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The majority of research regarding the expression of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain has been conducted using histochemistry to identify enzymatic activity in frozen fixed tissue. However, retrospective human neurochemistry studies are generally restricted to formalin-fixed, paraffin-embedded (FFPE) tissues that are not suitable for histochemical procedures. The availability of commercially available antibody formulations provides the means to study such tissues by immunohistochemistry (IHC). In this study, we optimised IHC conditions for evaluating the expression of AChE and BuChE in the brainstem, focusing on the dorsal motor nucleus of the vagus, in human and piglet FFPE tissues, using commercially available antibodies. Our results were compared to published reports of histochemically determined AChE and BuChE expression. We varied antibody concentrations and antigen retrieval methods, and evaluated different detection systems, with the overall aim to optimise immunohistochemical staining. The primary findings, consistent across both species, are: (1) AChE and BuChE expression dominated in the neuronal somata, specifically in the neuronal cytoplasm; and (2) no change in the protocol resulted in axonal/neuropil expression of AChE. These results indicate that IHC is a suitable tool to detect AChE and BuChE in FFPE tissue using commercial antibodies, albeit the staining patterns obtained differed from those using histochemistry in frozen tissue. The underlying cause(s) for these differences are discussed in detail and may be associated with the principal components of the staining method, the antibody protein target and/or limitations to the detection of epitopes by tissue fixation.
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Acetilcolinesterase , Butirilcolinesterase , Animais , Humanos , Acetilcolinesterase/metabolismo , Anticorpos , Butirilcolinesterase/metabolismo , Formaldeído , Imuno-Histoquímica , Inclusão em Parafina , Estudos Retrospectivos , SuínosRESUMO
Routine asymptomatic testing strategies for COVID-19 have been proposed to prevent outbreaks in high-risk healthcare environments. We used simulation modeling to evaluate the optimal frequency of viral testing. We found that routine testing substantially reduces risk of outbreaks, but may need to be as frequent as twice weekly.
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COVID-19 , Atenção à Saúde , Surtos de Doenças/prevenção & controle , Instalações de Saúde , Humanos , SARS-CoV-2RESUMO
BACKGROUND: Pathology in the noradrenergic A6 locus coeruleus has not been compared with more rostral dopaminergic A9 substantia nigra and A10 ventral tegmental area, and cholinergic Ch4 basal nucleus and Ch1/2 septal regions in the same cases of Parkinson's disease (PD). OBJECTIVE: To determine whether there is a gradient of caudal to rostral cell loss in PD. METHODS: Postmortem brains were collected from longitudinally followed donors with PD (n = 14) and aged-matched healthy donors (n = 13), six with restricted brainstem Lewy pathology (RLP), fixed in formalin and serial tissue slabs processed for cell and pathological quantitation. Noradrenergic A6 neurons were assessed and compared with previously published midbrain and basal forebrain data. From these data, regression estimates of pathological onset and progression were determined. RESULTS: Restricted Lewy pathology (RLP) cases had high pathological variability but no significant reduction in neurons. Pathology containing A6 neuron loss started at PD diagnosis and progressed faster (2.4% p.a) than the loss of dopaminergic A9 neurons (2% loss p.a.). Cases with dementia had significantly more pathology in noradrenergic and cholinergic neurons, had greater noradrenergic A6 neuron loss (29% more, progressing at 3.2% p.a.), and a selective loss of lateral A10 nonmelanized dopamine-producing neurons (starting a decade following diagnosis). CONCLUSIONS: These findings show that in the same Parkinson's disease cases cell loss in these neurotransmitter systems does not follow a strict caudal to rostral trajectory and suggests symptom onset may relate to substantial pathology in the noradrenergic A6 locus coeruleus neurons in people with reduced dopamine-producing A9 substantia nigra neurons. © 2021 International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Idoso , Neurônios Dopaminérgicos , Humanos , Locus Cerúleo , Prosencéfalo , Substância NegraRESUMO
BACKGROUND: School closures have been enacted as a measure of mitigation during the ongoing coronavirus disease 2019 (COVID-19) pandemic. It has been shown that school closures could cause absenteeism among healthcare workers with dependent children, but there remains a need for spatially granular analyses of the relationship between school closures and healthcare worker absenteeism to inform local community preparedness. METHODS: We provide national- and county-level simulations of school closures and unmet child care needs across the USA. We develop individual simulations using county-level demographic and occupational data, and model school closure effectiveness with age-structured compartmental models. We perform multivariate quasi-Poisson ecological regressions to find associations between unmet child care needs and COVID-19 vulnerability factors. RESULTS: At the national level, we estimate the projected rate of unmet child care needs for healthcare worker households to range from 7.4 to 8.7%, and the effectiveness of school closures as a 7.6% and 8.4% reduction in fewer hospital and intensive care unit (ICU) beds, respectively, at peak demand when varying across initial reproduction number estimates by state. At the county level, we find substantial variations of projected unmet child care needs and school closure effects, 9.5% (interquartile range (IQR) 8.2-10.9%) of healthcare worker households and 5.2% (IQR 4.1-6.5%) and 6.8% (IQR 4.8-8.8%) reduction in fewer hospital and ICU beds, respectively, at peak demand. We find significant positive associations between estimated levels of unmet child care needs and diabetes prevalence, county rurality, and race (p<0.05). We estimate costs of absenteeism and child care and observe from our models that an estimated 76.3 to 96.8% of counties would find it less expensive to provide child care to all healthcare workers with children than to bear the costs of healthcare worker absenteeism during school closures. CONCLUSIONS: School closures are projected to reduce peak ICU and hospital demand, but could disrupt healthcare systems through absenteeism, especially in counties that are already particularly vulnerable to COVID-19. Child care subsidies could help circumvent the ostensible trade-off between school closures and healthcare worker absenteeism.
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Absenteísmo , Cuidado da Criança/economia , Infecções por Coronavirus/epidemiologia , Pessoal de Saúde/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Instituições Acadêmicas , Betacoronavirus , COVID-19 , Criança , Simulação por Computador , Estudos de Viabilidade , Previsões , Geografia , Mão de Obra em Saúde , Humanos , Unidades de Terapia Intensiva , Avaliação das Necessidades , Pandemias , SARS-CoV-2 , Estados Unidos/epidemiologiaRESUMO
Importance: There is no level of lead in drinking water considered to be safe, yet lead service lines are still commonly used in water systems across the US. Objective: To identify the extent of lead-contaminated drinking water in Chicago, Illinois, and model its impact on children younger than 6 years. Design, Setting, and Participants: For this cross-sectional study, a retrospective assessment was performed of lead exposure based on household tests collected from January 2016 to September 2023. Tests were obtained from households in Chicago that registered for a free self-administered testing service for lead exposure. Machine learning and microsimulation were used to estimate citywide childhood lead exposure. Exposure: Lead-contaminated drinking water, measured in parts per billion. Main Outcomes and Measures: Number of children younger than 6 years exposed to lead-contaminated water. Results: A total of 38â¯385 household lead tests were collected. An estimated 68% (95% uncertainty interval, 66%-69%) of children younger than 6 years were exposed to lead-contaminated water, corresponding to 129â¯000 children (95% uncertainty interval, 128â¯000-131â¯000 children). Ten-percentage-point increases in block-level Black and Hispanic populations were associated with 3% (95% CI, 2%-3%) and 6% (95% CI, 5%-7%) decreases in odds of being tested for lead and 4% (95% CI, 3%-6%) and 11% (95% CI, 10%-13%) increases in having lead-contaminated drinking water, respectively. Conclusions and Relevance: These findings indicate that childhood lead exposure is widespread in Chicago, and racial inequities are present in both testing rates and exposure levels. Machine learning may assist in preliminary screening for lead exposure, and efforts to remediate the effects of environmental racism should involve improving outreach for and access to lead testing services.
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Água Potável , Exposição Ambiental , Intoxicação por Chumbo , Chumbo , Humanos , Chicago , Estudos Retrospectivos , Estudos Transversais , Exposição Ambiental/efeitos adversos , Pré-Escolar , Chumbo/sangue , Lactente , Intoxicação por Chumbo/epidemiologia , Intoxicação por Chumbo/diagnóstico , Intoxicação por Chumbo/etiologia , Masculino , Feminino , Poluentes Químicos da Água/análise , CriançaRESUMO
BACKGROUND: Exposure to food additives is widespread but up-to-date and accurate intake estimates are rarely available. The safety of the food additive aspartame is the subject of recent controversy and intake estimates for this nonnutritive sweetener are typically derived from surrogates such as diet soda consumption. OBJECTIVE: We describe an approach for developing nationally representative dietary exposure estimates for food additives that combines intake from dietary recalls and grocery purchasing information. METHODS: We combined NielsenIQ Homescan Consumer Panel purchasing data with the USDA Global Branded Food Products database and the National Health and Nutrition Examination Survey to estimate aspartame intake and prevalence of consumption for the US population. We examined points of departure for aspartame from CompTox Chemicals Dashboard to provide context for exposures and potential effects. RESULTS: Mean, 90th percentile, and 95th percentile aspartame intake estimates are below the acceptable daily intake (50 mg/kg/day) and are lower than estimates from previous decades. Groups with the highest aspartame intakes are non-Hispanic whites, 60- to 69-year-olds, and individuals on diabetic diets. Aspartame exposure is highly prevalent (62.6%) in the US including sensitive populations such as pregnant women and children. IMPACT STATEMENT: Exposure to the widely consumed food additive aspartame is not well characterized, and concerns about potential health effects remain despite assurances of safety when consumed under conditions of intended use. This work provides current intake estimates for the US population with important comparisons across demographic groups and individuals on special diets. The approach includes ingredient statement and grocery purchasing data to capture all aspartame-containing products, beyond diet soda, in intake estimates. This framework also has the potential for application to other food ingredients.
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The possibility of a massive oil spill in the Red Sea is increasingly likely. The Safer, a deteriorating oil tanker containing 1.1 million barrels of oil, has been deserted near the coast of Yemen since 2015 and threatens environmental catastrophe to a country presently in a humanitarian crisis. Here, we model the immediate public health impacts of a simulated spill. We estimate that all of Yemen's imported fuel through its key Red Sea ports would be disrupted and that the anticipated spill could disrupt clean-water supply equivalent to the daily use of 9.0-9.9 million people, food supply for 5.7-8.4 million people and 93-100% of Yemen's Red Sea fisheries. We also estimate an increased risk of cardiovascular hospitalization from pollution ranging from 5.8 to 42.0% over the duration of the spill. The spill and its potentially disastrous impacts remain entirely preventable through offloading the oil. Our results stress the need for urgent action to avert this looming disaster.
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BACKGROUND: Routine viral testing strategies for SARS-CoV-2 infection might facilitate safe airline travel during the COVID-19 pandemic and mitigate global spread of the virus. However, the effectiveness of these test-and-travel strategies to reduce passenger risk of SARS-CoV-2 infection and population-level transmission remains unknown. METHODS: In this simulation study, we developed a microsimulation of SARS-CoV-2 transmission in a cohort of 100 000 US domestic airline travellers using publicly available data on COVID-19 clinical cases and published natural history parameters to assign individuals one of five health states of susceptible to infection, latent period, early infection, late infection, or recovered. We estimated a per-day risk of infection with SARS-CoV-2 corresponding to a daily incidence of 150 infections per 100 000 people. We assessed five testing strategies: (1) anterior nasal PCR test within 3 days of departure, (2) PCR within 3 days of departure and 5 days after arrival, (3) rapid antigen test on the day of travel (assuming 90% of the sensitivity of PCR during active infection), (4) rapid antigen test on the day of travel and PCR test 5 days after arrival, and (5) PCR test 5 days after arrival. Strategies 2 and 4 included a 5-day quarantine after arrival. The travel period was defined as 3 days before travel to 2 weeks after travel. Under each scenario, individuals who tested positive before travel were not permitted to travel. The primary study outcome was cumulative number of infectious days in the cohort over the travel period without isolation or quarantine (population-level transmission risk), and the key secondary outcome was the number of infectious people detected on the day of travel (passenger risk of infection). FINDINGS: We estimated that in a cohort of 100 000 airline travellers, in a scenario with no testing or screening, there would be 8357 (95% uncertainty interval 6144-12831) infectious days with 649 (505-950) actively infectious passengers on the day of travel. The pre-travel PCR test reduced the number of infectious days from 8357 to 5401 (3917-8677), a reduction of 36% (29-41) compared with the base case, and identified 569 (88% [76-92]) of 649 actively infectious travellers on the day of flight; the addition of post-travel quarantine and PCR reduced the number of infectious days to 2520 days (1849-4158), a reduction of 70% (64-75) compared with the base case. The rapid antigen test on the day of travel reduced the number of infectious days to 5674 (4126-9081), a reduction of 32% (26-38) compared with the base case, and identified 560 (86% [83-89]) actively infectious travellers; the addition of post-travel quarantine and PCR reduced the number of infectious days to 3124 (2356-495), a reduction of 63% (58-66) compared with the base case. The post-travel PCR alone reduced the number of infectious days to 4851 (3714-7679), a reduction of 42% (35-49) compared with the base case. INTERPRETATION: Routine asymptomatic testing for SARS-CoV-2 before travel can be an effective strategy to reduce passenger risk of infection during travel, although abbreviated quarantine with post-travel testing is probably needed to reduce population-level transmission due to importation of infection when travelling from a high to low incidence setting. FUNDING: University of California, San Francisco.
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Teste para COVID-19/métodos , COVID-19/diagnóstico , Portador Sadio/diagnóstico , Pandemias/prevenção & controle , Aeronaves/estatística & dados numéricos , Infecções Assintomáticas , COVID-19/transmissão , COVID-19/virologia , Portador Sadio/virologia , Simulação por Computador , Testes Diagnósticos de Rotina/estatística & dados numéricos , Humanos , SARS-CoV-2/patogenicidade , Viagem/estatística & dados numéricosRESUMO
OBJECTIVES: Armed conflict has contributed to an unprecedented number of internally displaced persons (IDPs), individuals who are forced out of their homes but remain within their country. IDPs often urgently require shelter, food, and healthcare, yet prediction of when IDPs will migrate to an area remains a major challenge for aid delivery organizations. We sought to develop an IDP migration forecasting framework that could empower humanitarian aid groups to more effectively allocate resources during conflicts. METHODS: We modeled monthly IDP migration between provinces within Syria and within Yemen using data on food prices, fuel prices, wages, location, time, and conflict reports. We compared machine learning methods with baseline persistence methods of forecasting. RESULTS: We found a machine learning approach that more accurately forecast migration trends than baseline persistence methods. A random forest model outperformed the best persistence model in terms of root mean square error of log migration by 26% and 17% for the Syria and Yemen datasets, respectively. CONCLUSIONS: Integrating diverse data sources into a machine learning model appears to improve IDP migration prediction. Further work should examine whether implementation of such models can enable proactive aid allocation for IDPs in anticipation of forecast arrivals.
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Migração Humana/estatística & dados numéricos , Refugiados/estatística & dados numéricos , Altruísmo , Previsões/métodos , Humanos , Síria , IêmenRESUMO
Background: School closures have been enacted as a measure of mitigation during the ongoing COVID-19 pandemic. It has been shown that school closures could cause absenteeism amongst healthcare workers with dependent children, but there remains a need for spatially granular analyses of the relationship between school closures and healthcare worker absenteeism to inform local community preparedness. Methods: We provide national- and county-level simulations of school closures and unmet child care needs across the United States. We develop individual simulations using county-level demographic and occupational data, and model school closure effectiveness with age-structured compartmental models. We perform multivariate quasi-Poisson ecological regressions to find associations between unmet child care needs and COVID-19 vulnerability factors. Results: At the national level, we estimate the projected rate of unmet child care needs for healthcare worker households to range from 7.5% to 8.6%, and the effectiveness of school closures to range from 3.2% (R0 = 4) to 7.2% (R0 = 2) reduction in fewer ICU beds at peak demand. At the county-level, we find substantial variations of projected unmet child care needs and school closure effects, ranging from 1.9% to 18.3% of healthcare worker households and 5.7% to 8.8% reduction in fewer ICU beds at peak demand (R0 = 2). We find significant positive associations between estimated levels of unmet child care needs and diabetes prevalence, county rurality, and race (p < 0.05). We estimate costs of absenteeism and child care and observe from our models that an estimated 71.1% to 98.8% of counties would find it less expensive to provide child care to all healthcare workers with children than to bear the costs of healthcare worker absenteeism during school closures. Conclusions: School closures are projected to reduce peak ICU bed demand, but could disrupt healthcare systems through absenteeism, especially in counties that are already particularly vulnerable to COVID-19. Child care subsidies could help circumvent the ostensible tradeoff between school closures and healthcare worker absenteeism.
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Routine asymptomatic testing strategies for COVID-19 have been proposed to prevent outbreaks in high-risk healthcare environments. We used simulation modeling to evaluate the optimal frequency of viral testing. We found that routine testing substantially reduces risk of outbreaks, but may need to be as frequent as twice weekly.
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BACKGROUND: Airline travel has been significantly reduced during the COVID-19 pandemic due to concern for individual risk of SARS-CoV-2 infection and population-level transmission risk from importation. Routine viral testing strategies for COVID-19 may facilitate safe airline travel through reduction of individual and/or population-level risk, although the effectiveness and optimal design of these "test-and-travel" strategies remain unclear. METHODS: We developed a microsimulation of SARS-CoV-2 transmission in a cohort of airline travelers to evaluate the effectiveness of various testing strategies to reduce individual risk of infection and population-level risk of transmission. We evaluated five testing strategies in asymptomatic passengers: i) anterior nasal polymerase chain reaction (PCR) within 3 days of departure; ii) PCR within 3 days of departure and PCR 5 days after arrival; iii) rapid antigen test on the day of travel (assuming 90% of the sensitivity of PCR during active infection); iv) rapid antigen test on the day of travel and PCR 5 days after arrival; and v) PCR within 3 days of arrival alone. The travel period was defined as three days prior to the day of travel and two weeks following the day of travel, and we assumed passengers followed guidance on mask wearing during this period. The primary study outcome was cumulative number of infectious days in the cohort over the travel period (population-level transmission risk); the secondary outcome was the proportion of infectious persons detected on the day of travel (individual-level risk of infection). Sensitivity analyses were conducted. FINDINGS: Assuming a community SARS-CoV-2 incidence of 50 daily infections, we estimated that in a cohort of 100,000 airline travelers followed over the travel period, there would be a total of 2,796 (95% UI: 2,031, 4,336) infectious days with 229 (95% UI: 170, 336) actively infectious passengers on the day of travel. The pre-travel PCR test (within 3 days prior to departure) reduced the number of infectious days by 35% (95% UI: 27, 42) and identified 88% (95% UI: 76, 94) of the actively infectious travelers on the day of flight; the addition of PCR 5 days after arrival reduced the number of infectious days by 79% (95% UI: 71, 84). The rapid antigen test on the day of travel reduced the number of infectious days by 32% (95% UI: 25, 39) and identified 87% (95% UI: 81, 92) of the actively infectious travelers; the addition of PCR 5 days after arrival reduced the number of infectious days by 70% (95% UI: 65, 75). The post-travel PCR test alone (within 3 days of landing) reduced the number of infectious days by 42% (95% UI: 31, 51). The ratio of true positives to false positives varied with the incidence of infection. The overall study conclusions were robust in sensitivity analysis. INTERPRETATION: Routine asymptomatic testing for COVID-19 prior to travel can be an effective strategy to reduce individual risk of COVID-19 infection during travel, although post-travel testing with abbreviated quarantine is likely needed to reduce population-level transmission due to importation of infection when traveling from a high to low incidence setting.
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We present a breast lesion classification methodology, based on four-dimensional (4-D) dynamic contrast-enhanced magnetic resonance images (DCE-MRI), using recurrent neural networks in combination with a pretrained convolutional neural network (CNN). The method enables to capture not only the two-dimensional image features but also the temporal enhancement patterns presented in DCE-MRI. We train a long short-term memory (LSTM) network on temporal sequences of feature vectors extracted from the dynamic MRI sequences. To capture the local changes in lesion enhancement, the feature vectors are obtained from various levels of a pretrained CNN. We compare the LSTM method's performance to that of a CNN fine-tuned on "RGB" MRIs, formed by precontrast, first, and second postcontrast MRIs. LSTM significantly outperformed the fine-tuned CNN, resulting in AUC LSTM = 0.88 and AUC fine - tuned = 0.84 , p = 0.00085 , in the task of distinguishing benign and malignant lesions. Our method captures clinically useful information carried by the full 4-D dynamic MRI sequence and outperforms the standard fine-tuning method.
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BACKGROUND: Deep learning methods for radiomics/computer-aided diagnosis (CADx) are often prohibited by small datasets, long computation time, and the need for extensive image preprocessing. AIMS: We aim to develop a breast CADx methodology that addresses the aforementioned issues by exploiting the efficiency of pre-trained convolutional neural networks (CNNs) and using pre-existing handcrafted CADx features. MATERIALS & METHODS: We present a methodology that extracts and pools low- to mid-level features using a pretrained CNN and fuses them with handcrafted radiomic features computed using conventional CADx methods. Our methodology is tested on three different clinical imaging modalities (dynamic contrast enhanced-MRI [690 cases], full-field digital mammography [245 cases], and ultrasound [1125 cases]). RESULTS: From ROC analysis, our fusion-based method demonstrates, on all three imaging modalities, statistically significant improvements in terms of AUC as compared to previous breast cancer CADx methods in the task of distinguishing between malignant and benign lesions. (DCE-MRI [AUC = 0.89 (se = 0.01)], FFDM [AUC = 0.86 (se = 0.01)], and ultrasound [AUC = 0.90 (se = 0.01)]). DISCUSSION/CONCLUSION: We proposed a novel breast CADx methodology that can be used to more effectively characterize breast lesions in comparison to existing methods. Furthermore, our proposed methodology is computationally efficient and circumvents the need for image preprocessing.
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Neoplasias da Mama/diagnóstico por imagem , Diagnóstico por Computador/métodos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação , Humanos , Curva ROC , Estudos RetrospectivosRESUMO
To evaluate deep learning in the assessment of breast cancer risk in which convolutional neural networks (CNNs) with transfer learning are used to extract parenchymal characteristics directly from full-field digital mammographic (FFDM) images instead of using computerized radiographic texture analysis (RTA), 456 clinical FFDM cases were included: a "high-risk" BRCA1/2 gene-mutation carriers dataset (53 cases), a "high-risk" unilateral cancer patients dataset (75 cases), and a "low-risk dataset" (328 cases). Deep learning was compared to the use of features from RTA, as well as to a combination of both in the task of distinguishing between high- and low-risk subjects. Similar classification performances were obtained using CNN [area under the curve [Formula: see text]; standard error [Formula: see text]] and RTA ([Formula: see text]; [Formula: see text]) in distinguishing BRCA1/2 carriers and low-risk women. However, in distinguishing unilateral cancer patients and low-risk women, performance was significantly greater with CNN ([Formula: see text]; [Formula: see text]) compared to RTA ([Formula: see text]; [Formula: see text]). Fusion classifiers performed significantly better than the RTA-alone classifiers with AUC values of 0.86 and 0.84 in differentiating BRCA1/2 carriers from low-risk women and unilateral cancer patients from low-risk women, respectively. In conclusion, deep learning extracted parenchymal characteristics from FFDMs performed as well as, or better than, conventional texture analysis in the task of distinguishing between cancer risk populations.
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Convolutional neural networks (CNNs) show potential for computer-aided diagnosis (CADx) by learning features directly from the image data instead of using analytically extracted features. However, CNNs are difficult to train from scratch for medical images due to small sample sizes and variations in tumor presentations. Instead, transfer learning can be used to extract tumor information from medical images via CNNs originally pretrained for nonmedical tasks, alleviating the need for large datasets. Our database includes 219 breast lesions (607 full-field digital mammographic images). We compared support vector machine classifiers based on the CNN-extracted image features and our prior computer-extracted tumor features in the task of distinguishing between benign and malignant breast lesions. Five-fold cross validation (by lesion) was conducted with the area under the receiver operating characteristic (ROC) curve as the performance metric. Results show that classifiers based on CNN-extracted features (with transfer learning) perform comparably to those using analytically extracted features [area under the ROC curve [Formula: see text]]. Further, the performance of ensemble classifiers based on both types was significantly better than that of either classifier type alone ([Formula: see text] versus 0.81, [Formula: see text]). We conclude that transfer learning can improve current CADx methods while also providing standalone classifiers without large datasets, facilitating machine-learning methods in radiomics and precision medicine.