The paper HPV screening for cervical cancer in rural India published in N Engl J Med.(one of the most important journal of medicine in the world) 2009 Apr 2;360(14):1385-94.

The conclusion of the paper: In a low resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cancers or deaths from cervical cancer.Furthermore, the study abstract asserted, "No significant reductions in the numbers of associated deaths were observed in the cytology testing group or in the VIA group, as compared with the control group".

In other words, this clinical trial in India demostrate HPV testing can reduce the rate of cervical cancer and its related death, but Pap cytology and VIA have no reduction of cervical cancer related death, same as no any test group (control).

The authors manupulated the statistical numbers and made the results they hope to have.

Why? Industry-company involved the clinical trials. Interests are what people are looking for.

I pasted the original abstract here and also Dr. Austin and I wrote the editorial commentary.

 在这些大型科研国际社会为什么选择在印度这些发展中国家进行呢？又为什么产生那么多在发达国家不会而在发展国家进行的科研的伦理或者人为的操纵科研结果的问题呢？个人认为原因有很都多，主要有以下几点：

1、有人出钱资助，所以科研需要给出钱人做点事情——“理所当然”——也就是“知恩图报”；但是自觉或不自觉的就加入了人为的控制。

2、在发展国家有更多的廉价病例和劳动力，用更少的投入可以产出更多的产值；从经济学上来说是划算的；科研的规模上是空前的，时间短、投入少不是吗？但是无形的就降低了科研的质量。

3、再是科研的人员有私心，为了事先自己预测的成果；通过各种手段来控制着科研朝预测结果走；即使最后没有到达，还可以修改数据吧——这是为什么在有些学术交流会中可以看到预测值99%或100%（比世界是上其他任何人做出来的都高很多）；或者说我们这里没有误诊的笑话——正如我一个老师在判科研论文的时候说：“修改数据没有痕迹是一个天才；但是修改到到处是漏洞就是蠢才了”。

4、正如赵老师引用的毛爷爷的话说的：“阶级斗争存在于世界的每一个角落”——伟人的伟大之处就在如此；能前知几千年后知几千年。如果没有赵老师这些真正懂的人来指出这些科研的毛病，那可能被一些制品公司利用引诱多少人的健康付出代价呀。

5、还是邓爷爷说的那句话：“国家落后要挨打，我们必须发展”。在学术同样如此呀！

以下内容来自我一个师妹的翻译

我还没来得及看

请大家多多批评指正

致编辑：据Sankaranarayanan等（4月2日出版）¹报道，在女性普查中通过细胞学检查、第二代杂交捕获法检测HPV、醋酸肉眼观察，对高危宫颈肿瘤的检出率没有统计学差异。降低宫颈癌死亡率仅见于那些进行HPV检测的妇女。筛选试验检出率与随后死亡率之间的相关性比较异常缺乏需要慎重考虑。Sankaranarayanan承认，不能用筛选试验的效果差异，而要用随访护理的不确定差异解释目前研究中通过醋酸肉眼观察与更早研究中通过醋酸肉眼观察时，在妇女普查中存在死亡率的不同²。当前的数据同样表明，筛选试验检出率之间没有统计学意义，而要用随访护理的不确定差异来解释很多发展中国家中普查的妇女存在死亡率的差异，这些政治结构中真正缺乏对宫颈癌预防的支持³，这将会被一种不可靠的理念所进一步消弱，即仅有一种难以承担的筛查总比什么都没有要强¹。

致编辑：印度医学研究理事会研究发现，醋酸肉眼观察宫颈的降期效应和死亡率的下降还持续发生在印度次大陆。关于醋酸肉眼观察宫颈的好处，作者的早期的研究结果和目前的研究结果之间的偏差需要更多的解释。

致编辑：在先前的一篇文章中，Sankaranarayanan等报道，应用醋酸肉眼观察和“屏障和治疗”的方法，宫颈癌死亡率下降，而目前的文章呼吁在活检中证实患有2级或3级宫颈上皮内瘤的妇女需要多次随访和治疗。在目前的报道中，没有关于这两项研究差异的讨论。

目前对醋酸肉眼观察宫颈提出质疑，对发展中国家的宫颈癌预防具有非常重要的价值。醋酸肉眼观察宫颈在资源不足的地区中的好处在于，它可以廉价地用于检测宫颈癌前病变，而且它可以帮助检查者制定即时而正确的治疗方案。这种方法降低了具有癌前病变的病人失去随访机会的风险。

我们坚信，当前文献报道的缺乏生存受益不应该除外先前已经证明的屏障与治疗计划的救生结果。

致编辑：发展中国家在实现宫颈癌预防服务中的兴趣可能是Sankaranarayanan等报道的强有力证据的一个结果。不幸的是，由于全球经济的衰退，卫生保健和卫生保健相关的开发辅助设备的经费开支可能会紧缩。在本方案中，宫颈癌预防服务和其他以人口为基础的卫生保健计划的一体化可能为有效的启动、扩展、坚持这些服务提供宝贵的机会。HIV感染和AIDS的预防和治疗计划在很多发展中国家正在实施，而这些地方宫颈癌的发生率和死亡率也很高。HIV-AIDS计划缓慢但持久地提高卫生基础设施并增加卫生保健的可利用性。如最近我们在赞比亚所示的那样，宫颈癌预防服务和HIV-AIDS计划的一体化对于宫颈癌高危的妇女是一个不错的机会。这些努力使从明显可预防的癌症中挽救生命并加强广泛的初级护理环境成为可能，这对坚持垂直健康计划非常重要。

致编辑：Sankaranarayanan等发现，针对子宫颈癌相关HPV株的单个DNA筛查试验对于资源有限的地区是非常合算的。另一项策略能够进一步增加公共卫生的预算，通过对更多妇女扩大筛查而增加早期癌症的检出数目。

1943年，Dorfmanl为集中筛选新兵梅毒提出了一个巧妙的方法。他的想法是，如果有效的检测性能在1：K的稀释度下，就可以检测大量的样本，每次以K个人为准，如果大样本检测是阳性的，就可以检测单个样本。在低流行率的人群中筛查N个人，α，这个检查的数目需要调整，平均起来，可能仅为1。N× [κ+1−(1−α)κ].

在Sankaranarayanan等的研究中，α大约为0.01.假设检测的默认稀释度为1：3，预算允许N次检测。三组将需要（0.6）N次检测，而能够筛查的女性数量将为（1/0.6）N，或为1.67N。如果筛查的妇女可以根据风险度划分组，对于高危女性进行单个检测，低危女性进行集体检测，那么将会获得更多的收益。

作者答复：经过醋酸肉眼观察宫颈法、细胞学检查法后，宫颈癌在8年的随访过程中，死亡率没有显著减少，对此，Suba 、Ankit 和 Cremer等呼吁更多的解释。虽然，研究过程中没有什么新的不同，但是在两种随即试验中，醋酸肉眼观察宫颈后，偏差结果引起了关注，尤其在那些开始实行以醋酸肉眼观察宫颈为基础的屏障与治疗计划的国家。

产生偏差的原因还未完全明了。研究组的随访护理没有差别。从我们的结果中，已经清楚的是，HPV检测潜在的前期病变比细胞学检测和醋酸肉眼观察宫颈的方法有更高的灵敏度。然而，在醋酸肉眼观察宫颈或细胞学检测后，研究组的长期随访可能阐明目前缺乏的效应。也许给对照组妇女提供健康教育会对宫颈癌的负担产生影响，导致在对照组、醋酸肉眼观察宫颈组和细胞学检查组中，宫颈癌的重病率或死亡率缺乏显著的检出差异。由于宫颈癌在有症状的对照组妇女中被诊断出来了，她们正在寻求诊断服务，而卫生服务在Osmanabad区还未开发，因此不能排除会低估对照组中宫颈癌病例和死亡数目。患病的妇女可能不会寻求临床护理，这些患者由于缺乏医院记录，这些病例和死亡资料可能会丢失。

目前，上述可能性也许能够解释为什么醋酸肉眼观察宫颈和细胞学检测会缺乏显著的效应。然而，由于我们计划这几年继续研究组宫颈癌发病率和死亡率的随访，因此我们将会阐明这些干扰的长期效应，包括细胞学检测和醋酸肉眼观察宫颈中死亡率的任何延迟减少。

答复Mwanahamuntu 和 Wein­berg等：筛查30岁以上妇女的方法，即在高危HPV型的妇女中用很少的高敏检测方法筛查并针对早期诊断，这对最大化利用公共卫生预算是一些好的策略。我们期待不久的将来，HPV检测在所有的地区都能承受。

这次内容实在太长太多，所以只能一段一段翻译，有兴趣者大家认领。

 Other aspects of the study data also support the hypothesis that bias was introduced in the study group arms during treatment of patients who developed cervical cancer. For example, the death rate for clinically detected cervical cancer patients in the HPV test-negative group of the HPV arm was 0% as compared to 40.9% among clinically detected cancer patients in the cytology-negative group of the cytology arm [Table 3]. Remarkably, the 0% death rate occurred in the HPV group despite the fact that 62.5% of the HPV test-negative cervical cancers were "advanced stage" (Stage II+). Among patients with positive screening results, similar unexpected outcome differences are also evident [Table 1]. Even though the numbers of cervical cancers in both screen-detected groups were essentially the same (HPV 87; cytology 88), more favorable Stage IA screen-detected cancers were detected in the cytology arm (58) than in the HPV arm (45). Also, fewer unfavorable Stage II+ cancers were screen detected in the cytology arm (10) than in the HPV arm (14). Even after acknowledging the higher negative predictive value of HPV testing reflected in [Table 3], deaths in the HPV arm were unexpectedly one-third lower (12) than in the more stage-favorable cytology arm (18). The 2005 publication ^[3] states that "Women with suspected invasive cancer were referred to the surgical oncology department of NDMCH (Nargis Dutt Memorial Cancer Hospital) for investigations and treatment with surgery and radiation." The study also notes that "The most common form of treatment for invasive carcinoma in the intervention arm was radical hysterectomy followed by radical radiotherapy." No data are reported on the extent of similarities or differences in cancer treatments between the test group arms. The effect of the bias of unexpectedly favorable treatment outcomes in the HPV arm contributes to the study conclusion that HPV screening (rather than some other factor) preferentially prevented cervical cancer deaths. The NEJM report does acknowledge that "both practitioners and subjects were aware of the study group assignments." ^[1]

该项研究资料的其它方面也支持了这个假说，即偏倚被引入到那些已进展为宫颈癌病人接受治疗的研究小组中。例如，HPV组中HPV检测阴性组临床检查处的宫颈癌病人死亡率为0%，而细胞学组中细胞学阴性组中临床检出的宫颈癌病人死亡率为40.9%（表3）。但是值得注意的是，尽管HPV组中死亡率为0%，但事实是62.5%HPV检测阴性的宫颈癌是处于“进展期”（II期及以上）。在阳性筛查结果的病人中，相似的意外结果差异也非常明显【表1】。 即使在该2组筛查中宫颈癌的数量本质上是相同的（HPV87例，细胞学88例），但筛查检出的IA期癌在细胞学组（58）高于HPV组（45）。而预后不好的II期及以上的癌在细胞学组的检出数为10例，低于HPV组（14例）。虽然从表3中可看出HPV检测具有较高的阴性预测值，但HPV组宫颈癌死亡人数比较高分期预后的细胞学组出乎意料地低1/3。2005年出版的文章指出：“那些怀疑为浸润性癌的女性被推荐到NDMCH肿瘤外科进行检查和手术及放疗。”该研究也指出：“干扰组中大多数浸润性癌最常见的治疗方法是根治性子宫切除术和放疗。”在检测组中有关癌症治疗的相似性或差异性的程度没有资料报道。HPV组这种意想不到的较好治疗后果的偏倚，其结果是导致该研究得出了HPV筛查（而不是其它因素）可优先防止宫颈癌死亡的结论。这篇NEJM论文的作者也承认“研究者和受试者都知道该研究的实验分组。”

Test group biases and ethical concerns mar New England Journal of Medicine articles promoting HPV screening for cervical cancer in rural India

The paper HPV screening for cervical cancer in rural India published in N Engl J Med.(one of the most important journal of medicine in the world)(one of the most important journal of medicine in the world) 2009 Apr 2;360(14):1385-94.

The conclusion of the paper: In a low resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cancers or deaths from cervical cancer.Furthermore, the study abstract asserted, "No significant reductions in the numbers of associated deaths were observed in the cytology testing group or in the VIA group, as compared with the control group".

In other words, this clinical trial in India demostrate HPV testing can reduce the rate of cervical cancer and its related death, but Pap cytology and VIA have no reduction of cervical cancer related death, same as no any test group (control).

The authors manupulated the statistical numbers and made the results they hope to have.

Why? Industry-company involved the clinical trials. Interests are what people are looking for.

I pasted the original abstract here and also Dr. Austin and I wrote the editorial commentary.

印度乡村宫颈癌HPV筛查的论文发表于《新英格兰医学杂志》（2009 Apr 2;360(14):1385-94.）。该杂志是全世界医学杂志中最著名的杂志之一。

发表于该杂志的这篇文章得出的结论是：在医疗资源欠发达地区，单一的HPV检测可明显减少进展期宫颈癌及其死亡率。而且，这篇论文的摘要指出：“与对照组比较，细胞学检查或醋酸检查没有明显减少宫颈癌的发生及其死亡率。”

换句话说，印度的这个临床实验证实了HPV检测能减少宫颈癌及其死亡率，但与未进行任何检测一样（对照组），宫颈涂片和醋酸实验却不能减低宫颈癌相关的死亡。

这些作者对统计数字进行了人为控制，使得结果成为他们所希望的。

为什么？这是因为有企业参与了这项临床实验。这正是这些人所希望的。

这里我贴出了原始摘要，也贴出了我和Austin博士写给编辑部的评论。

Test group biases and ethical concerns mar New England Journal of Medicine articles promoting HPV screening for cervical cancer in rural India
R Marshall Austin, Chengquan Zhao
 Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213, USA

 Ok. I spend more than one hour to paste these information here. Just hope more our Chinese physicians, researchers know some hot issues in the world.

Mao is right: class struggle is present every where. Ha, ha, just kidding.

We analized the India paper with very detailed  study of their data and background. Our comment paper is very long. There is limitation of word number for the letter to editor in NEJM. This is why we sent our comment paper to CytoJournal as a View Point. Our comment was just available online yesterday. We are waiting for the correspondence from Dr. Rengaswamy Sankaranarayanan,the author for the india trial paper.

By the way CytoJournal is the only one free online journal for cytology. Dr. DeMay is the Editors-in chief. Every one can get in to read the papers for free. You also can submit your studis for publication.

http://www.cytojournal.com/

The Authors Reply: Suba et al., Ankit et al., and Cremer et al. call for more explanation regarding the lack of significant reductions in mortality from cervical cancer during the 8-year follow-up period after VIA screening or cytologic testing in our study. Although interstudy differences are not new, the discrepant results after VIA screen­ing in the two randomized trials in India¹ have caused concern, especially in some countries that are beginning to implement VIA-based screen-and-treat programs.

The above possibilities may account for the apparent lack of effectiveness of VIA and cyto­logic screening at this time. However, since we plan to continue the follow-up of the study groups for cervical-cancer incidence and mortal­ity for several years, we will clarify the long-term effects of the interventions, including any delayed reductions in mortality in the cytologic-testing and VIA groups.

In reply to Mwanahamuntu et al. and Wein­berg: approaches to the screening of women older than 30 years of age that involve using fewer rounds of screening with a highly sensitive test and targeting early diagnosis among women who are positive for high-risk HPV types are al­ready good strategies to maximize the utiliza­tion of public health budgets. We hope that HPV testing will become affordable in all settings in the near future.

Rengaswamy Sankaranarayanan, M.D.

International Agency for Research on Cancer 69372 Lyon CEDEX 08, France sankar@iarc.fr

Kasturi Jayant, M.Sc.

Nargis Dutt Memorial Cancer Hospital Barshi 413 401, India

Surendra S. Shastri, M.D.

Tata Memorial Center Mumbai 400 012, India

1. Sankaranarayanan R, Esmy PO, Rajkumar R, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet 2007;370: 398-406.

科学就是要这样的认真态度。

To the Editor: Sankaranarayanan et al. found that a single DNA screening test for cervical-cancer–related HPV strains can be cost-effective in a resource-limited setting. An additional strat­egy could stretch a public health budget even fur-

ther, increasing the number of early cancers de­tected by extending screening to more women. In 1943, Dorfman¹ proposed a clever pooling ap­proach for screening military recruits for syphi­lis. His idea was that if the available assay per­forms well under a dilution of 1:k, then one can assay pools of specimens, each based on k per­sons, testing only individual specimens if their pool tested positive. To screen N persons in a population with a low prevalence, α, the number of assays one would need to conduct, on average, would be only

ther, increasing the number of early cancers de­tected by extending screening to more women. In 1943, Dorfman¹ proposed a clever pooling ap­proach for screening military recruits for syphi­lis. His idea was that if the available assay per­forms well under a dilution of 1:k, then one can assay pools of specimens, each based on k per­sons, testing only individual specimens if their pool tested positive. To screen N persons in a population with a low prevalence, α, the number of assays one would need to conduct, on average, would be only

1

N× _[κ+1−(1−α)κ_].

In the study by Sankaranarayanan et al., α was approximately 0.10. Suppose an assay tolerates a dilution of 1:3 and the budget permits N assays. Pooling in groups of three would require (0.6)N assays, and the number of women who could be screened would be (1/0.6)N, or 1.67N. Further gains would accrue if women who presented for screening could be grouped according to risk, with individual-level assays reserved for high-risk women and pooling used for lower-risk women.

Clarice R. Weinberg, Ph.D.

National Institute of Environmental Health Sciences Research Triangle Park, NC 27709

1. Dorfman R. The detection of defective members of large populations. Ann Math Stat 1943;14:436-40.

To the Editor: In a previous article,¹ Sankara­narayanan et al. reported a decrease in cervical-cancer mortality with the use of VIA and the “screen and treat” approach, whereas the current article calls for multiple visits and treatment only of women with grade 2 or 3 cervical intraepithe­lial neoplasia confirmed on biopsy. In the current report, there is no discussion of this difference between the two studies.

The current data cast doubt on VIA, which is an invaluable asset to cervical-cancer prevention in developing countries. The benefit of VIA in low-resource settings is that it can be used to detect cervical precancer inexpensively and that it en­ables the examiner to institute immediate and appropriate therapy. This strategy decreases the risk that a patient with a potentially precancerous lesion will be lost to follow-up.

We strongly believe that the lack of survival benefit reported in the current article should not preclude the lifesaving results of screen-and-treat programs that have been demonstrated previ­ously.

Miriam L. Cremer, M.D., M.P.H.

Basic Health International San Salvador, El Salvador mlcremer@hotmail.com

Elizabeth Conlisk, Ph.D.

Hampshire College Amherst, MA 01002

Juan C. Felix, M.D.

University of Southern California Los Angeles, CA 90033

Dr. Felix reports receiving lecture fees from Qiagen and Ho-logic. No other potential conflict of interest relevant to this letter was reported.

1. Sankaranarayanan R, Esmy PO,  Rajkumar R, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet 2007;370: 398-406.