. 2022 May 30;14(11):2708. doi: 10.3390/cancers14112708

Table 2.

Details of evidence grading for meta-analysis of risk factors for ovarian cancer incidence or mortality—only cohort studies included *.

Exposure	Exposure Contrast	N ˆ	Sample Size Cases/Cohort	Largest Study ^#	Random Effects Summary RR (95% CI) ^¥	Random p-Value ^\|\|	95% Prediction Interval	Egger’s p ^∞	I² (%)	Excess Significance ^§		Evidence Grading **^,†,¶
Exposure	Exposure Contrast	N ˆ	Sample Size Cases/Cohort	Largest Study ^#	Random Effects Summary RR (95% CI) ^¥	Random p-Value ^\|\|	95% Prediction Interval	Egger’s p ^∞	I² (%)	O/E ^α	p-Value ^φ	Evidence Grading **^,†,¶
Strong evidence
Anthropometric measure
Height	Per 10 cm	16	18663/13600000	1.14 (1.10–1.18)	1.16 (1.11–1.20)	2.2 × 10⁻¹³	1.06–1.26	0.18	27	9/6.22	0.15	Strong
BMI	Obese vs. normal	13	6947/20560388 ^τ	1.27 (1.19–1.36)	1.27 (1.17–1.38)	2.6 × 10⁻⁸	1.09–1.47	0.88	12	3/5.30	NP	Strong
Past drug history
HRT-Prospective	Current/recent vs. never	12	11664/948390	1.28 (1.14–1.44)	1.37 (1.27–1.48)	1.3 × 10⁻¹⁵	1.26–1.50	0.68	0	3/7.20	NP	Strong
HRT-Prospective	Ever vs. never	17	12110/950663	1.15 (1.06–1.26)	1.20 (1.13–1.28)	2.1 × 10⁻⁹	1.13–1.28	0.71	0	4/4.90	NP	Strong
HRT-Prospective	Ever vs. never (info duration of use and time since last use)	14	11866/949657	1.16 (1.05–1.28)	1.24 (1.16–1.32)	6.0 × 10⁻¹⁰	1.15–1.33	0.97	0	2/4.87	NP	Strong
OCP	Ever vs. never	45	7726/32201	0.74 (0.67–0.82)	0.74 (0.69–0.80)	5.8 × 10⁻¹⁶	0.68–0.81	0.61	0	3/6.68	NP	Strong
Highly suggestive evidence
Past drug history
HRT	Ever vs. never ET only	11	7512/2302683	1.31 (1.11–1.54)	1.44 (1.25–1.66)	7.1 × 10⁻⁷	0.99–2.09	0.71	48	6/7.01	NP	Highly suggestive
Metformin	Ever vs. never	3	3288/513702	0.16 (0.14–0.17)	0.18 (0.12–0.25)	2.5 × 10⁻²³	0.01–4.31	0.38	14	2/2.42	NP	Highly suggestive
Anthropometric measure
Height	per 5 cm increase	13	16198/3514114	1.07 (1.05–1.09)	1.07 (1.05–1.10)	1.2 × 10⁻⁹	1.02–1.14	0.31	32	8/2.77	<0.01	Highly suggestive
Medical history
Metformin	Ever vs. never	3	3288/513702	0.16 (0.14–0.17)	0.18 (0.12–0.25)	2.5 × 10⁻²³	0.01–4.31	0.38	14	2/2.42	NP	Highly suggestive
Suggestive evidence
Environmental factors
Asbestos	Any vs. none	14	5165/906145	1.30 (0.90–1.80)	1.86 (1.46–2.36)	5.0 × 10⁻⁷	1.05–3.29	0.64	28	4/1.87	0.10	Suggestive
Anthropometric measures
BMI	per 5 kg/m² increase	24	17734/16300000	0.97 (0.93–1.01)	1.07 (1.04–1.11)	<0.01	0.96–1.21	0.07	48	6/1.80	<0.01	Suggestive
BMI	iya per 5 kg/m² increase	6	9452/11100000	1.16 (1.04–1.29)	1.12 (1.05–1.19)	<0.01	1.03–1.23	0.60	0	0/1.00	NP	Suggestive
Medical history
Diabetes Mellitus	DM vs. no DM	17	5036/2868215	1.23 (1.15–1.32)	1.32 (1.14–1.52)	<0.01	0.81–2.15	0.30	80	6/6.71	NP	Suggestive
Past drug history
HRT	Current vs. ever	5	3958/1342899	1.20 (1.09–1.32)	1.28 (1.15–1.42)	6.5 × 10⁻⁶	1.01–1.62	0.08	14	3/2.91	0.93	Suggestive
Weak evidence
Asbestos
Asbestos	Total exp vs. nonexp	20	126/21973	1.12 (0.66–1.80)	1.77 (1.37–2.27)	9.7 × 10⁻⁶	0.85–3.66	0.72	35	6/1.06	<0.01	Weak
Asbestos	High exp vs. nonexp	6	20/6149	1.10 (0.37–2.21)	2.78 (1.36–5.66)	0.01	0.42–18.44	0.78	45	2/0.31	<0.01	Weak
Anthropometric measure
BMI	PrMP Obese vs. normal	3	71/350211	1.56 (1.14–2.16)	1.57 (1.20–2.06)	<0.01	0.27–9.02	0.61	0	1/0.66	0.64	Weak
BMI	PoMP Obese vs. normal	5	350/546195	1.02 (0.82–1.26)	1.23 (1.03–1.47)	2.6 × 10⁻¹	0.72–2.09	0.52	46	1/ 0.25	0.13	Weak
Weight	Per 5 kg weight	4	1006/297350	1.02 (1.00–1.05)	1.03 (1.01–1.05)	<0.01	0.98–1.08	0.42	7	1/0.21	0.08	Weak
Weight gain	per 5 kg increase PoMP, HRT	2	217/23984	1.16 (1.03–1.31)	1.13 (1.03–1.24)	0.01	NA	NA	NA	1/0.27	0.13	Weak
Dietary intake
Dairy, total products	Highest vs. lowest	2	427/90001	1.61 (1.07–2.42)	1.66 (1.19–2.31)	<0.01	NA	NA	NA	1/1.87	NP	Weak
Dairy, skim/low fat	Highest vs. lowest	3	728/170327	1.32 (0.97–1.82)	1.35 (1.09–1.68)	<0.01	0.35–5.43	0.21	0	0/1.93	NP	Weak
Dairy, lactose	Highest vs. lowest	3	728/170327	1.48 (1.05–2.09)	1.47 (1.17–1.84)	<0.01	0.34–6.29	0.42	0	1/2.64	NP	Weak
Meat; processed	Highest vs. lowest	3	1018/696100	1.23 (0.92–1.63)	1.26 (1.02–1.56)	3.5 × 10⁻²	0.31–5.07	0.37	0	0/1.56	NP	Weak
Meat; red and processed	Per 100 g/week increment	21	6536/2140286	1.02 (0.98–1.06)	1.01 (1.00–1.04)	3.4 × 10⁻²	1.00–1.04	0.12	0	0/1.14	NP	Weak
Non starchy vegetables	Per 100 g/day	6	2053/641079	1.00 (0.93–1.07)	0.94 (0.89–1.00)	4.0 × 10⁻²	0.82–1.08	0.21	28	1/0.30	0.19	Weak
Tea; black	Highest vs. lowest	5	1299/203998	0.63 (0.40–0.99)	0.73 (0.56–0.93)	1.2 × 10⁻²	0.42–1.24	0.44	15	2/4.71	NP	Weak
Calcium	Highest vs. lowest	5	1726/351192	0.86 (0.68–1.10)	0.86 (0.74–1.00)	4.0 × 10⁻²	0.67–1.09	0.62	0	0/1.66	NP	Weak
Non herbal tea	Highest vs. lowest	3	734/164882	0.63 (0.40–0.99)	0.69 (0.52–0.93)	1.4 × 10⁻²	0.11–4.57	0.03	0	1/2.74	NP	Weak
Past drug history
HRT	Ever vs. never (continuous E + P)	4	3337/1265735	1.13 (0.96–1.34)	1.22 (1.06–1.40)	<0.01	0.90–1.65	0.07	0	1/1.63	NP	Weak
HRT	Ever vs. never (sequential E + P)	4	3337/1265736	1.14 (0.98–1.32)	1.35 (1.06–1.72)	1.5 × 10⁻²	0.54–3.35	0.18	50	2/1.75	0.80	Weak
HRT	Ever vs. never (ET + PT)	9	7512/2302683	1.50 (1.34–1.68)	1.23 (1.08–1.14)	2.3 × 10⁻³	0.87–1.75	0.40	53	3/8.65	NP	Weak
HRT	Ever vs. never (ET+ E/PT)	2	543/141880	1.50 (0.92–2.44)	1.55 (1.05–2.30)	2.7 × 10⁻²	NA	NA	NA	0/1.89	NP	Weak
NSAIDS Non aspirin	Ever vs. never	6	1782/505136	0.90 (0.75–1.08)	0.90 (0.81–1.00)	4.4 × 10⁻²	0.78–1.04	0.55	0	0/1.02	NP	Weak
OCP	Ever vs. never	3	60/80670	0.60 (0.30–1.40)	0.43 (0.25–0.75)	3.0 × 10⁻³	0.01–15.16	0.41	NA	1/0.73	0.71	Weak
Reproductive factors
PID	Ever vs. never	6	8285/2929284	1.05 (0.92–1.20)	1.32 (1.05–1.66)	1.6 × 10⁻²	0.71–2.47	0.35	65	2/1.01	0.28	Weak
IVF	Ever vs. never (reference group general population excluding OC diagnosis < 1yr post treatment)	6	31606/1438001	1.30 (0.90–1.88)	1.47 (1.06–2.03)	2.0 × 10⁻²	0.73–2.96	0.64	23	1/1.55	NP	Weak
IVF	Ever vs. never reference group IVF population; total follow up	6	31606/1438002	1.35 (0.93–1.96)	1.66 (1.08–2.55)	2.2 × 10⁻²	0.52–5.28	0.91	52	2/1.64	0.74	Weak
Breastfeeding	Per 5 mo increase in duration	3	1180/447386	0.98 (0.92–1.05)	0.94 (0.89–1.00)	0.03	0.80–1.49	0.59	22	1/0.17	0.04	Weak
Medical history
SLE	Observed vs. expected	4	44/40855	0.82 (0.54–1.20)	0.73 (0.53–1.00)	4.9 × 10⁻²	0.36–1.46	0.97	0	0/0.26	NP	Weak

(1) Abbreviations: BMI, body mass index; BMI iya, body mass index in young adulthood; BMI PoMP, body mass index postmenopausal; BMI PrMP, body mass index premenopausal; CC, case control; CRP, c-reactive protein; E + P, estrogen and progesterone; E + E/P, estrogen and estrogen/progesterone; HRT, hormone replacement therapy; IVF, in-vitro fertilization; NA, not available; np; not pertinent, because the estimated is larger than the observed, and there is no evidence of excess statistical significance based on the assumption made for the plausible effect size; NSAID, non- steroidal anti -inflammatory drugs; OC, ovarian cancer; OCP, oral contraceptive pill; PID, pelvic inflammatory disease; RR, relative risk; SLE, systemic lupus erythematous; WG, weight gain; (2) Key: * only meta-analyses meeting at least weak grade of evidence listed. ˆ Number of studies. ^# Relative risk and 95% confidence interval of largest study (smallest standard error) in each meta-analysis. ^¥ Random effects refer to summary risk ratio (95% confidence interval) using the random-effects model. ^|| p-value of summary random effects estimate. ^∞ p-value from the Egger’s regression asymmetry test. ^§ Expected number of statistically significant studies using the point estimate of the largest study (smallest standard error) as the plausible effect size. ^α Observed/Expected number of statistically significant studies. ^φ p value of the excess statistical significance test. All statistical tests were two-sided. ^¶ Small study effect is based on the p-value from the Egger’s regression asymmetry test (p > 0.1) where the random effects summary estimate was larger compared to the point estimate of the largest study in a meta-analysis. ^† Based on the p-value (p > 0.1) of the excess significance test using the largest study (smallest standard error) in a meta-analysis as the plausible effect size. ^τ Person years; (3) ** Summary of evidence grading criteria: (i) Weak: p < 0.05 ^||; (ii) Suggestive: p < 10⁻³ ^||; >1000 cases; (iii) Highly suggestive: p < 10⁻⁶ ^||; >1000 cases; p < 0.05 of the largest study in a meta-analysis; (iv) Strong: p < 10⁻⁶ ^||; >1000 cases; p < 0.05 of the largest study in a meta-analysis; I² < 50%; no small study effect ^¶; prediction interval excludes the null value; no excess significance bias ^†.