Estimation of random effects and identifying heterogeneous genes in meta-analysis of gene expression studies.

Combining effect sizes from individual studies using random-effects meta-analysis models are commonly applied in high-dimensional gene expression data. However, unknown study heterogeneity can arise from inconsistencies in sample quality and experimental conditions. High heterogeneity of effect sizes can reduce statistical power of the models. In this study, we describe three hypothesis-testing frameworks for meta-analysis of microarray data, and review several existing meta-analytic techniques that have been used in the genomic setting. These include P-value-based methods, rank-based methods and effect-size-based methods. We then discuss limitations of some of these methods and describe random-effects-based methods in detail. We introduce two methods for estimating the inter-study variance in random-effects meta-analytic models and another method for identifying heterogeneous genes for gene expression data. We compared various methods with the standard and existing meta-analytic techniques in the genomic framework. We demonstrate our results through a series of simulations and application in Alzheimer's gene expression data.

Patient Comorbidity and Serious Adverse Events after Outpatient Colonoscopy: Population-based Study From Three States, 2006 to 2009.

BACKGROUND AND OBJECTIVE: Serious GI adverse events in the outpatient setting were examined for patients with a full spectrum of comorbid conditions and combinations of multiple comorbidities. DESIGN: This is a retrospective follow-up study. SETTING: Ambulatory surgery and hospital discharge data sets from California, Florida, and New York, 2006 to 2009, were used. PATIENTS: The outpatient colonoscopies of 4,234,084 adults aged 19 to 85 and over and payers were examined. MAIN OUTCOME: Thirty-day hospitalizations due to colonic perforations and GI bleeding, measured as cumulative outcomes, were investigated. RESULTS: About 24% of patients undergoing outpatient colonoscopy had a comorbid condition. In comparison with patients without comorbidities, the adjusted risks of adverse events were greater for patients with several single comorbidities and combinations of multiple comorbid conditions. Elderly patients and those treated in freestanding Ambulatory Surgery Centers had higher odds of colonic perforations and GI bleeding than younger patients and patients treated in hospital outpatient departments. LIMITATION: The study was constrained by limitations inherent in administrative data. CONCLUSIONS: Given the large number of outpatient colonoscopies performed in the United States, these procedures should be provided with caution to patients with chronic and multiple comorbidities and the elderly, because these populations are associated with higher rates of colonic perforations and GI bleeding.

Delivery system characteristics and their association with quality and costs of care: implications for accountable care organizations.

BACKGROUND: Implementation of accountable care organizations (ACOs) is currently underway, but there is limited empirical evidence on the merits of the ACO model. PURPOSE: The aim was to study the associations between delivery system characteristics and ACO competencies, including centralization strategies to manage organizations, hospital integration with physicians and outpatient facilities, health information technology, infrastructure to monitor community health and report quality, and risk-adjusted 30-day all-cause mortality and case-mixed-adjusted inpatient costs for the Medicare population. METHODOLOGY: Panel data (2006-2009) were assembled from Florida and multiple sources: inpatient hospital discharge, vital statistics, the American Hospital Association, the Healthcare Information and Management Systems Society, and other databases. We applied a panel study design, controlling for hospital and market characteristics. PRINCIPAL FINDINGS: Hospitals that were in centralized health systems or became more centralized over the study period had significantly larger reductions in mortality compared with hospitals that remained freestanding. Surprisingly, tightly integrated hospital-physician arrangements were associated with increased mortality; as such, hospitals may wish to proceed cautiously when developing specific types of alignment with local physician organizations. We observed no statistically significant differences in the growth rate of costs across hospitals in any of the health systems studied relative to freestanding hospitals. Although we observed quality improvement in some organizational types, these outcome improvements were not coupled with the additional desired objective of lower cost growth. This implies that additional changes not present during our study period, potentially changes in provider payment approaches, are essential for achieving the ACO objectives of higher quality of care at lower costs. PRACTICE IMPLICATIONS: Provider organizations implementing ACOs should consider centralizing service delivery as a viable strategy to improve quality of care, although the strategy did not result in lower cost growth.

Polypectomy techniques, endoscopist characteristics, and serious gastrointestinal adverse events.

BACKGROUND: A use of polypectomy techniques by endoscopist specialty (primary care, surgery, and gastroenterology) and experience (volume), and associations with serious gastrointestinal adverse events, were examined. METHODS: A retrospective follow-up study with ambulatory surgery and hospital discharge datasets from Florida, 1999-2001, was used. Thirty-day hospitalizations due to colonic perforations and gastrointestinal bleeding were investigated for 323,585 patients. RESULTS: Primary care endoscopists and surgeons used hot biopsy forceps/ablation, while gastroenterologists provided snare polypectomy or complex colonoscopy. Low-volume endoscopists were more likely to use simpler rather than complex procedures. For hot forceps/ablation and snare polypectomy, low- and medium-volume endoscopists reported higher odds of adverse events. For complex colonoscopy, higher odds of adverse events were reported for primary care endoscopists (1.74 [95% CI, 1.18-2.56]) relative to gastroenterologists. CONCLUSIONS: Endoscopists regardless of specialty and experience can safely use cold biopsy forceps. For hot biopsy and snare polypectomy, low volume, but not specialty, contributed to increased odds of adverse events. For complex colonoscopy, primary care specialty, but not low volume, added to the odds of adverse events. Comparable outcomes were reported for surgeons and gastroenterologists. Cross-training and continuing medical education of primary care endoscopists in high-volume endoscopy settings are recommended for complex colonoscopy procedures.

Association of polypectomy techniques, endoscopist volume, and facility type with colonoscopy complications.

BACKGROUND AND OBJECTIVE: Serious GI adverse events in the outpatient setting were examined by polypectomy technique, endoscopist volume, and facility type (ambulatory surgery center and hospital outpatient department). DESIGN: Retrospective follow-up study. SETTING: Ambulatory surgery and hospital discharge datasets from Florida (1997-2004) were used. PATIENTS: A total of 2,315,126 outpatient colonoscopies performed in patients of all ages and payers were examined. MAIN OUTCOME: Thirty-day hospitalizations because of colonic perforations and GI bleeding, measured as cumulative and specific outcomes, were investigated. RESULTS: Compared with simple colonoscopy, the adjusted risks of cumulative adverse events were greater with the use of cold forceps (1.21 [95% CI, 1.01-1.44]), ablation (3.75 [95% CI, 2.97-4.72]), hot forceps (5.63 [95% CI, 4.97-6.39]), snares (7.75 [95% CI, 6.95-8.64]), or complex colonoscopy (8.83 [95% CI, 7.70-10.12]). Low-volume endoscopists had higher risks of adverse events (1.18 [95% CI, 1.07-1.30]). A higher risk of adverse events was associated with procedures performed in ambulatory surgery centers (1.27 [95% CI, 1.16-1.40]). Important findings were also reported for the analyses stratified by specific outcomes and procedures. LIMITATION: The study was constrained by limitations inherent in administrative data pertaining to a single state. CONCLUSIONS: As the complexity of polypectomy increases, a higher risk of adverse events is reported. Using lower risk procedures when clinically appropriate or referring patients to high-volume endoscopists can reduce the rates of perforations and GI bleeding. Given the large number of colonoscopies performed in the United States, it is critical that the rates of adverse events be considered when choosing procedures.

HIV risk behavior among HIV-infected men who have sex with men in Bangkok, Thailand.

We assessed prevalence of sexually transmitted infection (STIs), sexual risk behaviors, and factors associated with risk behaviors among HIV-infected MSM attending a public STI clinic serving MSM in Bangkok, Thailand. Between October 2005-October 2007, 154 HIV-infected MSM attending the clinic were interviewed about sexual risk behaviors and evaluated for STIs. Patients were examined for genital ulcers and had serologic testing for syphilis and PCR testing for chlamydia and gonorrhea. Results showed that sexual intercourse in the last 3 months was reported by 131 men. Of these, 32% reported anal sex without a condom. STIs were diagnosed in 41%. Factors associated with having sex without a condom were having a steady male partner, having a female partner and awareness of HIV status <1 month. Sexual risk behaviors and STIs were common among HIV-infected MSM in this study. This highlights the need for increased HIV prevention strategies for HIV-infected MSM.

High virologic response rate after second-line boosted protease inhibitor-based antiretroviral therapy regimens in children from a resource limited setting.

BACKGROUND: Limited data exist for the efficacy of second-line antiretroviral therapy among children in resource limited settings. We assessed the virologic response to protease inhibitor-based ART after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. METHODS: A retrospective chart review was conducted at 8 Thai sites of children who switched to PI -based regimens due to failure of NNRTI -based regimens. Primary endpoints were HIV RNA < 400 copies/ml and CD4 change over 48 weeks. RESULTS: Data from 241 children with median baseline values before starting PI-based regimens of 9.1 years for age, 10% for CD4%, and 4.8 log10 copies/ml for HIV RNA were included; 104 (41%) received a single ritonavir-boosted PI (sbPI) with 2 NRTIs and 137 (59%) received double-boosted PI (dbPI) with/without NRTIs based on physician discretion. SbPI children had higher baseline CD4 (17% vs. 6%, p < 0.001), lower HIV RNA (4.5 vs. 4.9 log10 copies/ml, p < 0.001), and less frequent high grade multi-NRTI resistance (12.4% vs 60.5%, p < 0.001) than the dbPI children. At week 48, 81% had HIV RNA < 400 copies/ml (sbPI 83.1% vs. dbPI 79.8%, p = 0.61) with a median CD4 rise of 9% (+7%vs. + 10%, p < 0.005). However, only 63% had HIV RNA < 50 copies/ml, with better viral suppression seen in sbPI (76.6% vs. 51.4%, p 0.002). CONCLUSION: Second-line PI therapy was effective for children failing first line NNRTI in a resource-limited setting. DbPI were used in patients with extensive drug resistance due to limited treatment options. Better access to antiretroviral drugs is needed.

Neurocognitive impairment and psychiatric comorbidity in well-controlled human immunodeficiency virus-infected Thais from the 2NN Cohort Study.

This research is a cross-sectional study to determine the frequency of neurocognitive impairment and psychiatric comorbidity among Thais maintained on highly active antiretroviral therapy (HAART) with undetectable plasma human immunodeficiency virus (HIV) RNA in the 2NN Cohort. Sixty-four subjects were evaluated with neurological examinations, neuropsychological testing, and psychiatric questionnaires. Twenty-four subjects (37.5%) were found to have neurocognitive impairment, with 13 (20.3%), 10 (15.6%), and 1 (1.6%) classified as asymptomatic neurocognitive disorder (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD), respectively. Three subjects (4.7%) had depression and no cases had significant symptoms of anxiety. A notable proportion of well-controlled individuals exhibited neurocognitive impairment. Anxiety and depression were uncommon.

External quality assessment program on CD4+ T-lymphocyte counts for persons with HIV/AIDS in Thailand: history and accomplishments.

A CD4 count External Quality Assessment (EQA) program is important for the clinical monitoring of persons infected with HIV/AIDS. The purpose of the present study was to evaluate the CD4 EQA performance program of the flow cytometer laboratories that perform routine CD4 counts for these patients in Thailand. Stabilized whole blood samples were sent to participating laboratories to determine the percentage and absolute counts of CD4+ T-lymphocytes using their routine procedures. The data were analyzed and reports sent to the participants within one month. Most participating laboratories produced results that were within two standard deviations (SD) of the mean, while the average inter-laboratory coefficients of variation were less than 8% for CD4+ T-lymphocytes. This program was found to improve the reliability of CD4+ T-lymphocyte determinations. This test is becoming increasingly important as Thailand and other Southeast Asian countries scale up their national programs that provide access to antiretroviral therapy for persons living with HIV/AIDS.

A feasibility study of immediate versus deferred antiretroviral therapy in children with HIV infection.

OBJECTIVE: To evaluate the feasibility of a large immediate versus deferred antiretroviral therapy (ART) study in children. METHODS: We conducted an open-label pilot randomized clinical trial study in 43 Thai children with CD4 15 to 24% of starting generic AZT/3TC/NVP immediately (Arm 1) or deferring until CD4 < 15% or CDC C (Arm 2). Primary endpoints were recruitment rate, adherence to randomized treatment and retention in trial. Secondary endpoints were % with CDC C or CD4 < 15%. Children were in the trial until the last child reached 108 weeks. Intention to treat and on treatment analyses were performed. RESULTS: Recruitment took 15 months. Twenty-six of 69 (37.7%) were not eligible due mainly to low CD4%. Twenty four and 19 were randomized to arms 1 and 2 respectively. All accepted the randomized arm; however, 3 in arm 1 stopped ART and 1 in arm 2 refused to start ART. Ten/19 (53%) in arm 2 started ART. At baseline, median age was 4.8 yrs, CDC A:B were 36:7, median CD4 was 19% and viral load was 4.8 log. All in arm 1 and 17/19 in arm 2 completed the study (median of 134 weeks). No one had AIDS or death. Four in immediate arm had tuberculosis. Once started on ART, deferred arm children achieved similar CD4 and viral load response as the immediate arm. Adverse events were similar between arms. The deferred arm had a 26% ART saving. CONCLUSION: Almost 40% of children were not eligible due mainly to low CD4% but adherence to randomized treatment and retention in trial were excellent. A larger study to evaluate when to start ART is feasible.

Comparison of Low Back Pain Recovery and Persistence: A Descriptive Study of Characteristics at Pain Onset.

BACKGROUND: Persistent low back pain is a significant problem worldwide. Early identification and treatment of individuals at high risk for persistent low back pain have been suggested as strategies to decrease the rate of disability associated with this condition. PURPOSE: To examine and compare demographic, pain-related, psychological, and somatosensory characteristics in a cohort of participants with acute low back pain who later went on to experience persistent low back pain or whose pain resolved within the first 6 weeks after initial onset. METHODS: A descriptive study was conducted among men and women 18-50 years of age who had an acute episode of low back pain. Study questionnaires were administered to collect demographic information and measures of pain, coping, reactivity, mood, work history and satisfaction, and disability. A standardized protocol of quantitative sensory testing was performed on each participant at the painful area of their low back and at a remote site on their arm. RESULTS: The sample consisted of 48 participants, of whom 19 went on to develop persistent low back pain and 29 resolved. Compared to the resolved group, the persistent low back pain group was significantly older and had a lower level of educational attainment, a higher body mass index, and higher mean "least" pain score on the Brief Pain Inventory-Short Form. Significantly higher thermal detection thresholds at the painful and remote sites as well as signs of central sensitivity differentiated the persistent pain group from the resolved group during the acute stage of low back pain.

Acute Low Back Pain: Differential Somatosensory Function and Gene Expression Compared With Healthy No-Pain Controls.

OBJECTIVES: Low back pain (LBP) is the second most frequently diagnosed pain condition in the United States, and although a majority of individuals have resolution of pain during the acute period, an estimated 40% of individuals will experience persistent pain. Given the heterogenous nature of LBP, this study sought to describe and compare somatosensory and molecular (gene expression) profiles between individuals with acute LBP and healthy no-pain controls. METHODS: Using a previously established protocol, we comprehensively assessed somatosensory parameters among 31 no-pain control participants and 31 participants with acute LBP. Samples of whole blood were drawn to examine mRNA expression of candidate genes involved in the transduction, maintenance, and modulation of pain. RESULTS: The acute LBP group exhibited increased pain sensitivity to cold stimuli, mechanical stimuli, including mechanical temporal summation at both the painful back area and remote location suggesting a mechanism of enhanced central nervous system excitability. In addition, deep tissue-specific peripheral sensitization was suggested due to significant differences in pressure pain threshold of the painful back area, but not the remote body site. Several genes that were differentially expressed were significantly associated with somatosensory alterations identified in the acute LBP group. DISCUSSION: Acute LBP participants showed selective pain sensitivity enhancement and differential gene expression profiles compared with pain-free controls. Further research to characterize pain-associated somatosensory changes in the context of altered mRNA expression levels may provide insight on the molecular underpinnings of maladaptive chronic pain.

Incidence and risk factors for rash in Thai patients randomized to regimens with nevirapine, efavirenz or both drugs.

OBJECTIVE: To determine the incidence and risk factors for rash in Thai patients taking four different non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. METHODS: HIV-positive, antiretroviral-naive patients enrolled in the 2NN study in Thailand and followed for at least 1 week were included. Patients were randomized to efavirenz (EFV) 600 mg once daily (OD) versus nevirapine (NVP) 200 mg twice daily (BD) versus NVP 400 mg OD versus NVP 400 mg OD + EFV 800 mg OD with stavudine/lamivudine. RESULTS: Of 202 patients, 95 (47%) and 69 (34.2%) developed a rash from all reasons and from NNRTI, respectively. For NNRTI-related rash the incidences were EFV (20%), NVP BD (21%), NVP OD (38%) and NVP + EFV (67%). The proportions of patients with grade I, II and III within the four treatment arms are as follows: EFV, 4.3, 13 and 2.9%; NVP BD, 2.3, 15.9 and 2.3%; NVP OD, 12.8, 19.1 and 6.4%; and NVP + EFV, 11.9, 47.6 and 7.1%. Multivariate analyses showed females with CD4 cell count > or =250 x 10 cells/l, high body mass index (>21.3 kg/m), and a rise in CD4 (> or =53 x 10 cells/l) and alanine aminotransferase (ALT) (> or =34 U/l) at week 4 to be risk factors for rash. CONCLUSIONS: Thai patients had a high incidence of NNRTI-related rash when treated with NVP + EFV or NVP OD. NVP if used BD had the same rash incidence as EFV for rash of all grades. Females, and persons with earlier HIV disease or with a large rise in CD4+ cell count after starting therapy are at greater risk for NNRTI-related rash.

Development of HIV with drug resistance after CD4 cell count-guided structured treatment interruptions in patients treated with highly active antiretroviral therapy after dual-nucleoside analogue treatment.

BACKGROUND: For patients with human immunodeficiency virus (HIV) infection, structured treatment interruption (STI) is an attractive alternative strategy to continuous treatment, particularly in resource-restrained settings, because it reduces both side effects and costs. One major concern, however, is the development of resistance to antiretroviral drugs that can occur during multiple cycles of starting and stopping therapy. METHODS: HIV genotypic drug resistance was investigated in 20 HIV-infected Thai patients treated with highly active antiretroviral therapy (HAART) and CD4 cell count-guided STI after dual nucleoside reverse-transcriptase inhibitor (NRTI) treatment. Resistance was tested at the time of the switch from dual-NRTI treatment to HAART and when HAART was stopped during the last interruption. RESULTS: After STI, one major drug-resistance mutation occurred (T215Y), and, in the 4 samples with preexisting major mutations (D67N [n=2], K70R [n=2], T215Y [n=2], and T215I [n=1]), the mutations disappeared. All mutations in the HIV protease gene were minor mutations already present, in most cases, before STI was started, and their frequency was not increased through STI, whereas the frequency of reverse-transcriptase gene mutations significantly decreased after the interruptions. After the 48-week study period, no patients had virological failure. Long-term follow-up (108 weeks) showed 1 case of virological failure in the STI arm and 1 in the continuous arm. No virological failure was seen in patients with major mutations. CONCLUSIONS: Major HIV drug-resistance mutations were not induced through CD4 cell count-guided treatment interruptions in HIV-infected patients successfully treated with HAART after dual-NRTI therapy.

Resistance to dual nucleoside reverse-transcriptase inhibitors in children infected with HIV clade A/E.

The prevalence of nucleoside reverse-transcriptase inhibitor (NRTI) mutations was determined among 95 human immunodeficiency virus-infected Thai children who were treated with dual nucleoside reverse-transcriptase inhibitors. Almost all children had resistance to at least 1 NRTI, and approximately half of the children had resistance to multiple NRTIs. Cross-resistance to stavudine and azidothymidine was universal.

A prospective study of efficacy and safety of once-daily saquinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors in treatment-naive Thai patients.

OBJECTIVE: To assess the efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir with two nucleoside reverse transcriptase inhibitors (NRTIs), as induction therapy before enrollment in a randomized trial of structured treatment interruption strategies. DESIGN: Two-hundred antiretroviral-naive patients with CD4+ cell counts between 200-350 at screening were enrolled in this open-label 24week study. METHODS: Patients were followed up every 8 weeks for CD4+ cells, HIV RNA, and clinical and laboratory toxicities. RESULTS: Two-hundred patients were enrolled with median baseline CD4+ cell count of 267 cells/microl and HIV RNA 50 118 (4.7 log10) copies/mi. After 24 weeks of treatment, 191 of 200 (96%) patients had below 400 copies/ml HIV RNA, with 177/200 (89%) below 50 copies/ml (intent to treat, missing equals failure method), with a median rise in CD4+ cell count of 122 cells/microl. There was no significant correlation between the minimum concentration of saquinavir and HIV RNA reductions at week 8 (P = 0.957) or absolute HIV RNA at week 24 (P = 0.77). CONCLUSION: First-line highly active antiretroviral therapy (HAART) with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy over 24 weeks, and should be evaluated in larger prospective randomized clinical trials.

Pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children.

OBJECTIVE: To assess the pharmacokinetics and 24-week efficacy and safety of dual boosted saquinavir/lopinavir/ritonavir combination in children. DESIGN: Twenty reverse transcription inhibitor-pretreated children at 2 centers in Thailand were treated with saquinavir/lopinavir/ritonavir in an open label, single arm, 6-month prospective study. The dosage was 50 mg/kg twice daily (bid) for saquinavir and 230/57.5 mg/m bid for lopinavir/ritonavir. Ten children also received lamivudine. METHODS: Samples were collected for a 12-hour pharmacokinetic profile in all children. Plasma concentrations of saquinavir, lopinavir and ritonavir were determined using a validated high performance liquid chromatography technique. RESULTS: At baseline, the median age was 8.5 years, with human immunodeficiency virus (HIV) RNA 4.9 log10 copies/mL, CD4 count 129 cells/microL and CD4%, 6.5%. Median area under the concentration curve at 0-12 hours and Cmin were 39.4 mg/L.h and 1.4 mg/L for saquinavir and 118 mg/L.hr and 5.9 mg/L for lopinavir. After 24 weeks of treatment, HIV RNA was suppressed below 400 copies/mL for 16 of 20 (80%) children (intent-to-treat analysis) and below 50 copies/mL for 12 of 20 children (60%), and CD4% (count) rose by a median of 6% (216 cells/microL). Median changes of triglyceride and total cholesterol were 56 and 36.5 mg/dL, respectively (P = 0.01). Lopinavir Cmin <1 and saquinavir Cmin <0.28 mg/L correlated with HIV RNA >400 copies/mL, and lopinavir Cmax >15 mg/L correlated with rises in cholesterol (P < 0.05). CONCLUSION: Plasma drug concentrations of saquinavir, lopinavir and ritonavir were at the higher limits of expected ranges for adult treatment at approved dosages (1000/100 mg bid for saquinavir, 400/100 mg bid for lopinavir/ritonavir). The regimen was well-tolerated and had good efficacy at 24 weeks. This dual boosted protease inhibitor combination should be assessed in larger trials of reverse transcription inhibitor-experienced children.

No effect of interleukin-2 on IgE levels given in addition to antiretroviral therapy in HIV-infected adults with CD4 >300 cells/mm3.

HIV-infected patients may have frequent atopy caused by an imbalance of Th1 and Th2 cytokines. The objective of the present study was to investigate whether IL-2 given in addition to antiretrovirals (ARV) would result in lower IgE levels and less allergic symptoms. Patients naive to IL-2 (n=28) began IL-2 plus ARV and were followed for 12 months. IgE, eosinophil and CD4 counts, HIV RNA, symptom scoring, PFT and skin prick test (SPT) were performed. It was found that the baseline median CD4 and IgE were 386.5 cells/mm3 and 63.5 IU/ml, respectively. Four patients had allergic rhinitis (AR) and 61% had a positive SPT to at least 1 antigen. At month 12, patients had higher CD4 counts (p < 0.001) compared to the baseline; however, there were no differences in IgE levels, allergic symptom scores or HIV RNA. The eosinophil count was higher after IL-2 administration. It was concluded that IL-2 plus ARV resulted in higher CD4 counts but had no effect on atopy.

Gene Expression in HIV-Associated Neurocognitive Disorders: A Meta-Analysis.

OBJECTIVES: To identify differentially expressed (DE) genes in HIV-associated neurocognitive disorders (HAND) patients in comparison with HIV-infected patients without HAND and controls. DESIGN: A meta-analysis of publicly available gene expression data from HIV postmortem brain tissue studies. METHODS: We selected studies using clearly defined inclusion and exclusion criteria. Within study data preprocessing and individual analyses were performed for each brain region. The following meta-analytic methods were applied: combining P values, combining effect sizes with and without a permutation method. The DE genes were defined with a false discovery rate less than 5% using Benjamini-Hochberg method. RESULTS: Our meta-analysis on 3 studies encompasses analyses of over 48 postmortem brains [25 HAND, 7 HIV encephalitis (HIVE), 8 HIV-infected patients, and 8 controls]. Overall, 411 genes in white matter were DE in HAND with HIVE patients when comparing with controls. Of these, 94 genes were significantly expressed in all statistical methods. These 94 genes participate in significant pathways such as immune system, interferon response, or antigen presentation. Sixty-six of the 94 genes were significantly upregulated with log2 intensities greater than 2-fold. Strong examples of the highly upregulated genes were PSMB8-AS1, APOL6, TRIM69, PSME1, CTSB, HLA-E, GPNMB, UBE2L6, PSME2, NET1, CAPG, B2M, RPL38, GBP1, and PLSCR1. Only BTN3A2 was expressed in HAND with HIVE patients as compared with HAND patients without HIVE. CONCLUSION: A number of genes were DE in our meta-analysis that were not identified in the individual analyses. The meta-analytic approach has increased statistical power for identifying DE genes in HAND.

Evaluation of the performance of smoothing functions in generalized additive models for spatial variation in disease.

Generalized additive models (GAMs) with bivariate smoothing functions have been applied to estimate spatial variation in risk for many types of cancers. Only a handful of studies have evaluated the performance of smoothing functions applied in GAMs with regard to different geographical areas of elevated risk and different risk levels. This study evaluates the ability of different smoothing functions to detect overall spatial variation of risk and elevated risk in diverse geographical areas at various risk levels using a simulation study. We created five scenarios with different true risk area shapes (circle, triangle, linear) in a square study region. We applied four different smoothing functions in the GAMs, including two types of thin plate regression splines (TPRS) and two versions of locally weighted scatterplot smoothing (loess). We tested the null hypothesis of constant risk and detected areas of elevated risk using analysis of deviance with permutation methods and assessed the performance of the smoothing methods based on the spatial detection rate, sensitivity, accuracy, precision, power, and false-positive rate. The results showed that all methods had a higher sensitivity and a consistently moderate-to-high accuracy rate when the true disease risk was higher. The models generally performed better in detecting elevated risk areas than detecting overall spatial variation. One of the loess methods had the highest precision in detecting overall spatial variation across scenarios and outperformed the other methods in detecting a linear elevated risk area. The TPRS methods outperformed loess in detecting elevated risk in two circular areas.