Table 2.
First screening round cumulative CIN2/3 and CIN3 relative sensitivity, specificity and positive predictive value of the S5 methylation classifier and other triage approaches.
| Triage approach | Colposcopy referral ratea (95%CI) | CIN2/3 | CIN3 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Relative sensitivity (95%CI) | McNemar p valueb | Relative specificity (95%CI) | Unadjusted PPV (95%CI) | Adjusted PPVc (95%CI) | n | Relative sensitivity (95%CI) | McNemar p valueb | Relative specificity (95%CI) | Unadjusted PPV (95%CI) | Adjusted PPVc (95%CI) | ||
| S5 positive at baseline | 4.3 (4.0–4.6) | 81 | 75.7% (67.3–83.7) | 44.0% (36.1–52.2) | 49.1% (41.5–59.9) | 33.1% (29.3–37.3) | 41 | 93.2% (84.8–100.0) | 41.8% (35.3–48.4) | 24.8% (18.3–31.5) | 18.2% (16.2–20.4) | ||
| LBC ≥ASCUS or LBC NILM and HPV16/18 positive at baselined | 4.2 (3.9–4.5) | 73 | 68.2% (59.3–77.0) | 0.170 | 52.0% (43.9–60.0) | 50.3% (42.4–58.5) | 34.2% (29.7–39.3) | 38 | 86.4% (75.0–95.7) | 0.248 | 49.8% (43.1–56.6) | 26.2% (18.9–33.3) | 19.3% (16.6–22.2) |
| cobas HPV16/18 positive at baselined | 2.1 (1.9–2.3) | 53 | 49.5% (40.2–59.1) | <0.001 | 77.3% (70.3–83.9) | 60.9% (50.6–70.9) | 44.4% (36.3–54.1) | 32 | 72.7% (59.5–86.0) | 0.008 | 74.2% (68.2–80.0) | 36.8% (27.0–47.0) | 28.1% (22.6–34.7) |
| LBC ≥ASCUS at baseline | 3.0 (2.8–3.3) | 54 | 50.5% (41.1–59.8) | <0.001 | 66.7% (59.1–74.3) | 51.9% (42.2–61.9) | 35.7% (29.4–43.0) | 27 | 61.4% (46.7–75.6) | 0.001 | 63.8% (57.5–70.4) | 26.0% (17.7–34.6) | 19.1 % (14.7–24.0) |
| HPV FOCAL Round 1e (LBC ≥ASCUS at baseline OR LBC NILM at baseline and HC2+ at 12 mo. follow‐up) | 5.9 (5.5–6.3) | 107 | Ref | <0.001 | Ref | 27.9% (25.2–30.9) | 44 | Ref | 0.248 | Ref | 12.7% (10.7–15.0) | ||
The individual tests and combinations were modeled on baseline screening results, except for the HPV FOCAL Round 1 approach and those based on HPV genotyping, which also considered the 12‐month subsequent specimen results.
CIN: cervical intraepithelial neoplasia; CI: confidence interval; PPV: positive predictive value; HC2: hybrid capture 2 HPV test; cobas: cobas® 4800 HPV test; LBC: liquid‐based cytology; ASCUS: atypical squamous cells, undetermined significance; NILM: negative for intraepithelial lesions and malignancy; Ref: reference; the sensitivity and specificity of each modeled triage approach are relative to those for the FOCAL trial.
The colposcopy referral rate for S5+ triage was estimated for the overall trial HPV arms by re‐weighting the case–control study subset data. Rates for the other triage approaches were based on trial data for the HPV arms. Rates are per 100 women screened.
McNemar p value for each triage strategy compared to S5. We performed an additional McNemar's test for S5 vs. LBC≥ASCUS/HPV16/18 for CIN3, where the S5 cutoff was adjusted to 0.91 so that the specificities of the two triage approaches were the same (p = 0.617).
Due to oversampling of women with CIN2/3 lesions in the methylation study subset, adjusted PPVs were also calculated using the CIN2/3 and CIN3 prevalence for the FOCAL trial HPV arms: adjusted PPV = (Sn*Pr)/((Sn*Pr)+(1−Sp)*(1−Pr)), where Sn is sensitivity, Sp is specificity, and Pr is the CIN2/3 or CIN3 prevalence.
Baseline LBC NILM/HPV16/18 positive women were only referred to colposcopy if they were HC2 positive and/or LBC≥ASCUS at the 12 month subsequent test. Thus, we are unable to determine how many LBC NILM women may have had CIN2/3 at baseline, and were HC2 negative/LBC NILM at the 12 month test.
Published trial colposcopy referral rate and PPVs obtained from Ogilvie et al. 201617. The number of CIN2/3 and CIN3 cases is the total for the methylation case–control study subset.