Effectiveness and equity of cervical cancer prevention : real-life evidence from organised programmes in Sweden

Cervical cancer incidence has substantially declined since cervical screening was implemented five decades ago. The long-term hope of eliminating cervical cancer is promising with the development of effective Human papillomavirus (HPV) vaccines. Optimising effectiveness and promoting high and equal uptake of preventive approaches are essential for achieving this goal. This thesis aimed to use register data in Sweden to perform in-depth evaluation of the effectiveness of cervical screening and investigate the factors associated with HPV vaccine uptake. The work focused in detail upon the uncertain preventive effect against cervical adenocarcinoma in relation to the finding of glandular abnormalities in screening, the effectiveness of screening for the conspicuous incidence of cervical cancer at older ages, as well as social disparity of HPV vaccine uptake in different modes of vaccination delivery. Effectiveness of cervical screening in preventing invasive cervical cancer has been reported under a case-control audit framework in Sweden, based on cervical cancer cases diagnosed in 1999-2001. Yet, assessing long-term screening history and controlling for confounding factors were hampered by unavailable data, and statistical power was limited to stratify the evaluation by histopathological type. We therefore performed an updated case-control audit based on cervical cancer cases diagnosed in 2002-2011 (Study III), to examine the risk of invasive cervical cancer in relation to screening history in the past two screening rounds, adjusted for education and stratified by the two main histopathological types. We found that non-routine participation to cervical screening was associated with increased risk of invasive cervical cancer. Having an abnormality in previous two screening rounds was associated with elevated risk, particularly if not being screened in the subsequent screening round after an abnormality. The lower effectiveness of cervical screening in preventing adenocarcinoma compared to squamous cell carcinoma resulted from both lower assurance from normal screening results, and higher risk following abnormalities. These findings reinforce the evidence of the cancer-preventive effect of cervical screening and emphasise the importance of routine participation in screening. We also identify relative weaknesses of the screening programme that would guide future research to address improvement. Atypical glandular cells (AGC) found in cervical screening is a cytological abnormality of the same type of cells giving rise to cervical adenocarcinoma. However, the long-term risk of cervical cancer following AGC has not been comprehensively investigated due to its rarity. We used the Swedish National Cervical Screening Registry (NKCx) to identify all AGC diagnosed in cervical screening from 1980-2011, examined the risk of cervical cancer by histopathological type for up to 15 years, and compared the subsequent histological assessment and risk of cancer to that after high-grade squamous intraepithelial neoplasia (HSIL) (Study I). We found that AGC was associated with a moderate-high proportion of prevalent cancer, and a high long-term risk of incident cervical cancer, especially adenocarcinoma. Only 54% of AGC were followed by histology within six months, and among those being followed with histology, the cancer incidence after AGC was still statistically significantly higher than that after HSIL. Our findings confirm the considerable risk associated with AGC and revealed suboptimal management following this specific abnormality. We highlight one of the deeper causes of unsatisfactory preventive effects of screening against cervical adenocarcinoma, and the necessity of improving management practice for AGC. Cervical cancer is generally associated with middle-aged women, but the first Swedish case-control audit revealed that cervical cancer in women over 60 years of age accounted for more than one-third of annual cervical cancer cases. Data from other Nordic countries have also exhibited similar to higher incidence of cervical cancer among older-aged women compared to middle-aged women, leading to uncertainty on the underlying reason of biological or screening effect and the effectiveness of cervical screening after age 60. Therefore, we used NKCx and the Swedish Cancer Registry to investigate the risk of cervical cancer from age 61-80 years by screening history at ages 51-60 years, and evaluated the effectiveness of cervical screening at ages 61-65 stratified by screening history (Study II). We found that screening at ages 61-65 was associated with substantial risk reduction up to age 80 in women unscreened or having abnormalities in their 50s. Yet in women screened with normal results in their 50s, the subsequent risk of cervical cancer was remarkably lower than that in women unscreened or having abnormalities in the past, and in these women screening after age 60 was not associated with any statistically significant risk reduction. Our results should inform the current debate regarding when and how to discontinue cervical screening in older-aged women. HPV vaccines have been available worldwide since 2006-2007. Their efficacy and effectiveness in preventing cervical precursor lesions have been shown repeatedly. Pursuing high and equal coverage of HPV vaccination is the common goal to reduce inequality of cervical cancer development in the future. Various modes of delivery of HPV vaccination were implemented worldwide and in Sweden. We used Swedish vaccination registers and social-demographic registers to examine girls’ HPV vaccine uptake in relation to parental country of birth, education and family income, by three delivery modes of HPV vaccination (Study IV). We found that free-of-charge school-based delivery achieved the highest uptake of HPV vaccination with the lowest social disparity, suggesting the importance of reducing individual payment and providing easy access to promote equality of cervical cancer prevention. In conclusion, this thesis confirms the overall effectiveness of cervical screening in preventing invasive cervical cancer, addresses specific questions regarding unsatisfactory prevention for cervical adenocarcinoma and cervical cancer in older women, as well as identifies suboptimal aspects in screening for further investigation. It optimises the audit framework as an evaluation tool for screening programme quality assurance, and provides a benchmark for future comparisons with new screening practices. The thesis also verifies the role of delivery mode of HPV vaccination on reaching high and equal uptake of the vaccine, bolstering the hope of ultimate elimination of cervical cancer

LaSNN: Layer-wise ANN-to-SNN Distillation for Effective and Efficient Training in Deep Spiking Neural Networks

Spiking Neural Networks (SNNs) are biologically realistic and practically promising in low-power computation because of their event-driven mechanism. Usually, the training of SNNs suffers accuracy loss on various tasks, yielding an inferior performance compared with ANNs. A conversion scheme is proposed to obtain competitive accuracy by mapping trained ANNs' parameters to SNNs with the same structures. However, an enormous number of time steps are required for these converted SNNs, thus losing the energy-efficient benefit. Utilizing both the accuracy advantages of ANNs and the computing efficiency of SNNs, a novel SNN training framework is proposed, namely layer-wise ANN-to-SNN knowledge distillation (LaSNN). In order to achieve competitive accuracy and reduced inference latency, LaSNN transfers the learning from a well-trained ANN to a small SNN by distilling the knowledge other than converting the parameters of ANN. The information gap between heterogeneous ANN and SNN is bridged by introducing the attention scheme, the knowledge in an ANN is effectively compressed and then efficiently transferred by utilizing our layer-wise distillation paradigm. We conduct detailed experiments to demonstrate the effectiveness, efficacy, and scalability of LaSNN on three benchmark data sets (CIFAR-10, CIFAR-100, and Tiny ImageNet). We achieve competitive top-1 accuracy compared to ANNs and 20x faster inference than converted SNNs with similar performance. More importantly, LaSNN is dexterous and extensible that can be effortlessly developed for SNNs with different architectures/depths and input encoding methods, contributing to their potential development

ESL-SNNs: An Evolutionary Structure Learning Strategy for Spiking Neural Networks

Spiking neural networks (SNNs) have manifested remarkable advantages in power consumption and event-driven property during the inference process. To take full advantage of low power consumption and improve the efficiency of these models further, the pruning methods have been explored to find sparse SNNs without redundancy connections after training. However, parameter redundancy still hinders the efficiency of SNNs during training. In the human brain, the rewiring process of neural networks is highly dynamic, while synaptic connections maintain relatively sparse during brain development. Inspired by this, here we propose an efficient evolutionary structure learning (ESL) framework for SNNs, named ESL-SNNs, to implement the sparse SNN training from scratch. The pruning and regeneration of synaptic connections in SNNs evolve dynamically during learning, yet keep the structural sparsity at a certain level. As a result, the ESL-SNNs can search for optimal sparse connectivity by exploring all possible parameters across time. Our experiments show that the proposed ESL-SNNs framework is able to learn SNNs with sparse structures effectively while reducing the limited accuracy. The ESL-SNNs achieve merely 0.28% accuracy loss with 10% connection density on the DVS-Cifar10 dataset. Our work presents a brand-new approach for sparse training of SNNs from scratch with biologically plausible evolutionary mechanisms, closing the gap in the expressibility between sparse training and dense training. Hence, it has great potential for SNN lightweight training and inference with low power consumption and small memory usage

Neuromorphic Auditory Perception by Neural Spiketrum

Neuromorphic computing holds the promise to achieve the energy efficiency and robust learning performance of biological neural systems. To realize the promised brain-like intelligence, it needs to solve the challenges of the neuromorphic hardware architecture design of biological neural substrate and the hardware amicable algorithms with spike-based encoding and learning. Here we introduce a neural spike coding model termed spiketrum, to characterize and transform the time-varying analog signals, typically auditory signals, into computationally efficient spatiotemporal spike patterns. It minimizes the information loss occurring at the analog-to-spike transformation and possesses informational robustness to neural fluctuations and spike losses. The model provides a sparse and efficient coding scheme with precisely controllable spike rate that facilitates training of spiking neural networks in various auditory perception tasks. We further investigate the algorithm-hardware co-designs through a neuromorphic cochlear prototype which demonstrates that our approach can provide a systematic solution for spike-based artificial intelligence by fully exploiting its advantages with spike-based computation.Comment: This work has been submitted to the IEEE for possible publicatio

Benefits of laboratory personalized antiplatelet therapy in patients undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials

   Background: The preventive effects of laboratory personalized antiplatelet therapy (PAPT) strategy in­cluding genetic detection and platelet function testing (PFT) on major adverse cardiac events (MACEs) and bleeding events in coronary artery disease (CAD) patients undergoing stenting has been extensively studied. Despite that, no clear conclusion can be drawn. In this study, a meta-analysis was performed to explore a more precise estimation of the benefits of laboratory PAPT. Methods: Randomized controlled trials were identified by the use of search databases such as PubMed, Embase, and Cochrane Controlled Trials Register up to May 2017, and the estimates were pooled. Results: Fourteen studies including 9497 patients met the inclusion criteria. The laboratory PAPT reduced MACEs risk (risk ratio [RR] 0.58, 95% confidence interval [CI] 0.42–0.80, p = 0.001), stent thrombosis (RR 0.60, 95% CI 0.41–0.87, p = 0.008) and myocardial infarctions (RR 0.43, 95% CI 0.21–0.88, p = 0.02) compared to the non-PAPT group. No statistically significant difference was observed between the two groups regarding cardiovascular death (RR 0.77, 95% CI 0.51–1.16, p = 0.21), bleeding events (RR 0.96, 95% CI 0.81–1.13, p = 0.59) and ischemic stroke (RR 0.81; 95% CI 0.39–1.66, p = 0.57). The preventive effect on MACEs was more significant in patients with high on-treatment platelet reactivity (RR 0.46; 95% CI 0.27–0.80, p = 0.006). Conclusions: Coronary artery disease patients after stenting could obtain benefits from laboratory PAPT. (Cardiol J 2018; 25, 1: 128–141

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer

BACKGROUND: Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. METHODS: We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1-4 years and 218 remained disease-free. RESULTS: We developed the WID-CIN (Women's cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88-0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3-96.1) in all and 92.7% (85.9-99.6) and 65.6% (49.2-82.1) in women aged ≥30 and <30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0-61.5) cases developing 1-4 years after sample donation in all ages or 56.9% (47.6-66.2) and 53.5% (43.7-63.2) in ≥30 and <30-year-old women, at a specificity of 75%. CONCLUSIONS: The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future

Interferon-Gamma Release Assays for the Diagnosis of Active Tuberculosis in HIV-Infected Patients: A Systematic Review and Meta-Analysis

BACKGROUND: Interferon-gamma release assays (IGRAs) have provided a new method for the diagnosis of Mycobacterium tuberculosis infection. However, the role of IGRAs for the diagnosis of active tuberculosis (TB), especially in HIV-infected patients remains unclear. METHODS: We searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001-July 2011 that evaluated the evidence of using QuantiFERON-TB Gold in-tube (QFT-GIT) and T-SPOT.TB (T-SPOT) on blood for the diagnosis of active TB in HIV-infected patients. RESULTS: The search identified 16 eligible studies that included 2801 HIV-infected individuals (637 culture confirmed TB cases). The pooled sensitivity for the diagnosis of active TB was 76.7% (95%CI, 71.6-80.5%) and 77.4% (95%CI, 71.4-82.6%) for QFT-GIT and T-SPOT, respectively, while the specificity was 76.1% (95%CI, 74.0-78.0%) and 63.1% (95%CI, 57.6-68.3%) after excluding the indeterminate results. Studies conducted in low/middle income countries showed slightly lower sensitivity and specificity when compared to that in high-income countries. The proportion of indeterminate results was as high as 10% (95%CI, 8.8-11.3%) and 13.2% (95%CI, 10.6-16.0%) for QFT-GIT and T-SPOT, respectively. CONCLUSION: IGRAs in their current formulations have limited accuracy in diagnosing active TB in HIV-infected patients, and should not be used alone to rule out or rule in active TB cases in HIV-infected patients. Further modification is needed to improve their accuracy