SGA
FGA
Difference
N=17,137
Anxiolytic/Sedative/Hypnotic Rx
(100%)
N=9,060
(100%)
(%)
6486
37.8
3138
34.6
-3.2
Chronic lung disease
3150
18.4
1809
20.0
1.6
Diabetes
2776
16.2
1469
16.2
0.0
337
2.0
185
2.0
0.0
1872
10.9
880
9.7
-1.2
726
4.2
184
2.0
-2.2
Arthritis
749
4.4
431
4.8
0.4
Epilepsy
1469
8.6
976
10.8
2.2
Fracture
553
3.2
304
3.4
0.2
Fall history
717
4.2
312
3.4
-0.8
1370
8.0
457
5.0
-3.0
Gait disorder
633
3.7
261
2.9
-0.8
Hormone therapy Rx
243
1.4
112
1.2
-0.2
Impaired vision
308
1.8
141
1.6
-0.2
Hyperthyroidism
670
3.9
279
3.1
-0.8
Motor impairment
2239
13.1
441
4.9
-8.2
Other Conditions
Hepatic impairment
Renal impairment
Sleep disorder
Hip Fracture Risk Factors
Fecal incontinence
A6
eTable 1. Characteristics of FGA and SGA users in the 180 days prior to antipsychotic initiation
among FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New
Jersey and Pennsylvania from 1994 to 2005.
SGA
FGA
Difference
N=17,137
(100%)
Osteoporosis Rx
164
1.0
Postural hypotension
749
Recent weight change
(100%)
(%)
87
1.0
0.0
4.4
431
4.8
0.4
1064
6.2
352
3.9
-2.3
272
1.6
128
1.4
-0.2
621
3.6
263
2.9
-0.7
1864
10.9
550
6.1
-4.8
544
3.2
290
3.2
0.0
Pneumonia
1233
7.2
861
9.5
2.3
ACE inhibitor Rx
4320
25.2
2283
25.2
0.0
Immunosuppressive Rx
2733
15.9
1189
13.1
-2.8
Anti-infectious Rx
5924
34.6
2833
31.3
-3.3
Proton pump inhibitor Rx
3990
23.3
902
10.0
-13.3
Vertigo
N=9,060
Pneumonia/Infection Risk Factors
Dysphagia
Gastroesophageal reflux disease
Hernia
aVenous
thromboembolism
A7
eTable 2. Unadjusted and covariate-adjusted direct, indirect, and total effects for potential mediators (ignoring exposure-mediator interaction) of the
180-day mortality difference between FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New Jersey and
Pennsylvania from 1994 to 2005.
Unadjusted
Baseline covariate-adjusted
Direct
Indirect
Total
PMa
Direct
Indirect
Total
PMa
RR (95% CI)
RR (95% CI)
RR (95% CI)
(%)
RR (95% CI)
RR (95% CI)
RR (95% CI)
(%)
Stroke
1.23 (1.15, 1.31)
1.007 (1.001, 1.013)
1.23 (1.16, 1.32)
3.6
1.13 (1.05-1.22)
1.005 (1.001-1.011)
1.14 (1.06-1.22)
4.9
Arrhythmia
1.23 (1.15, 1.31)
1.004 (0.995, 1.014)
1.23 (1.15, 1.32)
2.4
1.14 (1.06-1.22)
1.002 (0.996-1.008)
1.14 (1.06-1.22)
1.6
1.23 (1.15, 1.31)
1.005 (0.999, 1.011)
1.23 (1.15, 1.32)
2.6
1.13 (1.06-1.22)
1.003 (0.999-1.007)
1.14 (1.06-1.22)
2.4
1.23 (1.16, 1.32)
0.999 (0.997, 1.000)
1.23 (1.16, 1.32)
-0.6
1.14 (1.06-1.22)
0.999 (0.998-1.000)
1.14 (1.06-1.22)
-0.9
1.22 (1.15, 1.31)
1.007 (1.003, 1.012)
1.23 (1.15, 1.32)
3.8
1.13 (1.06-1.22)
1.002 (1.000-1.004)
1.14 (1.06-1.22)
1.7
1.23 (1.15, 1.31)
1.000 (0.993, 1.007)
1.23 (1.15, 1.32)
0.0
1.14 (1.07-1.22)
0.999 (0.995-1.003)
1.14 (1.07-1.22)
-0.9
1.23 (1.15, 1.31)
1.002 (0.999, 1.005)
1.23 (1.16, 1.31)
1.0
1.14 (1.06-1.22)
1.001 (0.999-1.004)
1.14 (1.06-1.22)
1.3
Cardiovascular
Myocardial
Infarction
DVT/PEb
Infection
Pneumonia
Bacterial
Infectionc
Injury
Hip Fracture
aProportion
mediated on the risk difference scale.
thromboembolism.
c
Excluding pneumonia.
bVenous
A8
eTable 3. Adjusted direct, indirect, and total effects for potential mediators (ignoring exposure-mediator interaction) of the 180-day mortality difference between
FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New Jersey and Pennsylvania from 1994 to 2005, assuming particular nondifferential and differential mediator misclassification scenarios.
Naïvea
Non-differential Mediator Misclassificationb
Differential Mediator Misclassificationc
PMd
Direct
Indirect
Total
PMd
Direct
Indirect
Total
PMd
(%)
RR (95% CI)
RR (95% CI)
RR (95% CI)
(%)
RR (95% CI)
RR (95% CI)
RR (95% CI)
(%)
Cardiovascular
Stroke
4.9
1.13 (1.05-1.2)
1.012 (1.002-1.022)
1.14 (1.06-1.22)
10.1
1.12 (1.04-1.2)
1.014 (1.003-1.027)
1.14 (1.06-1.22)
12.9
Arrhythmia
1.6
1.14 (1.06-1.22)
1.007 (0.992-1.022)
1.14 (1.07-1.23)
6.0
1.14 (1.06-1.22)
1.009 (0.994-1.024)
1.14 (1.06-1.23)
7.2
2.4
1.13 (1.06-1.21)
1.007 (0.999-1.017)
1.14 (1.07-1.22)
6.5
1.13 (1.06-1.21)
1.009 (0.998-1.021)
1.14 (1.07-1.22)
7.7
-0.9
1.14 (1.06-1.22)
0.998 (0.995-1.001)
1.14 (1.06-1.22)
-1.4
1.13 (1.06-1.22)
0.998 (0.994-1.001)
1.13 (1.06-1.21)
-1.9
1.7
1.13 (1.06-1.21)
1.006 (1.002-1.012)
1.14 (1.06-1.22)
5.4
1.13 (1.05-1.21)
1.008 (1.003-1.014)
1.14 (1.05-1.22)
7.1
-0.9
1.14 (1.07-1.22)
1.002 (0.992-1.012)
1.15 (1.07-1.23)
1.3
1.15 (1.07-1.22)
1.003 (0.989-1.015)
1.15 (1.07-1.23)
2.1
1.3
1.14 (1.06-1.22)
1.003 (0.998-1.008)
1.14 (1.07-1.22)
2.8
1.14 (1.06-1.21)
1.005 (0.999-1.012)
1.14 (1.07-1.21)
4.3
Myocardial
Infarction
DVT/PEe
Infection
Pneumonia
Bacterial
Infectionf
Injury
Hip Fracture
a
Covariate-adjusted proportion mediated without adjustment for medical event misclassification, reproduced from eTable 1.
Non-differential misclassification model for all medical events: sensitivity=0.5 and specificity=1.0.
c
Differential misclassification model for all medical events: sensitivity=0.5 given survival at end of follow-up and 0.25 given death by end of follow-up; specificity=1.0.
d
Proportion-mediated on risk difference scale.
e
Venous thromboembolism.
f
Excluding pneumonia.
b
A9
eTable 4. Adjusted direct, indirect, and total effects for potential mediators (with and without exposure-mediator interaction) of the 180-day mortality difference
between FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New Jersey and Pennsylvania from 1994 to 2005, under a range of
non-differential and differential mediator misclassification scenarios.
Sensitivity for mediator
Without exposure-mediator interaction
With exposure-mediator interaction
misclassification
Stroke
Ventricular
Arrhythmia
Among
Among
Survivors
Deceased
(Y=0)
(Y=1)
0.25
Direct
Indirect
PM
Direct
Indirect
PM
RR (95% CI)
RR (95% CI)
(%)
RR (95% CI)
RR (95% CI)
(%)
0.25
1.13 (1.05-1.21)
1.021 (1.001-1.042)
17.2
1.12 (1.04-1.20)
1.019 (1.001-1.040)
16.4
0.50
0.25
1.12 (1.04-1.20)
1.014 (1.003-1.027)
12.9
1.12 (1.04-1.20)
1.013 (1.002-1.025)
11.6
0.50
0.50
1.13 (1.05-1.20)
1.012 (1.002-1.022)
10.1
1.13 (1.05-1.20)
1.010 (1.001-1.020)
9.1
0.75
0.25
1.12 (1.05-1.21)
1.011 (1.002-1.022)
10.2
1.13 (1.05-1.21)
1.010 (1.001-1.020)
8.9
0.75
0.50
1.13 (1.05-1.21)
1.009 (1.001-1.019)
8.5
1.13 (1.05-1.21)
1.008 (1.001-1.017)
7.5
0.75
0.75
1.13 (1.05-1.21)
1.007 (1.001-1.015)
6.8
1.13 (1.05-1.21)
1.007 (1.001-1.014)
6.1
0.25
0.25
1.13 (1.06-1.21)
1.013 (0.986-1.042)
9.5
1.13 (1.06-1.21)
1.013 (0.986-1.042)
9.5
0.50
0.25
1.14 (1.06-1.22)
1.009 (0.994-1.024)
7.2
1.14 (1.06-1.22)
1.009 (0.994-1.024)
7.1
0.50
0.50
1.14 (1.06-1.22)
1.007 (0.992-1.022)
6.0
1.14 (1.06-1.22)
1.008 (0.992-1.023)
6.1
0.75
0.25
1.13 (1.06-1.21)
1.005 (0.995-1.015)
4.1
1.13 (1.06-1.21)
1.005 (0.995-1.015)
4.1
0.75
0.50
1.13 (1.06-1.21)
1.004 (0.995-1.014)
3.5
1.13 (1.06-1.22)
1.004 (0.995-1.014)
3.5
0.75
0.75
1.14 (1.05-1.22)
1.003 (0.995-1.013)
2.8
1.14 (1.05-1.22)
1.003 (0.994-1.013)
3.0
A10
eTable 4. Adjusted direct, indirect, and total effects for potential mediators (with and without exposure-mediator interaction) of the 180-day mortality difference
between FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New Jersey and Pennsylvania from 1994 to 2005, under a range of
non-differential and differential mediator misclassification scenarios.
Sensitivity for mediator
Without exposure-mediator interaction
With exposure-mediator interaction
misclassification
Myocardial
Infarction
DVT/PE
Among
Among
Survivors
Deceased
(Y=0)
(Y=1)
0.25
Direct
Indirect
PM
Direct
Indirect
PM
RR (95% CI)
RR (95% CI)
(%)
RR (95% CI)
RR (95% CI)
(%)
0.25
1.13 (1.06-1.22)
1.015 (0.998-1.035)
11.5
1.13 (1.05-1.21)
1.012 (0.998-1.030)
10.2
0.50
0.25
1.13 (1.06-1.21)
1.009 (0.998-1.021)
7.7
1.13 (1.06-1.21)
1.007 (0.998-1.018)
6.4
0.50
0.50
1.13 (1.06-1.21)
1.007 (0.999-1.017)
6.5
1.13 (1.06-1.21)
1.006 (0.999-1.015)
5.4
0.75
0.25
1.13 (1.05-1.21)
1.007 (0.998-1.016)
5.6
1.13 (1.05-1.21)
1.005 (0.998-1.013)
3.9
0.75
0.50
1.13 (1.06-1.21)
1.005 (0.998-1.013)
4.8
1.14 (1.06-1.22)
1.004 (0.999-1.011)
3.8
0.75
0.75
1.13 (1.06-1.21)
1.005 (0.999-1.011)
4.4
1.14 (1.06-1.22)
1.004 (0.999-1.009)
3.5
0.25
0.25
1.14 (1.06-1.22)
0.997 (0.991-1.001)
-2.9
1.14 (1.06-1.22)
0.997 (0.990-1.002)
-2.7
0.50
0.25
1.13 (1.06-1.22)
0.998 (0.994-1.001)
-1.9
1.13 (1.06-1.22)
0.998 (0.993-1.001)
-1.7
0.50
0.50
1.14 (1.06-1.22)
0.998 (0.995-1.001)
-1.4
1.14 (1.06-1.22)
0.999 (0.995-1.001)
-1.3
0.75
0.25
1.14 (1.06-1.22)
0.998 (0.995-1.001)
-1.6
1.14 (1.06-1.22)
0.999 (0.995-1.001)
-1.4
0.75
0.50
1.14 (1.06-1.22)
0.999 (0.996-1.001)
-1.3
1.14 (1.06-1.22)
0.999 (0.996-1.001)
-1.1
A11
eTable 4. Adjusted direct, indirect, and total effects for potential mediators (with and without exposure-mediator interaction) of the 180-day mortality difference
between FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New Jersey and Pennsylvania from 1994 to 2005, under a range of
non-differential and differential mediator misclassification scenarios.
Sensitivity for mediator
Without exposure-mediator interaction
With exposure-mediator interaction
misclassification
Pneumonia
Bacterial
Infection
Among
Among
Survivors
Deceased
(Y=0)
(Y=1)
0.75
Direct
Indirect
PM
Direct
Indirect
PM
RR (95% CI)
RR (95% CI)
(%)
RR (95% CI)
RR (95% CI)
(%)
0.75
1.14 (1.06-1.22)
0.999 (0.997-1.000)
-1.0
1.14 (1.06-1.22)
0.999 (0.996-1.001)
-0.9
0.25
0.25
1.13 (1.06-1.22)
1.011 (1.003-1.023)
9.8
1.13 (1.06-1.22)
1.01 (1.002-1.022)
8.7
0.50
0.25
1.13 (1.05-1.21)
1.008 (1.003-1.014)
7.1
1.13 (1.05-1.21)
1.007 (1.002-1.014)
6.4
0.50
0.50
1.13 (1.06-1.21)
1.006 (1.002-1.012)
5.4
1.13 (1.06-1.21)
1.005 (1.001-1.011)
4.8
0.75
0.25
1.13 (1.05-1.22)
1.005 (1.001-1.010)
4.7
1.13 (1.05-1.22)
1.005 (1.001-1.009)
4.2
0.75
0.50
1.13 (1.05-1.22)
1.004 (1.001-1.008)
3.9
1.13 (1.05-1.22)
1.004 (1.001-1.008)
3.6
0.75
0.75
1.13 (1.05-1.22)
1.003 (1.001-1.007)
3.3
1.13 (1.05-1.22)
1.003 (1.001-1.007)
3.0
0.25
0.25
1.14 (1.07-1.22)
1.000 (0.979-1.024)
-0.8
1.13 (1.06-1.21)
1.000 (0.981-1.021)
-1.1
0.50
0.25
1.15 (1.07-1.22)
1.003 (0.989-1.015)
2.1
1.15 (1.07-1.22)
1.002 (0.991-1.015)
1.9
0.50
0.50
1.14 (1.07-1.22)
1.002 (0.992-1.012)
1.3
1.14 (1.07-1.22)
1.002 (0.992-1.011)
1.2
0.75
0.25
1.14 (1.07-1.22)
1.003 (0.992-1.013)
2.2
1.15 (1.07-1.23)
1.002 (0.993-1.012)
2.0
A12
eTable 4. Adjusted direct, indirect, and total effects for potential mediators (with and without exposure-mediator interaction) of the 180-day mortality difference
between FGA and SGA initiators enrolled in Medicare and pharmacy assistance programs in New Jersey and Pennsylvania from 1994 to 2005, under a range of
non-differential and differential mediator misclassification scenarios.
Sensitivity for mediator
Without exposure-mediator interaction
With exposure-mediator interaction
misclassification
Hip
Fracture
Among
Among
Survivors
Deceased
(Y=0)
(Y=1)
0.75
Direct
Indirect
PM
Direct
Indirect
PM
RR (95% CI)
RR (95% CI)
(%)
RR (95% CI)
RR (95% CI)
(%)
0.50
1.14 (1.07-1.22)
1.002 (0.993-1.011)
1.4
1.15 (1.07-1.23)
1.002 (0.994-1.01)
1.2
0.75
0.75
1.14 (1.06-1.22)
1.001 (0.995-1.008)
0.9
1.14 (1.06-1.22)
1.001 (0.995-1.007)
0.8
0.25
0.25
1.14 (1.06-1.22)
1.006 (0.997-1.016)
5.2
1.11 (1.04-1.20)
1.002 (0.998-1.010)
2.3
0.50
0.25
1.14 (1.06-1.21)
1.005 (0.999-1.012)
4.3
1.13 (1.06-1.21)
1.002 (1.000-1.008)
2.2
0.50
0.50
1.14 (1.06-1.22)
1.003 (0.998-1.008)
2.8
1.13 (1.06-1.21)
1.001 (0.999-1.005)
1.2
0.75
0.25
1.14 (1.06-1.22)
1.004 (0.999-1.010)
4.4
1.14 (1.06-1.22)
1.003 (1.000-1.007)
2.5
0.75
0.50
1.14 (1.06-1.22)
1.003 (0.999-1.008)
2.9
1.14 (1.07-1.22)
1.002 (1.000-1.005)
1.4
0.75
0.75
1.14 (1.06-1.22)
1.002 (0.999-1.006)
2.0
1.14 (1.06-1.22)
1.001 (1.000-1.003)
0.8
A13
eTable 5. Mediator classification algorithms, published and assumed misclassification characteristics, and observed frequency and risk in the
current study population of FGA and SGA initiations enrolled in Medicare and pharmacy assistance programs in New Jersey and Pennsylvania
from 1994 to 2005, by vital status.
N (%)
N (% )
Published characteristics
Medical
Definition
N (%)
Among
Among
(validation study population /
Event
Survivors
Deceased
setting)
Stroke1
Principal inpatient diagnosis of ischemic or
b
hemorrhagic stroke: ICD-9-CM codes
361
235
126
(1.38%)
(1.02%)
(3.94%)
430.xx-432.xx, 433.x1, 434.x1.
Ventricular
Principal inpatient diagnosis (any position for
Arrhythmia2
EDa claim) of paroxysmal ventricular
PPV=0.71-0.85
(Hospitalized Veterans Affairs
Patients)
114
18
96
(0.44%)
(0.08%)
(3.00%)
SN=0.77; SP=0.94; PPV=0.93
(Myocardial infarction /
tachycardia, ventricular fibrillation,
ischemic heart disease /
ventricular flutter, cardiac arrest: ICD-9-CM
ventricular fibrillation
codes 427.1, 427.4, 427.41, 427.42, 427.5.
survivors, Medicare patients, ≥
age 65)
Acute
Myocardial
3
Infarction
Principal inpatient diagnosis with length of
252
153
99
PPV=0.94
stay between 3 and 180 days (<3 accepted if
(0.96%)
(0.67%)
(3.09%)
(Medicare patients, ≥ age 65)
150
118
32
SN=0.77; SP=0.99; PPV=0.95
(0.57%)
(0.51%)
(1.00%)
patient dies in hospital) for the initial episode
of cardiac infarction:
ICD-9-CM codes 410.xx (excluding 410.x0
and 410.x1).
Venous
Principal inpatient diagnosis of venous
Thromboemb
thromboembolism in the lower extremity or
4
olism
pulmonary embolism in any location: ICD-9CM codes 415.11, or 415.19, or 451.11, or
451.19, or 451.2, or 451.9, or 453.1, or 453.2,
or 453.40, or 453.41, or 453.42, or 453.8, or
453.9.
A14
(33 academic hospitals, age>18)
eTable 5. Mediator classification algorithms, published and assumed misclassification characteristics, and observed frequency and risk in the
current study population of FGA and SGA initiations enrolled in Medicare and pharmacy assistance programs in New Jersey and Pennsylvania
from 1994 to 2005, by vital status.
N (%)
N (% )
Published characteristics
Medical
Definition
N (%)
Among
Among
(validation study population /
Event
Survivors
Deceased
setting)
Pneumonia5
(a) Principal inpatient diagnosis of pneumonia
OR (b) Principal inpatient diagnosis of
118
69
49
(0.45%)
(0.30%)
(1.53%)
Inpatient diagnosis:
SN=0.70; SP=0.99; PPV=0.85;
respiratory failure or sepsis PLUS secondary
NPV=0.94
diagnosis of pneumonia
Outpatient diagnosis:
ICD-9-CM codes: 480.xx-483.xx; 485.xx-
SN=0.66; SP=0.996;
487.0; 507.xx; 518.8x, 038.x
PPV=0.80; NPV=0.99
(academic hospital)
Bacterial
Principal inpatient diagnosis during an
6
Infection
inpatient stay of 3 or more days
(excluding
ICD-9-CM codes for: Meningitis,
pneumonia)
encephalitis, cellulitis, endocarditis,
569
376
193
(2.17%)
(1.63%)
(6.03%)
PPV=0.90
(Hospitalized Veterans Affairs
Patients)
pylonephritis, septric arthritis, osteomyelitis,
bacteriemia, tuberculosis, mycobacterial
infection, systemic candidiasis,
cryptococcosis, aspergillosis
Hip Fracture
7
Inpatient diagnosis of hip fracture PLUS
procedure code during hospitalization
Hospital ICD-9-CM/CPT-4
491
384
107
(1.87%)
(1.67%)
(3.34%)
c
0.84 (K=0.78) concordance
between Medicare Parts A and
B (Medicare patients)
a Emergency
department
Classification of Diseases, Ninth Revision, Clinical Modification
c Current Procedure Terminology
d These misclassification parameters were estimated in distinct study populations and may not apply to the current cohort of antipsychotic users in non-hospital settings
eThis set of codes has not been published as an algorithm. The range for PPV comes from the set of individual codes.
b International
A15
eTable 6. Mediator-mediator associations during follow-up reported as odds ratios (95% CI) conditional on antipsychotic-type and baseline covariates. P-values are
presented for the two-sided hypothesis test of no association. Temporality was examined for statistically significant associations (see footnotes).
Venous
Stroke
Stroke
Ventricular
Arrhythmia
Myocardial
Infarction
Venous
Thromboembolismb
Pneumoniac
Other Bacterial
Infection
Hip Fracture
---
Ventricular
Myocardial
Thromboemboli
Other Bacterial
Arrhythmia
Infarction
sm
Pneumonia
Infection
Hip fracture
1.69 (0.41-4.61)
0.65 (0.16-1.75)
0.48 (0.03-2.17)
0.60 (0.03-2.74)
1.15 (0.58-2.02)
0.53 (0.16-1.26)
p=0.38
p=0.47
p=0.47
p=0.61
p=0.66
p=0.21
2.62 (0.78-6.58)
2.21 (0.34-7.61)
3.00 (0.47-10.38)
1.13 (0.33-2.83)
1.58 (0.38-4.31)
p=0.07
p=0.29
p=0.15
p=0.82
p=0.44
1.44 (0.23-4.65)
2.39 (0.58-6.59)
1.23 (0.55-2.37)
1.32 (0.51-2.77)
p=0.62
p=0.15
p=0.58
p=0.51
5.86 (1.73-14.86)
0.76 (0.19-2.05)
3.33 (1.54-6.33)
p<0.01
p=0.65
p<0.01
3.76 (1.90-6.83)
1.71 (0.52-4.17)
p<0.01
p=0.30
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
1.16 (0.63-1.96)
p=0.61
---
b
the odds ratio (OR) between venous thromboembolism and preceding pneumonia was 1.4 (95%CI 0.2-10.3; p=.74); the OR between pneumonia and preceding venous thromboembolism was 3.1
(95%CI 0.9-11.0; p=0.08); the OR between venous thromboembolism and preceding hip fracture was 2.3 (95%CI 1.2-5.5; p=.02); the OR between hip fracture and preceding venous thromboembolism
was 0.4 (95%CI 0.1-2.6; p=0.30).
c the OR between pneumonia and preceding other bacterial infection was 1.3 (95%CI 0.5-3.5; p=0.66); the OR between other bacterial infection and preceding pneumonia was 0.8 (95%CI 0.2-2.6;
p=0.73)
We observed positive associations between venous thromboembolism and pneumonia, venous thromboembolism and hip fracture, and pneumonia
and other bacterial infection. These associations should not materially affect our conclusion that venous thromboembolism, hip fracture, and other
bacterial infection do not appear to be mediators (based on their small indirect effect in each misclassification scenario in eTable 4). The latter
association appears to be unidirectional with pneumonia preceding other bacterial infection, so these results do not suggest that the indirect effect for
pneumonia is confounded by other bacterial infection during follow-up.
A16
eTable 7. Two-way mediator-mediator (Mi×Mj) interaction presented as crude stratum specific mortality estimates and via a saturated marginal structural model
estimated via stabilized inverse probability weights with 95%CI obtained from robust standard errors.a
Unadjusted risk of 180 day mortality within mediator-mediator strata
Mediator 𝑴i
Stroke
Ventricular
Arrhythmia
Adjusted
Interaction
Mediator 𝑴j
𝑃[𝑌 = 1|𝑀𝑖 = 0, 𝑀𝑗 = 0]
n=[25150, 25935]
𝑃[𝑌 = 1|𝑀𝑖 = 0, 𝑀𝑗 = 1]
n=[106, 566]
𝑃[𝑌 = 1|𝑀𝑖 = 1, 𝑀𝑗 = 0]
n=[110, 556]
𝑃[𝑌 = 1|𝑀𝑖 = 1, 𝑀𝑗 = 1]
n=[1, 13]
Ventricular Arrhythmia
0.12
0.84
0.34
1.00
- 0.1 (-0.2, 0.1)
Myocardial Infarction
0.12
0.39
0.35
0.01
0.2 (-0.3, 0.7)
Venous Thromboembolism
0.12
0.21
0.35
0.00
-0.5 (-0.6, -0.4)b
Pneumonia
0.12
0.41
0.35
1.00
-0.3 (-0.6, 0.2)
Other Bacterial Infection
0.11
0.34
0.35
0.27
0.4 (0.3, 0.5)b
Hip Fracture
0.12
0.22
0.35
0.25
-0.3 (-0.5 , -0.2)b
Myocardial Infarction
0.12
0.38
0.84
1.00
-0.1 (-0.2, 0.1)
Venous Thromboembolism
0.12
0.20
0.84
1.00
0.0 (-0.1, 0.1)
Pneumonia
0.12
0.41
0.84
1.00
-0.0 (-0.1, 0.1)
Other Bacterial Infection
0.11
0.34
0.84
1.00
-0.1 (-0.3 , 0.0)
Hip Fracture
0.12
0.21
0.84
1.00
0.1 (-0.0, 0.2)
A17
Myocardial
Infarction
Venous
Thromboembolism
Pneumonia
Other Bacterial
Infection
Venous Thromboembolism
0.12
0.21
0.39
0.50
0.3 (-0.2 , 0.8)
Pneumonia
0.12
0.41
0.39
0.67
-0.3 (-0.9, 0.3)
Other Bacterial Infection
0.11
0.34
0.39
0.50
0.2 (-0.6, 0.2)
Hip Fracture
0.12
0.22
0.40
0.00
-0.4 (-0.5, -0.3)b
Pneumonia
0.12
0.41
0.21
0.50
-0.0 (-0.6, 0.5)
Other Bacterial Infection
0.12
0.34
0.21
0.33
-0.1 (-0.8, 0.5)
Hip Fracture
0.12
0.22
0.21
0.33
0.0 (-0.4, 0.5)
Other Bacterial Infection
0.12
0.40
0.33
0.58
-0.4 (-0.7, -0.1)b
Hip Fracture
0.12
0.22
0.41
0.50
-0.2 (-0.4, 0.0)
Hip Fracture
0.12
0.21
0.34
0.38
0.4 (0.1, 0.7)b
aThe
adjusted interaction (i.e. 𝑝11 − 𝑝01 − 𝑝10 + 𝑝00 where 𝑝𝑎𝑏 = 𝑃[𝑌 = 1|𝐴 = 𝑎, 𝐵 = 𝑏]) was calculated using a saturated marginal structural linear model for mortality conditional upon medical
events Mi and Mj and their product. The stabilized inverse probability weights used to fit this model were calculated (via logistic regression) as 𝑃[𝑀𝑖 ]/𝑃[𝑀𝑖 |𝐴, 𝐶] × 𝑃[𝑀𝑗 |𝑀𝑖 ]/𝑃[𝑀𝑗 |𝑀𝑖 , 𝐴, 𝐶] where A
is antipsychotic type and C are all baseline covariates in table 1 (main effects only). Generalized estimating equations were used to obtain point estimates and robust 95%CI for the marginal structural
model.
b95% confidence interval does not include the null value of zero
The estimates for interaction should be interpreted with caution as few persons experienced both events (between 1 and 13). Nevertheless, these results do suggest
evidence of interaction between some medical events. However, we did not find any evidence of interaction for mediator-mediator pairs whose individual
estimates for the proportion mediated were summed over in the main text: stroke, ventricular arrhythmia, myocardial infarction, and pneumonia. Joint mediated
effects were only calculated for this set of mediators, so the no mediator-mediator assumption does not appear to be violated for this particular estimate.
A18
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