Journal of Clinical Epidemiology

The 1960s cervical screening incident at National Women's Hospital, Auckland, New Zealand: insights for screening research, policy making, and practice

This article examines a cervical screening incident from the 1960s and draws lessons for screening policy. Concern about harmful overtreatment of symptomless lesions prompted university gynecologist Herbert Green to study, between 1965 and 1970, a 'special series' of 33 women with carcinoma in situ (CIS) who were managed with only limited punch or wedge biopsy. These women were carefully followed up but not treated unless they showed evidence of progression to invasive cancer. This paper examines source documents and subsequent publications in order to ascertain lessons from this incident. In keeping with the 1964 Helsinki Declaration, written consent was not sought. Green published the outcomes for his patients with CIS including the 'special series.' A Judicial inquiry (the Cartwright Inquiry) in 1987 concluded that some women had suffered harm and some had died, but numbers and evidence were not clearly stated. Medical case review for the Inquiry identified 25 women with only punch or wedge biopsy; in 21 of these, there were reasons why no further treatment was given; two had developed cervical cancer, and none were recorded as having died. The case review found eight patients, not necessarily in the 'special series,' who 'in retrospect and by 1987 standards' might have benefited from earlier conisation or hysterectomy. Subsequent claims relating to Green's practice have wrongly stated that as many as one hundred women or more had treatment withheld and over 30 died as a result. These claims are inaccurate.

The prevalence of HR-HPV infection based on self-sampling among women in China exhibited some unique epidemiologic features

Objective To investigate the epidemiological characteristics of high-risk human papillomavirus(HR-HPV) infection based on vaginal self-collected samples. Study Design and Setting The pooled data of 3045 self-collected samples used for the analysis derived from four previous studies on cervical cancer screening(The Chinese Multi-Center Screening Trial, CHIMUST; The Shenzhen Cervical Cancer Screening Trial-2, SHENCCAST-2; The Chinese Cervical Cancer Prevention Study, CHIPCAPS; Pingshan trial, PINGSHAN)conducted across China by our team since 2011. These cases were evaluated for HR-HPV type prevalence relative to lesion grade and age. The occurrence of cervical intraepithelial neoplasia(CIN) with specific HPV types and the influence of co-infection is explored. Results The top three most common genotypes among the HR-HPV positives were HPV-52(23.4%), HPV-16(18.0%), and HPV-58(15.50%). For women with CIN2+, the most frequent genotypes were HPV-16, 58, 52, and 18 in sequence. HPV-16 accounted for the majority of CIN2/CIN3/Ca with attribution rate of 23.86%, 44.78% and 50.00% respectively. HPV-58 accounted for 19.48%, 16.79% and 13.46% respectively. CIN2+ was found in the following types most frequently: HPV-16(31.23%), HPV-33(24.03%), HPV-58(18.41%), HPV-31(11.76%), HPV-18(7.75%), and HPV-52(7.30%). HPV-16 showed preference for co-infection with HPV-52 and HPV-58. Conclusion The prevalence of HR-HPV infection based on self-sampling among women in China exhibited some unique epidemiologic features.

Staged design recommendations for validating relative sensitivity of self-sample human papillomavirus tests for cervical screening

To ensure that the emerging methods for human papillomavirus (HPV) testing on self-collected samples in cervical screening are evaluated robustly. We assess paired study designs for relative sensitivity of self-collected vs. traditional clinician-collected samples in detection of high-grade cervical intraepithelial neoplasia. Designs considered are (D1) both samples at screening, with clinical actions triggered by HPV positivity; (D2) offering a self-sample test to clinician-collected HPV-positive women; (D3) as D2 but using a repeat clinician-sample as comparator; (D4) offering a choice of self- vs. clinician-sampling, and the alternative test in HPV-positive women; (D5) paired samples at referral appointment. D1 is simple to analyze but requires the largest sample size and referral of self-sample positive, clinician-sample negative women. D2 requires a much smaller sample size, and no change to clinical practice, and could be used to rule-in a test because estimates are conservative (against self-sampling). D3 mitigates this bias but requires a second clinician sample. D4 is only manageable where self-sampling already occurs. The liberal D5 might be used to rule-out a self-sampling test. A universal recommendation for an optimal study design is challenging. Staged validation might be useful with D5 as a gatekeeper for D1-D4.

Changing predictor measurement procedures affected the performance of prediction models in clinical examples

The aim of this study was to quantify the impact of predictor measurement heterogeneity on prediction model performance. Predictor measurement heterogeneity refers to variation in the measurement of predictor(s) between the derivation of a prediction model and its validation or application. It arises, for instance, when predictors are measured using different measurement instruments or protocols. We examined the effects of various scenarios of predictor measurement heterogeneity in real-world clinical examples using previously developed prediction models for diagnosis of ovarian cancer, mutation carriers for Lynch syndrome, and intrauterine pregnancy. Changing the measurement procedure of a predictor influenced the performance at validation of the prediction models in nine clinical examples. Notably, it induced model miscalibration. The calibration intercept at validation ranged from -0.70 to 1.43 (0 for good calibration), whereas the calibration slope ranged from 0.50 to 1.67 (1 for good calibration). The difference in C-statistic and scaled Brier score between derivation and validation ranged from -0.08 to +0.08 and from -0.40 to +0.16, respectively. This study illustrates that predictor measurement heterogeneity can influence the performance of a prediction model substantially, underlining that predictor measurements used in research settings should resemble clinical practice. Specification of measurement heterogeneity can help researchers explaining discrepancies in predictive performance between derivation and validation setting.

Cervical screening and overdiagnosis: continuation of Controversy and Debate

Editors Epilogue; Looking back and forward in the arena of screening, overdiagnosis, and optimizing outcome: editors’ epilogue

Authors' response to comments on “The 1960s cervical screening incident at National Women's Hospital, Auckland, New Zealand: insights for screening research, policy making, and practice”

Response to comments by defenders of the inquiry into the management of cervical carcinoma in situ in National Women's Hospital, New Zealand, in the 1960s and early 1970s

Letter to the editor: The 1960s cervical screening incident at National Women's Hospital, Auckland, New Zealand

Letter to the editor: A clinician's perspective of the ‘unfortunate experiment’

Commentary: Back to the future in cervical screening: applying a contemporary lens to an old controversy

The “unfortunate experiment” that was not, and the indebtedness of women and children to Herbert (“Herb”) Green (1916–2001)

All screening programs have the potential to result in harmful overdiagnosis and overtreatment. Sound evidence, policy, and standards are needed to keep this harm to a minimum. Screening for and "treating" cervical cytological abnormalities provides a sobering example. The term "carcinoma in situ" came into use from 1950 and implied-misleadingly-that an inevitable malignant process had been identified. Hysterectomy became widely used to "treat" it. New Zealand's Herbert Green was one of a minority of gynecologists around the world who recognized the possible dangers of harmful overtreatment. Green developed and monitored more conservative management approaches to avoid women being "subjected to hysterectomy". By the mid-1980s, his approaches had been adopted not only within National Women's Hospital in Auckland, but more widely. In 1987, it was alleged in a magazine article that an "experimental" research program had been undertaken at National Women's Hospital to study the natural course of untreated cervical "carcinoma in situ"; that this had entailed withholding "conventional treatment" from some patients indefinitely; and that some patients had died as a result. A public furore resulted and led 2 weeks later to the creation of a judicial inquiry-the Cartwright Inquiry-which reported the following year. The findings of the Inquiry, which criticized Green's practice, have been both disputed and defended ever since, often by individuals with competing interests. In the recently published 2nd edition of their book Screening: Evidence and Practice, Angela Raffle, Anne Mackie, and Muir Gray have provided a fresh analysis. This concludes (see accompanying article) that the Cartwright Inquiry provides no trustworthy evidence of harm from the adoption of the conservative management introduced by Green and adopted by some of his colleagues at National Women's Hospital. It is now clear that the treatment and monitoring methods introduced by Herb Green have benefited numerous women through avoidance of major surgery and preservation of fertility.