Publications by authors named "Howard D Strickler"

175 Publications

Frequency of high-grade squamous cervical lesions among women over age 65 years living with HIV.

Am J Obstet Gynecol 2021 May 3. Epub 2021 May 3.

Department of Epidemiology and Population Health, Albert Einstein School of Medicine, Bronx, NY.

Background: Current US cervical cancer screening guidelines recommend screening cessation at the age of 65 years provided women have adequate previous screening and no history of precancer. Women living with HIV are at higher risk of cervical cancer than women living without HIV. Furthermore, limited data exists to quantify the risk of cervical cancer among women who otherwise would qualify for screening cessation.

Objective: This study aimed to determine whether guidelines recommending women to discontinue cervical cancer screening at the age of 65 years are appropriate for women living with HIV.

Study Design: Semiannual Papanicolaou testing was performed as part of surveillance visits in the Women's Interagency HIV Study. Launched in October 1994, the Women's Interagency HIV Study is a federally funded US multisite cohort study that has enrolled 3678 women living with HIV and 1304 women living without HIV; we included data throughout September 2019 onward. Conventional Papanicolaou tests were collected at scheduled 6-month visits and read centrally according to the 1991 Bethesda System criteria. Results were analyzed among women at least 65 years of age. The primary endpoint was high-grade cytology, including high-grade squamous intraepithelial lesions; atypical glandular cells; atypical squamous cells, cannot exclude high-grade lesions; and malignant cytology. Wilcoxon rank-sum tests were used to compare the continuous variables, and Chi-square tests or the Fisher exact tests were used to compare the categorical variables. The Kaplan-Meier method was used to calculate the cumulative incidence. Poisson regression was used to compare 2 incidence rates.

Results: Of 169 eligible women (121 women living with HIV and 48 women living without HIV) who contributed 678.4 person-years of observation after reaching the age of 65 years, 2.2% had high-grade cytologic abnormalities. However, no cancer was found. Furthermore, 20 women had previous precancer results, and 74 women had abnormal Papanicolaou test results in the previous decade. Among 50 women (38 women living with HIV and 12 women living without HIV) with a previous hysterectomy and no history of cervical precancer, the cumulative incidence rates of high-grade squamous intraepithelial lesions were 0.6 (95% confidence interval, 0.0-3.2) per 100 person-years for women living with HIV and 0.0 (95% confidence interval, 0.0-8.1) per 100 person-years for women living without HIV (P=.61). Only 48 women (27 women living with HIV and 21 women living without HIV) had cervices and met the current guidelines to discontinue screening; their risk of experiencing high-grade squamous intraepithelial lesions was 2.2 (95% confidence interval, 0.6-5.5) per 100 person-years overall and did not vary by HIV status (2.3 [95% confidence interval, 0.5-6.8] per 100 person-years for women living with HIV and 1.8 [95% confidence interval, 0.0-9.8] per 100 person-years for women living without HIV; P=.81).

Conclusion: Most women living with HIV do not meet the criteria for cervical cancer screening cessation and will need to continue screening over the age of 65 years; however, women who meet the criteria for screening cessation have risks of high-grade squamous lesions similar to women living without HIV and may choose to discontinue.
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http://dx.doi.org/10.1016/j.ajog.2021.04.253DOI Listing
May 2021

Sex Hormones, Insulin, and Insulin-like Growth Factors in Recurrence of High-Stage Endometrial Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Apr 23;30(4):719-726. Epub 2021 Feb 23.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients.

Methods: Stage II-IV patients ( = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of , IGF-binding proteins () and , insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade.

Results: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47-0.95), IR positivity (HR, 0.53; 95% CI, 0.29-0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02-2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02-1.92) were associated with increased recurrence risk.

Conclusions: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer.

Impact: This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026669PMC
April 2021

The relationship of human papillomavirus and cytology co-testing results with endometrial and ovarian cancer diagnoses.

Gynecol Oncol 2021 Apr 14;161(1):297-303. Epub 2021 Jan 14.

Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA, USA.

Background: To investigate whether routine cervical screening using human papillomavirus (HPV) and cytology co-testing effectively identifies women with endometrial (EC) or ovarian (OvC) cancer.

Methods: In 2003, Kaiser Permanente Northern California implemented triennial co-testing in women aged ≥30 years. Index screening results (n = 2,385,729) were linked to subsequent EC (n = 3434) and OvC (n = 1113) diagnoses from January 1, 2003 to December 31, 2017. EC were categorized as type 1 or 2, and, selectively, EC and OvC diagnoses were stratified on whether symptoms were present at the time of the co-test. Fractions and absolute risks of EC or OvC of each co-testing result were calculated.

Results: Most EC (82.18%) and OvC (88.68%) were preceded by a negative HPV and negative cytology co-test. More EC were preceded by atypical squamous cells of undetermined significance (ASC-US) or more severe (ASC-US+) cytology and negative HPV test (n = 290) (8.44% of EC) compared to a negative cytology and a positive HPV test (n = 31) (0.89% of EC) (p < 0.001). The absolute risk of any EC diagnosis following ASC-US+ and negative HPV test was 0.48%. Atypical glandular cells (AGC) cytology and a negative HPV result preceded 6.92% of any EC diagnosis, with an absolute risk of 4.02%, but preceded only 1.13% of type 2 EC cases, with an absolute risk of 0.24%, in asymptomatic women. AGC cytology and a negative HPV result preceded 1.44% of OvC, with an absolute risk of 0.28%.

Conclusions: Abnormal cervical screening tests, even AGC cytology, rarely precedes and poorly predict women with EC or OvC.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.005DOI Listing
April 2021

Association of liver enzymes with incident diabetes in US Hispanic/Latino adults.

Diabet Med 2021 Aug 28;38(8):e14522. Epub 2021 Jan 28.

Albert Einstein College of Medicine, Bronx, NY, USA.

Introduction: Non-alcoholic fatty liver disease (NAFLD) has been associated with increased risk of incident diabetes. But such evidence is lacking in the Hispanic/Latino population, which has high prevalence of obesity and NAFLD.

Methods: We conducted a prospective cohort study of 6,928 adults of Hispanic/Latino background who had no diabetes, did not report excessive alcohol use, and no hepatitis B and C infection at baseline (2008-2011). We estimated risk ratios (RR) for incident diabetes, identified from visit 2 examination by glucose measurements or antidiabetic medication use, with baseline liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)).

Results: A total of 738 adults developed diabetes during 6 years of follow-up. After adjusting for participant characteristics at baseline, versus the lowest quartile, highest quartiles of ALT and GGT were associated with risks for incident diabetes (RR for ALT: 1.51 [95% CI 1.03-2.22], p-trend = 0.006; RR for GGT: 2.39 [1.60-3.55], p-trend = 0.001). Higher GGT levels predicted increased risk of incident diabetes even among those with ALT or AST below the median levels. The associations of ALT and GGT with incident diabetes were similar among most Hispanic background but were not seen among Dominicans (p for interaction <0.05). The association of AST with incident diabetes was found only among light-to-moderate alcohol drinkers (RR = 1.50 [1.20-1.86]) but not abstainers (RR = 0.91 [0.69-1.20], p for interaction = 0.006).

Conclusion: Higher ALT and GGT levels are associated with increased risk of developing diabetes among Latinos. Liver enzyme tests might aid in diabetes prevention by identifying high-risk individuals.
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http://dx.doi.org/10.1111/dme.14522DOI Listing
August 2021

Long-term Persistence of Oral HPV Over 7 Years of Follow-up.

JNCI Cancer Spectr 2020 Oct 5;4(5):pkaa047. Epub 2020 Jun 5.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Human papillomavirus-related oropharyngeal cancer (HPV-OPC) incidence is increasing, but the natural history of the precursor-oral HPV-has not been well described.

Methods: This observational cohort study of people living with HIV and at-risk HIV uninfected people evaluated participants semiannually using 30-second oral rinse and gargle specimens over 7 years. Initially, 447 participants were followed for 4 years as part of the Persistent Oral Papillomavirus Study, and a subset of 128 who showed persistent infections at the last Persistent Oral Papillomavirus Study visit had an additional visit, as part of the Men and Women Understanding Throat HPV Study, on average 2.5 years later. Extracted DNA from oral rinse and gargle specimens was amplified using polymerase chain reaction and type specification of 13 oncogenic HPV types. Risk factors for oncogenic oral HPV clearance were evaluated using Cox models.

Results: The majority of oncogenic oral HPV infections cleared quickly, with a median time to clearance of 1.4 years (interquartile range = 0.5-3.9 years). After 7 years of follow-up, 97% of incident and 71% of prevalent infections had cleared. Lower HPV-16 viral load was statistically significantly associated with clearance (per 10-fold decrease in copy number: adjusted hazard ratio [aHR] = 2.51, 95% confidence interval [CI] = 1.20 to 5.26; = .01). Adjusted analyses showed that oncogenic oral HPV clearance was lower among prevalent than incident-detected infections (aHR = 0.44, 95% CI = 0.35 to 0.55), among men than women (aHR = 0.74, 95% CI = 0.60 to 0.91), for older participants (aHR per 10 years increasing age = 0.81, 95% CI = 0.74 to 0.89), and among people living with HIV (aHR = 0.76, 95% CI = 0.60 to 0.95). One participant who had oral HPV-16 consistently detected at 10 study visits over 4.5 years was subsequently diagnosed with HPV-OPC.

Conclusions: This prospective study of oncogenic oral HPV infection is the longest and largest quantification of oral HPV-16 infections to date.
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http://dx.doi.org/10.1093/jncics/pkaa047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667996PMC
October 2020

Primary HPV and Molecular Cervical Cancer Screening in US Women Living With Human Immunodeficiency Virus.

Clin Infect Dis 2021 05;72(9):1529-1537

Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, USA.

Background: Primary human papillomavirus (HPV) screening (PHS) utilizes oncogenic human papillomavirus (oncHPV) testing as the initial cervical cancer screening method and typically, if positive, additional reflex-triage (eg, HPV16/18-genotyping, Pap testing). While US guidelines support PHS usage in the general population, PHS has been little studied in women living with HIV (WLWH).

Methods: We enrolled n = 865 WLWH (323 from the Women's Interagency HIV Study [WIHS] and 542 from WIHS-affiliated colposcopy clinics). All participants underwent Pap and oncHPV testing, including HPV16/18-genotyping. WIHS WLWH who tested oncHPV[+] or had cytologic atypical squamous cells of undetermined significance or worse (ASC-US+) underwent colposcopy, as did a random 21% of WLWH who were oncHPV[-]/Pap[-] (controls). Most participants additionally underwent p16/Ki-67 immunocytochemistry.

Results: Mean age was 46 years, median CD4 was 592 cells/µL, 95% used antiretroviral therapy. Seventy WLWH had histologically-determined cervical intraepithelial neoplasia grade 2 or greater (CIN-2+), of which 33 were defined as precancer (ie, [i] CIN-3+ or [ii] CIN-2 if concurrent with cytologic high grade squamous intraepithelial lesions [HSILs]). PHS had 87% sensitivity (Se) for precancer, 9% positive predictive value (PPV), and a 35% colposcopy referral rate (Colpo). "PHS with reflex HPV16/18-genotyping and Pap testing" had 84% Se, 16% PPV, 30% Colpo. PHS with only HPV16/18-genotyping had 24% Colpo. "Concurrent oncHPV and Pap Testing" (Co-Testing) had 91% Se, 12% PPV, 40% Colpo. p16/Ki-67 immunochemistry had the highest PPV, 20%, but 13% specimen inadequacy.

Conclusions: PHS with reflex HPV16/18-genotyping had fewer unnecessary colposcopies and (if confirmed) could be a potential alternative to Co-Testing in WLWH.
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http://dx.doi.org/10.1093/cid/ciaa1317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096228PMC
May 2021

Effect of child abuse and neglect on risk behaviors in inner-city minority female adolescents and young adults.

Child Abuse Negl 2020 03 26;101:104347. Epub 2019 Dec 26.

Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Cancer Prevention & Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Background: Over six million children each year are referred to child protective services for child abuse (sexual, physical and emotional) and neglect (physical and emotional).

Objective: While the relationship between child sexual abuse and sexually transmitted infections has been documented, there has been little research regarding the effects of other forms of maltreatment.

Participants And Setting: 882 inner-city females aged 12-20 years of age seen at a large adolescent and young adult (AYA) health center in New York City between 2012-2017.

Methods: History of maltreatment was assessed using the Childhood Trauma Questionnaire. Associations with depressive symptoms, antisocial behavior, peer deviancy, drug/alcohol use, and risky sexual behaviors were assessed.

Results: History of maltreatment was common in our cohort of inner-city AYA females, with 59.6 % reporting any type of maltreatment, including sexual abuse (17.5 %), physical abuse (19.5 %) or neglect (26.2 %), and emotional abuse (30.7 %) or neglect (40.4 %). We observed significant associations between all forms of maltreatment and risk of depression, drug/alcohol use, antisocial behaviors, peer deviancy, and risky sexual risk behaviors (including having a higher number of sexual partners, having a sexual partner 5+ years older, and anal sex). Physical and emotional abuse were associated with having unprotected sex while under the influence of drugs/alcohol.

Conclusions And Relevance: Reporting a history of maltreatment was associated with an increased likelihood of engaging in risky sexual and antisocial behaviors, as well as depression in inner-city female youth. These data highlight the broad, lingering repercussions of all types of child maltreatment.
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http://dx.doi.org/10.1016/j.chiabu.2019.104347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059863PMC
March 2020

Longitudinal assessment of abnormal Papanicolaou test rates among women with HIV.

AIDS 2020 01;34(1):73-80

Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri Albert Einstein College of Medicine, Bronx Maimonides Medical Center, Brooklyn, New York Georgetown University School of Medicine, Washington, DC University of Southern California, Los Angeles University of California, San Francisco, California Johns Hopkins University, Baltimore, Maryland University of North Carolina, Chapel Hill, North Carolina Mailman School of Public Health, Columbia University, New York, New York University of Miami, Miami, Florida University of Mississippi, Jackson, Mississippi, USA.

Objective: To describe longitudinal changes in the prevalence of abnormal Papanicolau testing among women living with HIV.

Design: Prospective cohort study with sequential enrollment subcohorts.

Methods: Four waves of enrollment occurred in the Women's Interagency HIV Study, the US women's HIV cohort (1994-1995, 2001-2002, 2011-2012, 2013-2015). Pap testing was done at intake, with colposcopy prescribed for any abnormality. Rates of abnormal Pap test results (atypical squamous cells of uncertain significance or worse) and cervical intraepithelial neoplasia grade 2 (CIN2) or worse were calculated. Logistic regression models assessed changes in prevalence across cohorts after controlling for severity of HIV disease and other risk factors for abnormal Pap tests.

Results: The unadjusted prevalence of any Pap abnormality was 679/1769 (38%) in the original cohort, 195/684 (29%) in the 2001-2002 cohort, 46/231 (20%) in the 2011-2012 cohort, and 71/449 (16%) in the 2013-2015 cohort. In multivariable analysis, compared with risk in the 1994-1995 cohort, the adjusted risk in the 2001-2002 cohort was 0.79 (95% CI 0.59-1.05), in the 2011-2012 cohort was 0.67 (95% CI 0.43-1.04), and in the 2013-2015 cohort was 0.41 (95% CI 0.27-0.62) with P for trend less than 0.0001.

Conclusion: Rates of abnormal cytology among women with HIV have fallen during the past two decades.
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http://dx.doi.org/10.1097/QAD.0000000000002388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138211PMC
January 2020

Risk of Oral Human Papillomavirus Infection Among Sexually Active Female Adolescents Receiving the Quadrivalent Vaccine.

JAMA Netw Open 2019 10 2;2(10):e1914031. Epub 2019 Oct 2.

Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York.

Importance: Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, and oral HPV infection is associated with increased risk of oropharyngeal cancer.

Objective: To describe the risk factors for oral HPV in sexually active female adolescents receiving the quadrivalent vaccine.

Design, Setting, And Participants: Longitudinal cohort study involving repeated collection of oral rinse specimens from sexually active female adolescents conducted between October 19, 2007, and March 9, 2017, at a large adolescent health center in New York, New York, that provides free health care, including HPV vaccination.

Exposures: Human papillomavirus vaccination and self-reported history of sexual behavior.

Main Outcomes And Measures: Prevalence of HPV in the oral cavity.

Results: Among the 1259 participants who were included in this study, median age at entry into the study was 18 (range, 13-21) years; 638 (50.7%) were of African American descent, 569 (45.2%) were of Hispanic descent, 43 (3.4%) reported another race/ethnicity, and race/ethnicity was unspecified for 9 (0.7%). The median (mode) age at first sexual activity was 14.8 (14) years, and 1161 (92.2%) reported having had oral sex. Human papillomavirus DNA was detected in baseline oral rinse samples of 78 of the 1259 participants (6.2%; 95% CI, 4.9%-7.6%). There was a significant decrease in oral HPV detection with time (in years) since first engaging in sexual activities, independent of age and concurrent detection of cervical HPV; comparing 4 or more years with 1 year or less, the odds ratio was 0.45 (95% CI, 0.21-0.96). Detection of vaccine types (HPV-6, HPV-11, HPV-16, and HPV-18) was significantly lower among participants who had received at least 1 dose of the quadrivalent HPV vaccine at the time of enrollment compared with those who were unvaccinated (odds ratio, 0.20; 95% CI, 0.04-0.998).

Conclusions And Relevance: This study's findings suggest that detection of HPV in the oral cavity is not uncommon in sexually active female adolescents. In addition, HPV vaccination is associated with a significant decrease in detection of HPV vaccine types in the oral cavity.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.14031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822084PMC
October 2019

Epidemiological evidence that common HPV types may be common because of their ability to evade immune surveillance: Results from the Women's Interagency HIV study.

Int J Cancer 2020 06 18;146(12):3320-3328. Epub 2019 Oct 18.

Albert Einstein College of Medicine, Bronx, NY.

Infection by human papillomavirus (HPV) type 16, the most oncogenic HPV type, was found to be the least affected by HIV-status and CD4 count of any of the approximately 13 oncogenic HPV types. This relative independence from host immune status has been interpreted as evidence that HPV16 may have an innate ability to avoid the effects of immunosurveillance. However, the impact of immune status on other individual HPV types has not been carefully assessed. We studied type-specific HPV infection in a cohort of 2,470 HIV-positive (HIV[+]) and 895 HIV-negative (HIV[-]) women. Semi-annually collected cervicovaginal lavages were tested for >40 HPV types. HPV type-specific prevalence ratios (PRs), incidence and clearance hazard ratios (HRs), were calculated by contrasting HPV types detected in HIV[+] women with CD4 < 200 to HIV[-] women. HPV71 and HPV16 prevalence had the weakest associations with HIV-status/CD4 count of any HPV, according to PRs. No correlations between PRs and HPV phylogeny or oncogenicity were observed. Instead, higher HPV type-specific prevalence in HIV[-] women correlated with lower PRs (ρ = -0.59; p = 0.0001). An alternative (quadratic model) statistical approach (P = a*P  + b*P ; R = 0.894) found similar associations (p = 0.0005). In summary, the most prevalent HPV types in HIV[-] women were the types most independent from host immune status. These results suggest that common HPV types in HIV[-] women may have a greater ability to avoid immune surveillance than other types, which may help explain why they are common.
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http://dx.doi.org/10.1002/ijc.32693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373334PMC
June 2020

Methods to improve the noninvasive diagnosis and assessment of disease severity in children with suspected nonalcoholic fatty liver disease (NAFLD): Study design.

Contemp Clin Trials 2018 12 27;75:51-58. Epub 2018 Oct 27.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity and is the most common liver disease in the developed world. In children with suspected NAFLD, present guidelines suggest consideration of alternative diagnoses via extensive blood testing, though the yield of this work up is unknown. Furthermore, the gold standard diagnostic test for NAFLD remains liver biopsy, making the development of non-invasive tests critically important.

Objectives: Our objectives are: 1) to determine the accuracy of elastography and multiple serum biomarkers - each assessed individually and as algorithms (including those previously tested in adults) - for the diagnosis of nonalcoholic steatohepatitis (NASH) and early fibrosis in children and (2) to examine the utility of extensive testing for rare alternative diagnoses in overweight or obese children with elevated alanine aminotransferase (ALT) suspected to have NAFLD.

Design: This is an ongoing, cross-sectional study in children 2-18 years of age with up to 2 years of prospective follow up. Eligible patients are asymptomatic, overweight or obese, and have an ALT ≥35 U/L upon enrollment. Two forms of elastography are obtained serially along with anthropometric data and routine laboratory tests. Elastography and serum biomarkers are also performed immediately prior to any clinically-indicated biopsy.

Methods: Between April 2015 and April 2018, 193 children have been enrolled in this ongoing study and 71 have undergone liver biopsy. Here we carefully report the rationale, methodology, and preliminary data for this study.
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http://dx.doi.org/10.1016/j.cct.2018.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249118PMC
December 2018

Impact of human papillomavirus vaccination on the clinical meaning of cervical screening results.

Prev Med 2019 01 11;118:44-50. Epub 2018 Oct 11.

Division of Cancer Epidemiology and Genetics, NCI, Bethesda, MD, USA.

Women previously vaccinated against human papillomavirus (HPV) type 16 and 18 are now reaching the age (21 years) at which cervical-cancer screening is recommended in the U.S. The impact of HPV vaccination on risks of cervical precancer following a positive and negative screen among women aged 21-24 years who just started routine cervical screening are not well described. Therefore, three-year absolute and relative (RR) cumulative risks of cervical intraepithelial neoplasia grade 2 or more severe diagnoses (≥CIN2) and grade 3 or more severe diagnoses (≥CIN3) were estimated for women undergoing cervical screening at Kaiser Permanente Northern California. Risks were estimated in women aged 21-24 years (n = 75,008) undergoing cervical screening since late 2006, 6 months after HPV vaccination became available; women were categorized vaccinated at ages <18, 18-20, and 21-24 years and compared to those who were unvaccinated. Three-year risks were estimated for normal, low-grade, and high-grade cytology results. Three-year risks of ≥CIN2 and ≥CIN3 for unvaccinated women following low-grade cytology were 10.89% for and 3.70%, respectively. By comparison, Three-year risks of ≥CIN2 and ≥CIN3 were 5.26% (RR = 0.48, 95%CI = 0.24-0.99) and 0.99% (RR = 0.27, 95%CI = 0.06-1.13), respectively, for women vaccinated under the age of 18 years. Three-year ≥CIN2 and ≥CIN3 risks were lower for those HPV vaccinated at younger age for any screening result (p ≤ 0.01 for all comparisons). These data support initiating cervical screening at an older age or changing the management of a low-grade cytology result in women aged 21-24 years who were vaccinated against HPV younger than age of 18 years.
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http://dx.doi.org/10.1016/j.ypmed.2018.10.001DOI Listing
January 2019

Natural History of Cervical Intraepithelial Neoplasia-2 in HIV-Positive Women of Reproductive Age.

J Acquir Immune Defic Syndr 2018 12;79(5):573-579

Department of Medicine, Georgetown University, Washington, DC.

Objective: To evaluate the natural history of treated and untreated cervical intraepithelial neoplasia-2 (CIN2) among HIV-positive women.

Methods: Participants were women enrolled in the Women's Interagency HIV Study between 1994 and 2013. One hundred four HIV-positive women diagnosed with CIN2 before age 46 were selected, contributing 2076 visits over a median of 10 years (interquartile range 5-16). The outcome of interest was biopsy-confirmed CIN2 progression, defined as CIN3 or invasive cervical cancer. CIN2 treatment was abstracted from medical records.

Results: Most women were African American (53%), current smokers (53%), and had a median age of 33 years at CIN2 diagnosis. Among the 104 HIV-positive women, 62 (59.6%) did not receive CIN2 treatment. Twelve HIV-positive women (11.5%) showed CIN2 progression to CIN3; none were diagnosed with cervical cancer. There was no difference in the median time to progression between CIN2-treated and CIN2-untreated HIV-positive women (2.9 vs. 2.7 years, P = 0.41). CIN2 treatment was not associated with CIN2 progression in multivariate analysis (adjusted hazard ratio 1.82; 95% confidence interval: 0.54 to 7.11), adjusting for combination antiretroviral therapy and CD4 T-cell count. In HIV-positive women, each increase of 100 CD4 T cells was associated with a 33% decrease in CIN2 progression (adjusted hazard ratio 0.67; 95% confidence interval: 0.47 to 0.88), adjusting for CIN2 treatment and combination antiretroviral therapy.

Conclusions: CIN2 progression is uncommon in this population, regardless of CIN2 treatment. Additional studies are needed to identify factors to differentiate women at highest risk of CIN2 progression.
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http://dx.doi.org/10.1097/QAI.0000000000001865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231968PMC
December 2018

Methylation of High-Risk Human Papillomavirus Genomes Are Associated with Cervical Precancer in HIV-Positive Women.

Cancer Epidemiol Biomarkers Prev 2018 12 20;27(12):1407-1415. Epub 2018 Sep 20.

Department of Pediatrics (Genetic Medicine), Albert Einstein College of Medicine, Bronx, New York.

Background: HIV-positive women are at substantial risk of HPV-associated cervical neoplasia caused by high-risk (HR) HPVs. Methylation of the HPV genome is associated with cervical intraepithelial neoplasia grade 3 (CIN3) in HIV-negative women, yet it is unknown whether this holds true for HIV-positive women.

Methods: We designed a case-control study within the Women's Interagency HIV Study (WIHS) cohort comparing HIV-positive CIN3 cases ( = 72) to HIV-positive controls without detectable CIN2. The unit of analysis and matching was HPV-type infection. Cases with ≥2 HR-HPV types ( = 23; 32%) had a separate control for each HR-HPV type. We developed and utilized next-generation sequencing (NGS) methylation assays for 12 different HR-HPVs, focusing on CpG sites in the L1/L2 regions.

Results: Significant case-control differences in individual CpG site methylation levels were observed for multiple alpha-9 (HPV16/31/35/58) and alpha-7 HPV (HPV18/39/45) types, based on dichotomization of tertile levels (T3 vs. T1 and T2). Analyses combining homologous CpG sites [e.g., HPV16-L1-5608/HPV31-L1-5521/HPV35-L2L1-5570; OR = 7.28; 95% confidence interval (CI): 2.75-19.3], and (e.g., HPV18-L1-7062/HPV45-L1-7066; OR = 6.94; 95% CI: 1.23-39.3) were significant in separate case-control comparisons. In cases with multiple HR-HPVs, we tested and confirmed the hypothesis that one HR-HPV type would have higher methylation than other types detected, consistent with there being a single HR-HPV causally related to a lesion.

Conclusions: CIN3 is associated with elevated L1/L2 CpG methylation levels in HIV-positive women.

Impact: HPV DNA CpG methylation is a promising triage option in HIV-positive women testing positive for HR-HPV types and provides risk attribution in women with multiple HPV type infections.
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http://dx.doi.org/10.1158/1055-9965.EPI-17-1051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279505PMC
December 2018

Racial differences in human papilloma virus types amongst United States women with HIV and cervical precancer.

AIDS 2018 11;32(18):2821-2826

Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.

Objective: Recent studies reported a lower human papillomavirus 16 (HPV16) prevalence in cervical precancer among African American than Caucasian women in the general population. We assessed this relationship in women with HIV.

Design: Women living with or at risk for HIV in the Women's Interagency HIV Study were followed semi-annually with Pap tests, colposcopy/histology (if indicated), and collection of cervicovaginal lavage samples for HPV testing by PCR. Racial and ethnic groups were defined using genomic Ancestry Informative Markers (AIMs).

Results: Among 175 cases of cervical intraepithelial neoplasia 3 or worse (CIN-3+), 154 were diagnosed in women with HIV. African American (27%) and Hispanic (37%) cases were significantly less likely than Caucasian (62%) women to test positive for HPV16 (P = 0.01). In multivariate logistic regression models, these associations remained significant for African Americans (odds ratio = 0.13; 95% confidence interval (CI) 0.04-0.44; P = 0.001) but not Hispanics, after controlling for HIV status, CD4 count, history of AIDS, age, smoking, and sexual behavior. Limiting the analysis to women with HIV did not change the findings.

Conclusion: HPV16 prevalence is lower in African American compared with Caucasian women with HIV and cervical precancer, independent of immune status. Future studies to determine why these racial differences exist are warranted, and whether there are similar associations between race and invasive cervical cancer in women with HIV. Further, HPV types not covered by quadrivalent and bivalent vaccines may play an especially important role in cervical precancer among HIV-positive African American women, a possible advantage to using nonavalent HPV vaccine in this population.
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http://dx.doi.org/10.1097/QAD.0000000000002005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499386PMC
November 2018

Comparison of Fecal Collection Methods for Microbiome and Metabolomics Studies.

Front Cell Infect Microbiol 2018 28;8:301. Epub 2018 Aug 28.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States.

Integrated microbiome and metabolomics analyses hold the potential to reveal interactions between host and microbiota in relation to disease risks. However, there are few studies evaluating how field methods influence fecal microbiome characterization and metabolomics profiling. Five fecal collection methods [immediate freezing at -20°C without preservative, OMNIgene GUT, 95% ethanol, RNA, and Flinders Technology Associates (FTA) cards] were used to collect 40 fecal samples from eight healthy volunteers. We performed gut microbiota 16S rRNA sequencing, untargeted metabolomics profiling, and targeted metabolomics focusing on short chained fatty acids (SCFAs). Metrics included α-diversity and β-diversity as well as distributions of predominant phyla. To evaluate the concordance with the "gold standard" immediate freezing, the intraclass correlation coefficients (ICCs) for alternate fecal collection systems were calculated. Correlations between SCFAs and gut microbiota were also examined. The FTA cards had the highest ICCs compared to the immediate freezing method for α-diversity indices (ICCs = 0.96, 0.96, 0.76 for Shannon index, Simpson's Index, Chao-1 Index, respectively), followed by OMNIgene GUT, RNA, and 95% ethanol. High ICCs (all >0.88) were observed for all methods for the β-diversity metric. For untargeted metabolomics, in comparison to immediate freezing which detected 621 metabolites at ≥75% detectability level, 95% ethanol showed the largest overlapping set of metabolites ( = 430; 69.2%), followed by FTA cards ( = 330; 53.1%) and OMNIgene GUT ( = 213; 34.3%). Both OMNIgene GUT (ICCs = 0.82, 0.93, 0.64) and FTA cards (ICCs = 0.87, 0.85, 0.54) had acceptable ICCs for the top three predominant SCFAs (butyric acid, propionic acid and acetic acid). Nominally significant correlations between bacterial genera and SCFAs ( < 0.05) were observed in fecal samples collected by different methods. Of note, a high correlation between the genus (known butyrate producer) and butyric acid was observed for both immediate freezing ( = 0.83) and FTA cards ( = 0.74). Four alternative fecal collection methods are generally comparable with immediate freezing, but there are differences in certain measures of the gut microbiome and fecal metabolome across methods. Choice of method depends on the research interests, simplicity of fecal collection procedures and ease of transportation to the lab, especially for large epidemiological studies.
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http://dx.doi.org/10.3389/fcimb.2018.00301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127643PMC
August 2019

The Relation of Obesity-Related Hormonal and Cytokine Levels With Multiple Myeloma and Non-Hodgkin Lymphoma.

Front Oncol 2018 16;8:103. Epub 2018 Apr 16.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States.

This article presents the first detailed overview of the mechanisms that may underlie the relation of obesity with B-cell non-Hodgkin lymphomas (NHLs) and multiple myeloma (MM). Epidemiologic studies, including meta-analyses of prospective cohorts, have reported that the risks of NHL and MM are significantly increased in obese, relative to normal weight, women and men. Accumulating experimental and clinical evidence suggests that inflammatory cytokines, hyperinsulinemia, and sex hormones could play a role in the association of obesity with B-cell NHL and MM carcinogenesis. There is, however, a paucity of data published from appropriate large prospective cohort studies, and studies concurrently measuring these correlated factors, to formally determine the likely biologic factors driving the relationship of obesity with NHL and MM. Additional strengths and weaknesses of the current literature, as well as study design issues that need to be considered in conducting these studies, such as the exclusion of type 2 diabetics or postmenopausal women using hormone therapy, are discussed.
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http://dx.doi.org/10.3389/fonc.2018.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911620PMC
April 2018

Regulatory CD4 T Cells Recognize Major Histocompatibility Complex Class II Molecule-Restricted Peptide Epitopes of Apolipoprotein B.

Circulation 2018 09;138(11):1130-1143

Department of Bioengineering, University of California, San Diego, La Jolla (K.L.).

Background: CD4 T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules.

Methods: We constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E-deficient ( Apoe) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined.

Results: In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4 T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3 regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4 T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-A-p18 tetramer identified the expansion of p18-specific CD4 T cells on vaccination, which were enriched for interleukin-10-producing Tregs.

Conclusions: These findings show that APOB p18-specific CD4 T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.031420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160361PMC
September 2018

Racial Differences in Survival From Epithelial Ovarian Cancer Are Associated With Stage at Diagnosis and Use of Neoadjuvant Therapy: A 10-Year Single-Institution Experience With a Racially Diverse Urban Population.

Int J Gynecol Cancer 2018 05;28(4):749-756

Objective: The aim of this study was to evaluate the racial/ethnic disparities in ovarian cancer survival in a diverse population.

Methods: We performed a retrospective cohort study evaluating all patients with epithelial ovarian cancer who received primary treatment at Montefiore Medical Center from 2005 to 2015. Clinicopathologic and survival data were abstracted from medical records. Two-sided statistical analyses were performed using SAS 9.3.

Results: Three hundred forty-four evaluable patients were identified: 85 (25%) black, 107 (31%) white, 74 (21%) Hispanic, and 78 (23%) other. Black patients were more likely to present with stage IV disease (P = 0.01) and receive neoadjuvant chemotherapy (P < 0.01). By Kaplan-Meier survival analysis, black race was associated with worse recurrence-free survival (P = 0.01) when compared with white race. In multivariate Cox regression model including treatment and stage, race was no longer associated with survival. In a separate multivariate analysis, utilization of neoadjuvant chemotherapy was associated with black race (odds ratio 4.03; 95% confidence interval, 1.56-10.38; P < 0.01) and stage IV disease (odds ratio 3.44; 95% confidence interval, 1.66-7.12; P < 0.01).

Conclusions: In a racially/ethnically diverse population with ovarian cancer, black women had poorer disease-free survival than whites, although this was statistically accounted for by stage at diagnosis and use of neoadjuvant therapy. Research is needed to determine how differences in access/utilization of care and genetic differences in tumor biology may impact late stage diagnosis and use of neoadjuvant chemotherapy among black ovarian cancer patients.
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http://dx.doi.org/10.1097/IGC.0000000000001238DOI Listing
May 2018

New methods for estimating follow-up rates in cohort studies.

BMC Med Res Methodol 2017 Dec 1;17(1):155. Epub 2017 Dec 1.

Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.

Background: The follow-up rate, a standard index of the completeness of follow-up, is important for assessing the validity of a cohort study. A common method for estimating the follow-up rate, the "Percentage Method", defined as the fraction of all enrollees who developed the event of interest or had complete follow-up, can severely underestimate the degree of follow-up. Alternatively, the median follow-up time does not indicate the completeness of follow-up, and the reverse Kaplan-Meier based method and Clark's Completeness Index (CCI) also have limitations.

Methods: We propose a new definition for the follow-up rate, the Person-Time Follow-up Rate (PTFR), which is the observed person-time divided by total person-time assuming no dropouts. The PTFR cannot be calculated directly since the event times for dropouts are not observed. Therefore, two estimation methods are proposed: a formal person-time method (FPT) in which the expected total follow-up time is calculated using the event rate estimated from the observed data, and a simplified person-time method (SPT) that avoids estimation of the event rate by assigning full follow-up time to all events. Simulations were conducted to measure the accuracy of each method, and each method was applied to a prostate cancer recurrence study dataset.

Results: Simulation results showed that the FPT has the highest accuracy overall. In most situations, the computationally simpler SPT and CCI methods are only slightly biased. When applied to a retrospective cohort study of cancer recurrence, the FPT, CCI and SPT showed substantially greater 5-year follow-up than the Percentage Method (92%, 92% and 93% vs 68%).

Conclusions: The Person-time methods correct a systematic error in the standard Percentage Method for calculating follow-up rates. The easy to use SPT and CCI methods can be used in tandem to obtain an accurate and tight interval for PTFR. However, the FPT is recommended when event rates and dropout rates are high.
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http://dx.doi.org/10.1186/s12874-017-0436-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709923PMC
December 2017

Associations of Insulin Resistance and Glycemia With Liver Enzymes in Hispanic/Latino Youths: Results From the Hispanic Community Children's Health Study/Study of Latino Youth (SOL Youth).

J Clin Gastroenterol 2019 02;53(2):e46-e53

Department of Epidemiology and Population Health.

Background: Associations of insulin resistance and hyperglycemia with a panel of liver enzymes have not been well studied in a young, heterogenous Hispanic/Latino population. We aimed to assess the associations of insulin resistance and glycemia with nonalcoholic fatty liver disease (NAFLD), as measured by liver enzymes and the pediatric NAFLD fibrosis index (PNFI), and whether these associations are modified by body mass index and mediated by inflammation or endothelial dysfunction.

Materials And Methods: We conducted a cross-sectional study of 1317 boys and girls aged 8 to 16 years from the Hispanic Community Children's Health Study/Study of Latino Youth. We used Poisson regression to assess the associations of fasting glucose, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) with elevated alanine aminotransferase (ALT) (>25 U/L in boys, >22 U/L in girls), aspartate aminotransferase (AST) (≥37 U/L), gamma-glutamyl transpeptidase (GGT) (≥17 U/L), and PNFI (≥9; a function of age, waist circumference, and triglyceride level).

Results: HOMA-IR was associated with elevated ALT, AST, GGT, and PNFI [prevalence ratios (95% confidence intervals) for each 1-unit increase in the natural log of HOMA-IR: 1.99 (1.40-2.81), 2.15 (1.12-4.12), 1.70 (1.26-2.30), and 1.98 (1.43-2.74), respectively]. Associations were observed in overweight/obese children, but not in normal weight children (P-interaction=0.04 for AST and P-interaction=0.07 for GGT). After further adjustment for adiponectin, high-sensitivity C-reactive protein, e-selectin, and PAI-1, associations of HOMA-IR with liver enzymes and PNFI were attenuated, but remained statistically significant for AST and PNFI.

Conclusion: Insulin resistance was associated with NAFLD in overweight/obese Hispanic/Latino youth, and this association may be partially mediated by inflammation and endothelial dysfunction.
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http://dx.doi.org/10.1097/MCG.0000000000000946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934331PMC
February 2019

The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study.

J Clin Endocrinol Metab 2017 12;102(12):4541-4547

Department of Epidemiology and Population Health, Albert Einstein College of Medicine.

Context: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I.

Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults.

Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged ≥65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates.

Setting: General community.

Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up.

Interventions: Not applicable.

Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) ≥126 mg/dL, non-FPG ≥200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare & Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx.

Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes.

Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.
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http://dx.doi.org/10.1210/jc.2017-01273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718696PMC
December 2017

Generalized linear mixed model for binary outcomes when covariates are subject to measurement errors and detection limits.

Stat Med 2018 Jan 5;37(1):119-136. Epub 2017 Oct 5.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.

Longitudinal measurement of biomarkers is important in determining risk factors for binary endpoints such as infection or disease. However, biomarkers are subject to measurement error, and some are also subject to left-censoring due to a lower limit of detection. Statistical methods to address these issues are few. We herein propose a generalized linear mixed model and estimate the model parameters using the Monte Carlo Newton-Raphson (MCNR) method. Inferences regarding the parameters are made by applying Louis's method and the delta method. Simulation studies were conducted to compare the proposed MCNR method with existing methods including the maximum likelihood (ML) method and the ad hoc approach of replacing the left-censored values with half of the detection limit (HDL). The results showed that the performance of the MCNR method is superior to ML and HDL with respect to the empirical standard error, as well as the coverage probability for the 95% confidence interval. The HDL method uses an incorrect imputation method, and the computation is constrained by the number of quadrature points; while the ML method also suffers from the constrain for the number of quadrature points, the MCNR method does not have this limitation and approximates the likelihood function better than the other methods. The improvement of the MCNR method is further illustrated with real-world data from a longitudinal study of local cervicovaginal HIV viral load and its effects on oncogenic HPV detection in HIV-positive women.
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http://dx.doi.org/10.1002/sim.7509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720942PMC
January 2018

Methodological considerations for disentangling a risk factor's influence on disease incidence versus postdiagnosis survival: The example of obesity and breast and colorectal cancer mortality in the Women's Health Initiative.

Int J Cancer 2017 12 31;141(11):2281-2290. Epub 2017 Aug 31.

Division of Research, Oakland, Kaiser Permanente Northern California, CA.

Often, studies modeling an exposure's influence on time to disease-specific death from study enrollment are incorrectly interpreted as if based on time to death from disease diagnosis. We studied 151,996 postmenopausal women without breast or colorectal cancer in the Women's Health Initiative with weight and height measured at enrollment (1993-1998). Using Cox regression models, we contrast hazard ratios (HR) from two time-scales and corresponding study subpopulations: time to cancer death after enrollment among all women and time to cancer death after diagnosis among only cancer survivors. Median follow-up from enrollment to diagnosis/censoring was 13 years for both breast (7,633 cases) and colorectal cancer (2,290 cases). Median follow-up from diagnosis to death/censoring was 7 years for breast and 5 years for colorectal cancer. In analyses of time from enrollment to death, body mass index (BMI) ≥ 35 kg/m versus 18.5-<25 kg/m was associated with higher rates of cancer mortality: HR = 1.99; 95% CI: 1.54, 2.56 for breast cancer (p trend <0.001) and HR = 1.40; 95% CI: 1.04, 1.88 for colorectal cancer (p trend = 0.05). However, in analyses of time from diagnosis to cancer death, trends indicated no significant association (for BMI ≥ 35 kg/m , HR = 1.25; 95% CI: 0.94, 1.67 for breast [p trend = 0.33] and HR = 1.18; 95% CI: 0.84, 1.86 for colorectal cancer [p trend = 0.39]). We conclude that a risk factor that increases disease incidence will increase disease-specific mortality. Yet, its influence on postdiagnosis survival can vary, and requires consideration of additional design and analysis issues such as selection bias. Quantitative tools allow joint modeling to compare an exposure's influence on time from enrollment to disease incidence and time from diagnosis to death.
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http://dx.doi.org/10.1002/ijc.30931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761345PMC
December 2017

Cancer risk in people living with HIV.

Lancet HIV 2017 11 10;4(11):e477-e479. Epub 2017 Aug 10.

Albert Einstein College of Medicine, Bronx, NY, USA.

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http://dx.doi.org/10.1016/S2352-3018(17)30147-9DOI Listing
November 2017

Relationship of Genotype for HLA B*57 and IFNL4 With Disease Progression in Female HIV Controllers.

Clin Infect Dis 2017 10;65(7):1243-1244

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

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http://dx.doi.org/10.1093/cid/cix481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848247PMC
October 2017

Cervical cancer screening intervals and management for women living with HIV: a risk benchmarking approach.

AIDS 2017 04;31(7):1035-1044

aJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland bAlbert Einstein College of Medicine, Bronx, New York City, New York cWashington University School of Medicine, St. Louis, Missouri dUniversity of California, San Francisco, San Francisco, California eMaimonides Medical Center, Brooklyn, New York City, New York fUniversity of Miami Miller School of Medicine, Miami, Florida gGrady Memorial Hospital and Emory University School of Medicine, Atlanta, Georgia hUniversity of North Carolina School of Medicine, Chapel Hill, North Carolina iUniversity of Southern California, Los Angeles, California jUniversity of Alabama at Birmingham School of Public Health, Birmingham, Alabama kGeorgetown University Medical Center, Washington DC, USA.

Objective: We suggested cervical cancer screening strategies for women living with HIV (WLHIV) by comparing their precancer risks to general population women, and then compared our suggestions with current Centers for Disease Control and Prevention (CDC) guidelines.

Design: We compared risks of biopsy-confirmed cervical high-grade squamous intraepithelial neoplasia or worse (bHSIL+), calculated among WLHIV in the Women's Interagency HIV Study, to 'risk benchmarks' for specific management strategies in the general population.

Methods: We applied parametric survival models among 2423 WLHIV with negative or atypical squamous cell of undetermined significance (ASC-US) cytology during 2000-2015. Separately, we synthesized published general population bHSIL+ risks to generate 3-year risk benchmarks for a 3-year return (after negative cytology, i.e. 'rescreening threshold'), a 6-12-month return (after ASC-US), and immediate colposcopy [after low-grade squamous intraepithelial lesion (LSIL)].

Results: Average 3-year bHSIL+ risks among general population women ('risk benchmarks') were 0.69% for a 3-year return (after negative cytology), 8.8% for a 6-12-month return (after ASC-US), and 14.4% for colposcopy (after LSIL). Most CDC guidelines for WLHIV were supported by comparing risks in WLHIV to these benchmarks, including a 3-year return with CD4 greater than 500 cells/μl and after either three negative cytology tests or a negative cytology/oncogenic human papillomavirus cotest (all 3-year risks≤1.3%); a 1-year return after negative cytology with either positive oncogenic human papillomavirus cotest (1-year risk = 1.0%) or CD4 cell count less than 500 cells/μl (1-year risk = 1.1%); and a 6-12-month return after ASC-US (3-year risk = 8.2% if CD4 cell count at least 500 cells/μl; 10.4% if CD4 cell count = 350-499 cells/μl). Other suggestions differed modestly from current guidelines, including colposcopy (vs. 6-12 month return) for WLHIV with ASC-US and CD4 cell count less than 350 cells/μl (3-year risk = 16.4%) and a lengthened 2-year (vs. 1-year) interval after negative cytology with CD4 cell count at least 500 cells/μl (2-year risk = 0.98%).

Conclusions: Current cervical cancer screening guidelines for WLHIV are largely appropriate. CD4 cell count may inform risk-tailored strategies.
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http://dx.doi.org/10.1097/QAD.0000000000001450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531443PMC
April 2017

Survival Deficit for HIV-Infected Lymphoma Patients in the National Cancer Database.

Cancer Epidemiol Biomarkers Prev 2017 03;26(3):289-290

Division of Epidemiology, Albert Einstein College of Medicine, Bronx, New York.

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http://dx.doi.org/10.1158/1055-9965.EPI-17-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340270PMC
March 2017

Influence of Fasting Status and Sample Preparation on Metabolic Biomarker Measurements in Postmenopausal Women.

PLoS One 2016 8;11(12):e0167832. Epub 2016 Dec 8.

International Agency for Research on Cancer, Lyon, France.

Background: Epidemiologic data linking metabolic markers-such as insulin, insulin-like growth factors (IGFs)-and adipose tissue-derived factors with cancer are inconsistent. Between-study differences in blood collection protocols, in particular participant's fasting status, may influence measurements.

Methods: We investigated the impact of fasting status and blood sample processing time on components of the insulin/IGF axis and in adipokines in a controlled feeding study of 45 healthy postmenopausal-women aged 50-75 years. Fasting blood samples were drawn (T0), after which subjects ate a standardized breakfast; subsequent blood draws were made at 1 hour (T1), 3 hours (T3), and 6 hours (T6) after breakfast. Serum samples were assayed for insulin, C-peptide, total- and free-IGF-I, IGF-binding protein [BP]-1 and -3, total and high molecular weight (HMW)-adiponectin, retinol binding protein-4, plasminogen activator inhibitor (PAI)-1, and resistin.

Results: Insulin and C-peptide levels followed similar postprandial trajectories; intra-class correlation coefficients [ICC] for insulin = 0.75, (95%CI:0.64-0.97) and C-peptide (ICC = 0.66, 95%CI:0.54-0.77) were similarly correlated in fasting (Spearman correlation, r = 0.78, 95%CI:0.64-0.88) and postprandial states (T1, r = 0.77 (95%CI: 0.62-0.87); T3,r = 0.78 (95%CI: 0.63-0.87); T6,r = 0.77 (95%CI: 0.61-0.87)). Free-IGF-I and IGFBP-1 levels were also affected by fasting status, whereas total-IGF-I and IGFBP-3 levels remained unchanged. Levels of adipokines were largely insensitive to fasting status and blood sample processing delays.

Conclusion: Several components of the insulin/IGF axis were significantly impacted by fasting state and in particular, C-peptide levels were substantially altered postprandially and in a similar manner to insulin.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167832PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145182PMC
July 2017

Reproductive and menstrual factors and colorectal cancer incidence in the Women's Health Initiative Observational Study.

Br J Cancer 2017 01 29;116(1):117-125. Epub 2016 Nov 29.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.

Background: Reproductive and menstrual factors have been evaluated as surrogates for long-term hormonal exposures in several prospective studies of colorectal cancer, yet findings have been conflicting.

Methods: The relation of reproductive and menstrual factors (self-reported via a reproductive history questionnaire) with incident colorectal cancer was investigated among women enrolled in the Women's Health Initiative Observational Study (WHI-OS), a longitudinal cohort of 93 676 postmenopausal women (aged 50-79 years at enrolment) in which 1149 incident cases of colorectal cancer occurred over a median follow-up of 11.9 years. Multivariable Cox proportional hazards models that included established colorectal cancer risk factors were constructed to examine the association of colorectal cancer incidence with reproductive and menstrual factors.

Results: Having had two children (vs nulliparous: hazard ratio (HR)=0.80, 95% confidence interval (CI): 0.64-0.99) was inversely associated with colorectal cancer risk. Compared with never users, ever use of oral contraceptives was associated with lower colorectal cancer risk (HR=0.74, 95% CI: 0.63-0.86); however, no relationship was observed for duration of oral contraceptives use (4 years vs 1 year: HR=0.94, 95% CI: 0.67-1.32). None of the remaining reproductive and menstrual factors was associated with colorectal cancer incidence.

Conclusions: Parity and prior use of oral contraceptives were associated with lower colorectal cancer risk in this cohort of postmenopausal women.
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http://dx.doi.org/10.1038/bjc.2016.345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220139PMC
January 2017