Detection of Atrial fibrillation from non-episodic ECG data: a review of methods.

Atrial fibrillation (A-fib) is the most common cardiac arrhythmia. To effectively treat or prevent A-fib, automatic A-fib detection based on Electrocardiograph (ECG) monitoring is highly desirable. This paper reviews recently developed techniques for A-fib detection based on non-episodic surface ECG monitoring data. A-fib detection methods in the literature can be mainly classified into three categories: (1) time domain methods; (2) frequency domain methods; and (3) non-linear methods. In general the performances of these methods were evaluated in terms of sensitivity, specificity and overall detection accuracy on the datasets from the Physionet repository. Based on our survey, we conclude that no promising A-fib detection method that performs consistently well across various scenarios has been proposed yet.

Detection of subjects with higher self-reporting stress scores using heart rate variability patterns during the day.

Heart rate variability (HRV) has been well established to measure instantaneous levels of mental stress. Circadian patterns of HRV features have been reported but their use to estimate levels of mental stress were not studied thoroughly. In this study, we investigated time dependent variations of HRV features to detect subjects under chronic mental stress. Sixty eight subjects were divided into high (n=10) and low stress group (n=43) depending on their self-reporting stress scores. HRV features were calculated during three different time periods of the day. High stress group showed decreased patterns of HRV features compared to low stress group. When logistic regression analysis was performed with raw multiple HRV features, the classification was 63.2% accurate. A new % deviance score reflecting the degree of difference from normal reference patterns increased the accuracy to 66.1%. Our data suggested that HRV patterns obtained at multiple time points of the day could provide useful data to monitor subjects under chronic stress.

Detection of atrial fibrillation episodes using multiple heart rate variability features in different time periods.

Circadian variations of cardiac diseases have been well known. For example, atrial fibrillation (AF) episodes show nocturnal predominance. In this study, we have developed multiple formulas that detect AF episodes in different times of the day. Heart rate variability features were calculated from randomly sampled three min ECG data. Logistic regression analyses were performed to generate three formulas for the entire day, daytime, and evening time. Compared to the first formula that disregarded the time of the day, the second formula for the daytime detection detected AF episodes more accurately (95.2% vs. 99.3%), whereas third formula for the evening time detection did less accurately (93.8%). These results suggest the detection of AF episodes might become more accurate by considering the time-dependent changes of HRV features. In addition, the detection method for the evening time requires further investigation.

Ultra short term analysis of heart rate variability for monitoring mental stress in mobile settings.

Heart rate variability (HRV) analysis is commonly used as a quantitative marker depicting the activity of autonomous nervous system (ANS) that may be related to mental stress. For mobile applications, short term ECG measurement may be used for HRV analysis since the conventional five minute long recordings might be inadequately long. Short term analysis of HRV features has been investigated mostly in ECG data from normal and cardiac patients. Thus, short term HRV features may not have any relevance on the assessment of acute mental stress. In this study, we obtained ultra short term HRV features from 24 subjects during baseline stage and Stroop color word test. We validated these HRV features by showing significant differences in HRV features existed between the two stages. Our results indicated that ultra short term analysis of heart rate and RR intervals within 10 s, RMSSD and PNN50 within 30 s, HF within 40 s, LF/HF, normalized LF, and normalized HF within 50 s could be reliably performed for monitoring mental stress in mobile settings.

Association of heart rates with stress response inventory scores in different age groups.

Many studies reported heart rate changes were associated with mental stress. Recently, a Stress Response Inventory (SRI) questionnaire has been devised to score physical, mental, and emotional symptoms related to mental stress occurred during the past two weeks. However, SRI has too many items to be asked routinely in a mobile device such as a cellular phone. Furthermore, its individual scores may not contribute equally to estimating stress levels in different age groups. Therefore, we sought to identify mental stress factors in the SRI that were associated with heart rate changes in different age groups. Subjects aged from 20 to 69 (n=369) scored a simplified SRI and then heart rates were measured. Multiple linear regression analysis was performed to detect subsets of SRI items that showed significant relationships with heart rates (p-value<0.1). We expect that these age dependent models could be used in identifying the cause of heart rate changes in a mobile application.

Java Web Start based software for automated quantitative nuclear analysis of prostate cancer and benign prostate hyperplasia.

BACKGROUND: Androgen acts via androgen receptor (AR) and accurate measurement of the levels of AR protein expression is critical for prostate research. The expression of AR in paired specimens of benign prostate and prostate cancer from 20 African and 20 Caucasian Americans was compared to demonstrate an application of this system. METHODS: A set of 200 immunopositive and 200 immunonegative nuclei were collected from the images using a macro developed in Image Pro Plus. Linear Discriminant and Logistic Regression analyses were performed on the data to generate classification coefficients. Classification coefficients render the automated image analysis software independent of the type of immunostaining or image acquisition system used. The image analysis software performs local segmentation and uses nuclear shape and size to detect prostatic epithelial nuclei. AR expression is described by (a) percentage of immunopositive nuclei; (b) percentage of immunopositive nuclear area; and (c) intensity of AR expression among immunopositive nuclei or areas. RESULTS: The percent positive nuclei and percent nuclear area were similar by race in both benign prostate hyperplasia and prostate cancer. In prostate cancer epithelial nuclei, African Americans exhibited 38% higher levels of AR immunostaining than Caucasian Americans (two sided Student's t-tests; P < 0.05). Intensity of AR immunostaining was similar between races in benign prostate. CONCLUSION: The differences measured in the intensity of AR expression in prostate cancer were consistent with previous studies. Classification coefficients are required due to non-standardized immunostaining and image collection methods across medical institutions and research laboratories and helps customize the software for the specimen under study. The availability of a free, automated system creates new opportunities for testing, evaluation and use of this image analysis system by many research groups who study nuclear protein expression.

The androgen axis in recurrent prostate cancer.

PURPOSE: Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen-independent. High levels of expression of androgen receptor and androgen receptor-regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence. EXPERIMENTAL DESIGN: Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied. Androgen receptor expression was measured using monoclonal antibody and automated digital video image analysis. Tissue androgens were measured using radioimmunoassay. RESULTS: Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer (mean optical density, 0.284 +/- SD 0.115 and percentage positive nuclei, 83.7 +/- 11.6) was similar to benign prostate (mean optical density, 0.315 +/- 0.044 and percentage positive nuclei, 77.3 +/- 13.0). Tissue levels of testosterone were similar in recurrent prostate cancer (2.78 +/- 2.34 pmol/g tissue) and benign prostate (3.26 +/- 2.66 pmol/g tissue). Tissue levels of dihydrotestosterone, dehydroepiandrosterone, and androstenedione were lower (Wilcoxon, P = 0.0000068, 0.00093, and 0.0089, respectively) in recurrent prostate cancer than in benign prostate, and mean dihydrotestosterone levels, although reduced, remained 1.45 nM. Androgen receptor activation in recurrent prostate cancer was suggested by the androgen-regulated gene product, prostate-specific antigen, at 8.80 +/- 10.80 nmol/g tissue. CONCLUSIONS: Testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor. Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue.

Androgen receptor gene amplification and protein expression in recurrent prostate cancer.

PURPOSE: The androgen receptor (AR) is highly expressed in androgen dependent and recurrent prostate cancer, suggesting that it has a role in tumor growth and progression after androgen deprivation. AR amplification may contribute to androgen receptor activation in relative androgen absence. MATERIALS AND METHODS: Formalin fixed and frozen specimens of recurrent prostate cancer were obtained by transurethral resection from men with increasing serum level of prostate specific antigen in whom urinary retention developed. AR amplification and X-chromosome number were determined by 2-color fluorescence in situ hybridization, and AR protein expression was determined by automated image analysis. We compared clinical characteristics and survival of patients with recurrent prostate cancer whose tumors did or did not exhibit AR amplification and X-chromosome polysomy. RESULTS: Thirty-three percent of the 24 recurrent prostate cancer specimens 8 (33%) showed AR amplification. AR was more intensely immunostained in tumors with amplified (AMP) AR (mean optical density 0.36 +/- 0.07) than in tumors lacking amplification (NO AMP) (mean optical density 0.24 +/- 0.09). No differences were found between the 2 groups when comparing serum levels of prostate specific antigen (AMP 11.9, 14.8; NO AMP 26.0, 60.3), Gleason sum (AMP 9.0, 0.5; NO AMP 9.0, 1.0), clinical TNM stage (AMP 4 cases M0, M1 4; NO AMP 8 M0, 8 M1), race (AMP 6 white and 2 black men, NO AMP white and 7 black men) or survival in months (AMP 47.5, 28.5; NO AMP 33.5, 72.0). Three of the recurrent prostate cancer specimens (13%) demonstrated X-chromosome copy number 2 or greater and no differences were found when comparing clinical characteristics between these groups. CONCLUSIONS: AR amplification in recurrent prostate cancer results in higher levels of AR protein expression but does not affect survival.

Racial differences in androgen receptor protein expression in men with clinically localized prostate cancer.

PURPOSE: Black American men experience disproportionate mortality from prostate cancer (CaP) compared with white American men. Differences in outcome may stem from differences within the androgen axis. Since serum testosterone levels appear to be similar by race in men with CaP, we measured and compared androgen receptor (AR) protein expression in malignant and benign prostate tissue from black and white men who underwent radical prostatectomy for clinically localized CaP. MATERIALS AND METHODS: Archived radical prostatectomy specimens obtained from 25 white and 25 black men had AR protein antigen retrieved and immunostained. AR protein expression from CaP and benign tissue was assessed by 2 methods. Automated digital color video image analysis was used to measure the percent area immunostained for AR protein and the intensity of expression (mean optical density). Visual scoring was performed to compare results with automated values. RESULTS: In black compared with white men malignant nuclei were 27% more likely to immunostain for AR (p = 0.005) and in immunopositive nuclei AR protein expression was 81% greater (p = 0.002). Visual scoring of malignant nuclei revealed that AR immunostaining was significantly increased in black vs white men (171 +/- 40 vs 149 +/- 37, p = 0.048). In immunopositive benign nuclei AR protein expression was 22% greater in black than in white men (p = 0.027). Visual scoring of benign nuclei revealed 20% increased immunostaining in black vs white men, although this difference did not attain statistical significance (p = 0.065). Racial differences in AR protein expression were not explained by age, pathological grade or stage, although serum prostate specific antigen levels were higher in black men (9.7 +/- 7.5 vs 15.5 +/- 12.2 ng/ml, p = 0.049). CONCLUSIONS: AR protein expression was 22% higher in the benign prostate and 81% higher in the CaP of black African compared with white men. CaP may occur at a younger age and progress more rapidly in black than in white men due to racial differences in androgenic stimulation of the prostate.

Androgen receptor expression and cellular proliferation during transition from androgen-dependent to recurrent growth after castration in the CWR22 prostate cancer xenograft.

Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 +/- 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 +/- 0.08). Cellular proliferation measured using Ki-67 revealed <1% immunostained cells on day 6. Androgen receptor immunostained cells increased to 63% on day 6 and 84% on day 32 although immunostaining remained weak. Cellular proliferation was undetectable beyond day 6 after castration until multiple foci of 5 to 20 proliferating cells became apparent on day 120. These foci expressed increased levels of prostate-specific antigen, an androgen receptor-regulated gene product. In tumors recurrent 150 days after castration androgen receptor-immunostaining intensity was similar to CWR22 tumors from intact mice although the percentage of cells immunostained was more variable. The appearance of proliferating tumor cells that expressed androgen receptor and prostate-specific antigen 120 days after castration suggests that these cells represent the origin of recurrent tumors.