Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional‐UMVUE and contrast it with other estimates, including naïve estimators, the well‐studied unconditional‐UMVUE and the mean and median Whitehead‐adjusted estimators. The conditional‐UMVUE appears to be a very good choice. Copyright © 2008 John Wiley & Sons, Ltd.     

Carcinoma of the breast

In the differential clinical diagnosis of mammary neoplasms, adenocarcinoma can safely be excluded only after biopsy and microscopic study.In a series of 177 cases of mammary cancer treated by surgery with x-ray therapy, 30.4 per cent of the patients are alive three years or more after treatment; 18 per cent five years or longer.Only one of every four patients presents herself with a lesion still within the breast. Exclusive of Group I this results in a cure in 86.1 per cent in Group II and 15.4 per cent in Group III. The mortality rate then increases five and one-half times as spread occurs beyond the breast.The results of irradiation therapy for curative purposes in recurrent or metastatic mammary adenocarcinoma are poor.

Percentage of cure by stages.

     

83.

Radical prostatectomy versus watchful waiting in early prostate cancer: Bill-Axelson A, Holmberg L, Ruutu M, Haggman M, Andersson SO, Bratell S, Spangberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlen BJ, Johansson JE, Scandinavian Prostate Cancer Group Study No. 4, Department of Urology, University Hospital, Uppsala, Sweden     

Joseph A. Smith M.D. 《Urologic oncology》2005,23(6):1291

     

84.

The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.   总被引：4，自引：0，他引：4  

Daniel A Hamstra  Kuei C Lee  Joseph M Tychewicz  Victor D Schepkin  Bradford A Moffat  Mark Chen  Kenneth J Dornfeld  Theodore S Lawrence  Thomas L Chenevert  Brian D Ross  Juri T Gelovani  Alnawaz Rehemtulla 《Molecular therapy》2004,10(5):916-928

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.     

85.

Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur.     

Nathan J Koewler  Katie T Freeman  Ryan J Buus  Monica B Herrera  Juan M Jimenez-Andrade  Joseph R Ghilardi  Christopher M Peters  Lucy J Sullivan  Michael A Kuskowski  Jack L Lewis  Patrick W Mantyh 《Journal of bone and mineral research》2007,22(11):1732-1742

A closed femur fracture pain model was developed in the C57BL/6J mouse. One day after fracture, a monoclonal antibody raised against nerve growth factor (anti-NGF) was delivered intraperitoneally and resulted in a reduction in fracture pain-related behaviors of approximately 50%. Anti-NGF therapy did not interfere with bone healing as assessed by mechanical testing and histomorphometric analysis. INTRODUCTION: Current therapies to treat skeletal fracture pain are limited. This is because of the side effect profile of available analgesics and the scarcity of animal models that can be used to understand the mechanisms that drive this pain. Whereas previous studies have shown that mineralized bone, marrow, and periosteum are innervated by sensory and sympathetic fibers, it is not understood how skeletal pain is generated and maintained even in common conditions such as osteoarthritis, low back pain, or fracture. MATERIALS AND METHODS: In this study, we characterized the pain-related behaviors after a closed femur fracture in the C57BL/6J mouse. Additionally, we assessed the effect of a monoclonal antibody that binds to and sequesters nerve growth factor (anti-NGF) on pain-related behaviors and bone healing (mechanical properties and histomorphometric analysis) after fracture. RESULTS: Administration of anti-NGF therapy (10 mg/kg, days 1, 6, and 11 after fracture) resulted in a reduction of fracture pain-related behaviors of approximately 50%. Attenuation of fracture pain was evident as early as 24 h after the initial dosing and remained efficacious throughout the course of fracture pain. Anti-NGF therapy did not modify biomechanical properties of the femur or histomorphometric indices of bone healing. CONCLUSIONS: These findings suggest that therapies that target NGF or its cognate receptor(s) may be effective in attenuating nonmalignant fracture pain without interfering with bone healing.     

86.

Changes to osteoporosis prevalence according to method of risk assessment.     

J Brent Richards  William D Leslie  Lawrence Joseph  Kerry Siminoski  David A Hanley  Jonathan D Adachi  Jacques P Brown  Suzanne Morin  Alexandra Papaioannou  Robert G Josse  Jerilynn C Prior  K Shawn Davison  Alan Tenenhouse  David Goltzman 《Journal of bone and mineral research》2007,22(2):228-234

The impact of clinical risk factor-based absolute risk methods on the prevalence of high risk for osteoporotic fracture is unknown. We applied absolute risk methods to 6646 subjects and found that the prevalence of elderly women deemed to be at high risk increased substantially, whereas the overall prevalence was highly dependent on the threshold used to designate high risk. INTRODUCTION: Many groups have advocated using absolute risk methods that incorporate clinical risk factors to target patients for osteoporosis therapy. We examined how the application of such absolute risk classification systems influences the prevalence of those considered to be at high risk for osteoporotic fracture and compared these systems to one based solely on BMD. MATERIALS AND METHODS: Using 6646 subjects from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based cohort, we assessed three different systems for determining prevalence of high risk for osteoporotic fracture: a BMD-based system; a simplified risk factor system incorporating age, sex, BMD, and two clinical risk factors; and a comprehensive system, incorporating age, sex, BMD, and seven clinical risk factors. The 10-year absolute risks of incident fragility fracture were compared across systems using three different high-risk thresholds. RESULTS: The prevalence of a T score < or = -2.5 was 18.8% (95% CI: 17.7-19.9%) in women and 3.9% (95% CI: 3.0-4.7%) in men. Using a 15% 10-year risk of fracture threshold, the prevalence of women at high risk increased to 46.9% (95% CI: 45.4-48.4) and 42.5% (95% CI: 41.1-43.9) when the comprehensive and simplified risk factor classification systems were used, respectively. Using a 25% 10-year absolute risk threshold, the prevalence of high risk was similar to that of the BMD-based system, whereas the 20% threshold gave intermediate rates. All thresholds analyzed resulted in an increased prevalence of older women at high risk for fracture, whereas only the 15% 10-year risk of fracture threshold resulted in an increase in the prevalence of men at high risk. CONCLUSIONS: The application of risk factor-based systems results in an increased prevalence of older women at high risk. The prevalence of individuals at high risk may increase with changes to the methods used to determine those who are eligible for therapy. These data have important implications for the pattern of care and costs of treating osteoporotic fractures.     

87.

Water-Deprivation Headache: A New Headache With Two Variants—A Response     

Joseph N. Blau  Christian A. Kell  Julia M. Sperling 《Headache》2004,44(10):1056-1057

     

88.

18F-FDG PET can replace conventional work-up in primary M staging of nonkeratinizing nasopharyngeal carcinoma.     

Feng-Yuan Liu  Chien-Yu Lin  Joseph T Chang  Shu-Hang Ng  Shy-Chyi Chin  Hung-Ming Wang  Chun-Ta Liao  Sheng-Chieh Chan  Tzu-Chen Yen 《Journal of nuclear medicine》2007,48(10):1614-1619

Conventional work-up (CWU) with chest radiography, abdominal ultrasonography, and skeletal scintigraphy has limited value in M staging of nonkeratinizing nasopharyngeal carcinoma (NPC). Our aim was to evaluate whether (18)F-FDG PET could replace CWU by comparing their diagnostic efficacies. METHODS: Patients with histologically proven nonkeratinizing NPC and no prior treatment were prospectively enrolled. All study participants underwent CWU and (18)F-FDG PET for primary M staging. Distant metastasis was considered to be present if there was any reliable evidence identified within 1 y after diagnosis. The comparative diagnostic efficacies of (18)F-FDG PET, CWU, and the combination of (18)F-FDG PET and CWU (PET+CWU) were evaluated using the areas under the receiver-operating-characteristic (ROC) curves. RESULTS: Sixty-one (20.3%) of 300 eligible patients were found to have distant metastases. On a patient-based analysis, (18)F-FDG PET was found to be more effective than CWU (P < 0.001), whereas it was equally effective with PET+CWU (P = 0.130). On region-based analyses, (18)F-FDG PET was more effective than skeletal scintigraphy and chest radiography for detecting bone metastases (P < 0.001) and chest metastases (P < 0.001), respectively. (18)F-FDG PET and abdominal ultrasound were equally effective for detecting hepatic metastases (P = 0.127). On region-based analyses, the combination of (18)F-FDG PET and CWU did not yield any noticeable increase in diagnostic efficacy. CONCLUSION: (18)F-FDG PET can replace CWU in primary M staging of nonkeratinizing NPC.     

89.

Positive, negative, unknown: assumptions of HIV status among HIV-positive men who have sex with men.     

Jeffrey T Parsons  Joseph Severino  Jose Nanin  Joseph C Punzalan  Kirk von Sternberg  Whitney Missildine  David Frost 《AIDS education and prevention》2006,18(2):139-149

Serosorting (i.e., engaging in unprotected sex with partners known to be of the same serostatus) can be a difficult process for men who have sex with men (MSM) who frequently make assumptions about their partners' serostatus. This process can be further complicated by a partner's dishonesty as well as other individual and contextual factors. The present study specifically examined how assumptions of serostatus made about unknown serostatus partners impact on the sexual behavior of 110 alcohol-abusing HIV-positive MSM. Although previous research has shown that HIV-positive MSM are more likely to serosort with other known HIV-positive men than with known HIV-negative men, our data suggest that unprotected sex behavior may not be specifically driven by whether or not they made assumptions of seroconcordance or serodiscordance. The types of assumptions these HIV-positive MSM made about their unknown status sexual partners and the basis for such assumptions were also examined. Owing to the ambiguities involved in assumptions of a partner's serostatus in sexual encounters, the 'unknown status' partner category is analytically distinct from 'known status' categories, and needs to be more fully explored because of its impact on perceived serosorting, rather than actual serosorting, among HIV-positive men.     

90.

Correlates of nonparticipation in an HIV prevention program for MSM.     

E Roberto Orellana  Joseph F Picciano  Roger A Roffman  Fred Swanson  Seth C Kalichman 《AIDS education and prevention》2006,18(4):348-361

Providing HIV prevention services to high-risk individuals remains challenging. We assessed factors associated with nonparticipation among high-risk, sexually active MSM found eligible to participate in a brief, telephone-delivered HIV prevention trial designed to evaluate the efficacy of motivational enhancement therapy (the Sex Check). Two levels of nonparticipation are evaluated: eligible participants who did versus those who did not complete their baseline/enrollment interview, and enrolled participants who did versus those who did not attend any of their counseling sessions. Nonenrollers were younger, less educated, more closeted, and were more likely to report sex with an injection drug using partner. Enrolled participants who did not engage in their counseling session(s) were less educated, reported greater use of alcohol and drugs during sex and use of injection drugs. Innovative methods to reduce barriers to engaging high-risk, sexually active MSM in risk reduction counseling are needed.     

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Stage	Patients Treated	Per Cent Cures
I	1	100.0
II and IIa	40	86.1
III and IIIa	130	15.4

The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.     

Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur.

A closed femur fracture pain model was developed in the C57BL/6J mouse. One day after fracture, a monoclonal antibody raised against nerve growth factor (anti-NGF) was delivered intraperitoneally and resulted in a reduction in fracture pain-related behaviors of approximately 50%. Anti-NGF therapy did not interfere with bone healing as assessed by mechanical testing and histomorphometric analysis. INTRODUCTION: Current therapies to treat skeletal fracture pain are limited. This is because of the side effect profile of available analgesics and the scarcity of animal models that can be used to understand the mechanisms that drive this pain. Whereas previous studies have shown that mineralized bone, marrow, and periosteum are innervated by sensory and sympathetic fibers, it is not understood how skeletal pain is generated and maintained even in common conditions such as osteoarthritis, low back pain, or fracture. MATERIALS AND METHODS: In this study, we characterized the pain-related behaviors after a closed femur fracture in the C57BL/6J mouse. Additionally, we assessed the effect of a monoclonal antibody that binds to and sequesters nerve growth factor (anti-NGF) on pain-related behaviors and bone healing (mechanical properties and histomorphometric analysis) after fracture. RESULTS: Administration of anti-NGF therapy (10 mg/kg, days 1, 6, and 11 after fracture) resulted in a reduction of fracture pain-related behaviors of approximately 50%. Attenuation of fracture pain was evident as early as 24 h after the initial dosing and remained efficacious throughout the course of fracture pain. Anti-NGF therapy did not modify biomechanical properties of the femur or histomorphometric indices of bone healing. CONCLUSIONS: These findings suggest that therapies that target NGF or its cognate receptor(s) may be effective in attenuating nonmalignant fracture pain without interfering with bone healing.     

Changes to osteoporosis prevalence according to method of risk assessment.

The impact of clinical risk factor-based absolute risk methods on the prevalence of high risk for osteoporotic fracture is unknown. We applied absolute risk methods to 6646 subjects and found that the prevalence of elderly women deemed to be at high risk increased substantially, whereas the overall prevalence was highly dependent on the threshold used to designate high risk. INTRODUCTION: Many groups have advocated using absolute risk methods that incorporate clinical risk factors to target patients for osteoporosis therapy. We examined how the application of such absolute risk classification systems influences the prevalence of those considered to be at high risk for osteoporotic fracture and compared these systems to one based solely on BMD. MATERIALS AND METHODS: Using 6646 subjects from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based cohort, we assessed three different systems for determining prevalence of high risk for osteoporotic fracture: a BMD-based system; a simplified risk factor system incorporating age, sex, BMD, and two clinical risk factors; and a comprehensive system, incorporating age, sex, BMD, and seven clinical risk factors. The 10-year absolute risks of incident fragility fracture were compared across systems using three different high-risk thresholds. RESULTS: The prevalence of a T score < or = -2.5 was 18.8% (95% CI: 17.7-19.9%) in women and 3.9% (95% CI: 3.0-4.7%) in men. Using a 15% 10-year risk of fracture threshold, the prevalence of women at high risk increased to 46.9% (95% CI: 45.4-48.4) and 42.5% (95% CI: 41.1-43.9) when the comprehensive and simplified risk factor classification systems were used, respectively. Using a 25% 10-year absolute risk threshold, the prevalence of high risk was similar to that of the BMD-based system, whereas the 20% threshold gave intermediate rates. All thresholds analyzed resulted in an increased prevalence of older women at high risk for fracture, whereas only the 15% 10-year risk of fracture threshold resulted in an increase in the prevalence of men at high risk. CONCLUSIONS: The application of risk factor-based systems results in an increased prevalence of older women at high risk. The prevalence of individuals at high risk may increase with changes to the methods used to determine those who are eligible for therapy. These data have important implications for the pattern of care and costs of treating osteoporotic fractures.     

18F-FDG PET can replace conventional work-up in primary M staging of nonkeratinizing nasopharyngeal carcinoma.

Conventional work-up (CWU) with chest radiography, abdominal ultrasonography, and skeletal scintigraphy has limited value in M staging of nonkeratinizing nasopharyngeal carcinoma (NPC). Our aim was to evaluate whether (18)F-FDG PET could replace CWU by comparing their diagnostic efficacies. METHODS: Patients with histologically proven nonkeratinizing NPC and no prior treatment were prospectively enrolled. All study participants underwent CWU and (18)F-FDG PET for primary M staging. Distant metastasis was considered to be present if there was any reliable evidence identified within 1 y after diagnosis. The comparative diagnostic efficacies of (18)F-FDG PET, CWU, and the combination of (18)F-FDG PET and CWU (PET+CWU) were evaluated using the areas under the receiver-operating-characteristic (ROC) curves. RESULTS: Sixty-one (20.3%) of 300 eligible patients were found to have distant metastases. On a patient-based analysis, (18)F-FDG PET was found to be more effective than CWU (P < 0.001), whereas it was equally effective with PET+CWU (P = 0.130). On region-based analyses, (18)F-FDG PET was more effective than skeletal scintigraphy and chest radiography for detecting bone metastases (P < 0.001) and chest metastases (P < 0.001), respectively. (18)F-FDG PET and abdominal ultrasound were equally effective for detecting hepatic metastases (P = 0.127). On region-based analyses, the combination of (18)F-FDG PET and CWU did not yield any noticeable increase in diagnostic efficacy. CONCLUSION: (18)F-FDG PET can replace CWU in primary M staging of nonkeratinizing NPC.     

Positive, negative, unknown: assumptions of HIV status among HIV-positive men who have sex with men.

Serosorting (i.e., engaging in unprotected sex with partners known to be of the same serostatus) can be a difficult process for men who have sex with men (MSM) who frequently make assumptions about their partners' serostatus. This process can be further complicated by a partner's dishonesty as well as other individual and contextual factors. The present study specifically examined how assumptions of serostatus made about unknown serostatus partners impact on the sexual behavior of 110 alcohol-abusing HIV-positive MSM. Although previous research has shown that HIV-positive MSM are more likely to serosort with other known HIV-positive men than with known HIV-negative men, our data suggest that unprotected sex behavior may not be specifically driven by whether or not they made assumptions of seroconcordance or serodiscordance. The types of assumptions these HIV-positive MSM made about their unknown status sexual partners and the basis for such assumptions were also examined. Owing to the ambiguities involved in assumptions of a partner's serostatus in sexual encounters, the 'unknown status' partner category is analytically distinct from 'known status' categories, and needs to be more fully explored because of its impact on perceived serosorting, rather than actual serosorting, among HIV-positive men.     

Correlates of nonparticipation in an HIV prevention program for MSM.

Providing HIV prevention services to high-risk individuals remains challenging. We assessed factors associated with nonparticipation among high-risk, sexually active MSM found eligible to participate in a brief, telephone-delivered HIV prevention trial designed to evaluate the efficacy of motivational enhancement therapy (the Sex Check). Two levels of nonparticipation are evaluated: eligible participants who did versus those who did not complete their baseline/enrollment interview, and enrolled participants who did versus those who did not attend any of their counseling sessions. Nonenrollers were younger, less educated, more closeted, and were more likely to report sex with an injection drug using partner. Enrolled participants who did not engage in their counseling session(s) were less educated, reported greater use of alcohol and drugs during sex and use of injection drugs. Innovative methods to reduce barriers to engaging high-risk, sexually active MSM in risk reduction counseling are needed.