Confounding and Negative Control Methods in Observational Study of SARS-CoV-2 Vaccine Effectiveness: A Nationwide, Population-Based Danish Health Registry Study

Figures & data

Table 1 Characteristics of the Study Cohorts

Characteristic	Vaccinated	Non-Vaccinated
N	61,046	61,046
Female	31,374 (51.4%)	31,374 (51.4%)
Age (IQR)	69.0 (63.8–76.0)	69.0 (63.8–76.0)
Observation time (years)	119,432	112,765
Charlson=0	36,936 (60.5%)	38,260 (62.7%)
Charlson=1	9,870 (16.2%)	9,796 (16%)
Charlson=2	8,008 (13.1%)	6,691 (11%)
Charlson=3	3,194 (5.2%)	3,036 (5%)
Charlson=4	1,334 (2.2%)	1,388 (2.3%)
Charlson=5	618 (1%)	723 (1.2%)
Charlson=6	1,086 (1.8%)	1,152 (1.9%)
Number of SARS-CoV-2 tests (IQR)	0 (1–5)	1 (4–9)
Positive SARS-CoV-2 tests	1,537 (2.5%)	2,379 (3.9%)
Vaccinated as of 1 July 2023	61,046 (100%)	19,190 (31.4%)
Outpatient visits (IQR)	0 (0–2)	0 (1–2)
Geographical region quartile 1	13,462 (22.1%)	14,564 (23.9%)
Geographical region quartile 2	15,884 (26%)	14,998 (24.6%)
Geographical region quartile 3	19,179 (31.4%)	20,352 (33.3%)
Geographical region quartile 4	12,517 (20.5%)	10,509 (17.2%)
Mammography screening	25,542 (81.4%)	16,667 (53.1%)
Prostate biopsy	2,327 (7.8%)	1,293 (4.4%)
Examination associated with screening for blood in faeces	4,348 (7.1%)	1,956 (3.2%)
Cataract operation	9,003 (14.7%)	6,799 (11.1%)
Melanoma	727 (1.2%)	346 (0.6%)
Skin cancer	2,147 (3.5%)	1,362 (2.2%)
In hospital examination of the eye	9,704 (15.9%)	7,870 (12.9%)
In hospital examination of the ear	9,537 (15.6%)	6,926 (11.3%)
Acute myocardial infarction	2,249 (3.7%)	2,331 (3.8%)
Stroke	3,046 (5%)	3,810 (6.2%)
Cancer	7,651 (12.5%)	5,925 (9.7%)
Trauma	32,728 (53.6%)	30,552 (50%)
Low energy fracture	7,862 (12.9%)	8,323 (13.6%)
Head trauma	8,247 (13.5%)	9,287 (15.2%)

Table 2 Risk of Positive SARS-CoV-2 Tests and Negative Control Outcomes in Individuals Who Had and Had Not Received First SARS-CoV-2 Vaccine as of 1 July 2021

Outcome	Number with Outcome		Vaccinated vs Non-Vaccinated		Vaccinated vs Non-Vaccinated*
	Vaccinated	Non-Vaccinated	IRR Unadjusted	IRR Unadjusted^§	IRR Unadjusted	IRR Adjusted^§
First positive SARS-CoV-2 test	20,180	14,785	1.32 (1.29–1.35)	1.32 (1.29–1.35)	1.38 (1.35–1.41)	1.29 (1.27–1.32)
Mammography screening	11,755	5231	2.43 (2.35–2.51)	2.43 (2.35–2.51)	2.56 (2.48–2.64)	2.63 (2.54–2.72)
Prostate biopsy	338	178	1.84 (1.54–2.21)	1.84 (1.54–2.21)	1.97 (1.64–2.36)	1.91 (1.59–2.30)
Examination due to a positive faecal blood screening result	1,171	530	2.10 (1.89–2.32)	2.10 (1.89–2.32)	2.22 (2.00–2.46)	2.10 (1.89–2.33)
Operation for cataract	1,804	1,160	1.53 (1.42–1.65)	1.53 (1.42–1.65)	1.63 (1.51–1.75)	1.58 (1.46–1.71)
Skin cancer	510	300	1.63 (1.41–1.88)	1.63 (1.41–1.88)	1.72 (1.49–1.99)	1.63 (1.41–1.88)
Malignant melanoma	186	54	3.27 (2.42–4.43)	3.27 (2.42–4.43)	3.46 (2.56–4.69)	3.24 (2.37–4.42)
Examination of eye	3,716	2,630	1.36 (1.29–1.43)	1.36 (1.29–1.43)	1.42 (1.35–1.50)	1.25 (1.18–1.31)
Examination of ear	3,551	2,365	1.44 (1.37–1.52)	1.44 (1.37–1.52)	1.51 (1.43–1.59)	1.39 (1.32–1.47)

Notes: *With death as competing risk. ^§Adjusted for age, sex, Charlson Comorbidity Index, number of inpatient and outpatient hospital contact in the year before study inclusion and geographical region.

Abbreviation: IRR, incidence rate ratio.

Figure 1 Cumulative incidence (%) of first positive SARS-COV-2 test and negative control outcomes among non-vaccinated and vaccinated individuals.

Table 3 Risk of Death After SARS-CoV-2 Infection and in Negative Control Population in Individuals Who Have and Have Not Received First SARRAS-CoV-2 Vaccine 1 July 2021

Cohorts	Number in Cohort		Number of Deaths		Vaccinated vs Non-Vaccinated		Vaccinated vs Non-Vaccinated*
	Vaccinated	Non-Vaccinated	Vaccinated	Non-Vaccinated	MRR_unadjusted	MRR_adjusted^§	MRR_unadjusted	MRR_adjusted^§
Positive SARS-CoV-2 test	20,180	14,789	211	702	0.22 (0.19–0.25)	0.23 (0.19–0.26)	NA	NA
Acute myocardial infarction	376	383	40	65	0.58 (0.38–0.90)	0.48 (0.31–0.75)	0.64 (0.38–1.07)	0.53 (0.31–0.90)
Stroke	910	809	72	140	0.56 (0.42–0.75)	0.50 (0.37–0.67)	0.63 (0.45–0.86)	0.53 (0.38–0.74)
Diagnosis of cancer	1,622	1,971	208	337	0.48 (0.41–0.57)	0.46 (0.38–0.54)	0.46 (0.38–0.57)	0.44 (0.36–0.53)
Trauma	2,225	2,417	69	169	0.37 (0.28–0.49)	0.36 (0.27–0.48)	0.37 (0.27–0.51)	0.33 (0.24–0.46)
Low energy fracture	1,451	1,473	60	133	0.44 (0.32–0.60)	0.43 (0.32–0.59)	0.45 (0.32–0.64)	0.43 (0.30–0.62)
Head trauma	1,028	1,072	40	74	0.53 (0.36–0.78)	0.47 (0.32–0.70)	0.50 (0.32–0.77)	0.42 (0.27–0.66)

Notes: *Time censored at positive SARS-CoV-2 test or SARS-CoV-2 vaccination (in the non-vaccinated cohort). ^§Adjusted for age, sex, and Charlson Comorbidity Index.

Abbreviations: NA, not applicable; MRR, mortality rate ratio.

Figure 2 Cumulative incidence (%) of death after positive SARS-COV-2 test and after diagnosis of non-infectious diseases among non-vaccinated and vaccinated individuals.

Data Sharing Statement

The ethical approval of this study from the Danish Data Protection Agency states that the data that have been used in this article cannot be shared publicly.