SPH Biostatistics Papers

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Whole genome sequences of a male and female supercentenarian, ages greater than 114 years
(2011) Sebastiani, Paola; Riva, Alberto; Montano, Monty; Pham, Phillip; Torkamani, Ali; Scherba, Eugene; Benson, Gary; Milton, Jacqueline N.; Baldwin, Clinton T.; Andersen, Stacy; Schork, Nicholas J.; Steinberg, Martin H.; Perls, Thomas T.
Supercentenarians (age 110+ years old) generally delay or escape age-related diseases and disability well beyond the age of 100 and this exceptional survival is likely to be influenced by a genetic predisposition that includes both common and rare genetic variants. In this report, we describe the complete genomic sequences of male and female supercentenarians, both age >114 years old. We show that: (1) the sequence variant spectrum of these two individuals' DNA sequences is largely comparable to existing non-supercentenarian genomes; (2) the two individuals do not appear to carry most of the well-established human longevity enabling variants already reported in the literature; (3) they have a comparable number of known disease-associated variants relative to most human genomes sequenced to-date; (4) approximately 1% of the variants these individuals possess are novel and may point to new genes involved in exceptional longevity; and (5) both individuals are enriched for coding variants near longevity-associated variants that we discovered through a large genome-wide association study. These analyses suggest that there are both common and rare longevity-associated variants that may counter the effects of disease-predisposing variants and extend lifespan. The continued analysis of the genomes of these and other rare individuals who have survived to extremely old ages should provide insight into the processes that contribute to the maintenance of health during extreme aging.
Design of the WHIP-PD study: a phase II, twelve-month, dual-site, randomized controlled trial evaluating the effects of a cognitive-behavioral approach for promoting enhanced walking activity using mobile health technology in people with Parkinson-disease
(2020-04-20) Rawson, K.S.; Cavanaugh, J.T.; Colon-Semenza, C.; DeAngelis, T.; Duncan, R.P.; Fulford, Daniel; LaValley, Michael P.; Mazzoni, P.; Nordahl, T.; Quintiliani, Lisa M.; Saint-Hilaire, Marie-Helene; Thomas, Cathi A.; Earhart, G.M.; Ellis, Theresa D.
BACKGROUND: Parkinson disease (PD) is a debilitating and chronic neurodegenerative disease resulting in ambulation difficulties. Natural walking activity often declines early in disease progression despite the relative stability of motor impairments. In this study, we propose a paradigm shift with a "connected behavioral approach" that targets real-world walking using cognitive-behavioral training and mobile health (mHealth) technology. METHODS/DESIGN: The Walking and mHealth to Increase Participation in Parkinson Disease (WHIP-PD) study is a twelve-month, dual site, two-arm, randomized controlled trial recruiting 148 participants with early to mid-stage PD. Participants will be randomly assigned to connected behavioral or active control conditions. Both conditions will include a customized program of goal-oriented walking, walking-enhancing strengthening exercises, and eight in-person visits with a physical therapist. Participants in the connected behavioral condition also will (1) receive cognitive-behavioral training to promote self-efficacy for routine walking behavior and (2) use a mHealth software application to manage their program and communicate remotely with their physical therapist. Active control participants will receive no cognitive-behavioral training and manage their program on paper. Evaluations will occur at baseline, three-, six-, and twelve-months and include walking assessments, self-efficacy questionnaires, and seven days of activity monitoring. Primary outcomes will include the change between baseline and twelve months in overall amount of walking activity (mean number of steps per day) and amount of moderate intensity walking activity (mean number of minutes per day in which > 100 steps were accumulated). Secondary outcomes will include change in walking capacity as measured by the six-minute walk test and ten-meter walk test. We also will examine if self-efficacy mediates change in amount of walking activity and if change in amount of walking activity mediates change in walking capacity. DISCUSSION: We expect this study to show the connected behavioral approach will be more effective than the active control condition in increasing the amount and intensity of real-world walking activity and improving walking capacity. Determining effective physical activity interventions for persons with PD is important for preserving mobility and essential for maintaining quality of life. Clinical trials registration NCT03517371, May 7, 2018. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03517371. Date of registration: May 7, 2018. Protocol version: Original.
Long-term yogurt consumption and risk of incident hypertension in adults
(LIPPINCOTT WILLIAMS & WILKINS, 2018-08-01) Buendia, Justin R.; Li, Yanping; Hu, Frank B.; Cabral, Howard J.; Bradlee, M. Loring; Quatromoni, Paula A.; Singer, Martha R.; Curhar, Gary C.; Moore, Lynn L.
Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model
(OXFORD UNIV PRESS, 2018-02-01) Tagge, Chad A.; Fisher, Andrew M.; Minaeva, Olga V.; Gaudreau-Balderrama, Amanda; Moncaster, Juliet A.; Zhang, Xiao-Lei; Wojnarowicz, Mark W.; Casey, Noel; Lu, Haiyan; Kokiko-Cochran, Olga N.; Saman, Sudad; Ericsson, Maria; Onos, Kristen D.; Veksler, Ronel; Senatorov, Vladimir V.; Kondo, Asami; Zhou, Xiao Z.; Miry, Omid; Vose, Linnea R.; Gopaul, Katisha R.; Upreti, Chirag; Nowinski, Christopher J.; Cantu, Robert C.; Alvarez, Victor E.; Hildebrandt, Audrey M.; Franz, Erich S.; Konrad, Janusz; Hamilton, James A.; Hua, Ning; Tripodis, Yorghos; Anderson, Andrew T.; Howell, Gareth R.; Kaufer, Daniela; Hall, Garth F.; Lu, Kun P.; Ransohoff, Richard M.; Cleveland, Robin O.; Kowall, Neil W.; Stein, Thor D.; Lamb, Bruce T.; Huber, Bertrand R.; Moss, William C.; Friedman, Alon; Stanton, Patric K.; McKee, Ann C.; Goldstein, Lee E.
The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood–brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood–brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.
Selective Disruption of the Cerebral Neocortex in Alzheimer's Disease
(Public Library of Science, 2010-9-23) Desikan, Rahul S.; Sabuncu, Mert R.; Schmansky, Nicholas J.; Reuter, Martin; Cabral, Howard J.; Hess, Christopher P.; Weiner, Michael W.; Biffi, Alessandro; Anderson, Christopher D.; Rosand, Jonathan; Salat, David H.; Kemper, Thomas L.; Dale, Anders M.; Sperling, Reisa A.; Fischl, Bruce
BACKGROUND. Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS. In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aß levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n=724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals. CONCLUSIONS/SIGNIFICANCE. Cortical Aß and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.
The "ART" of Linkage: Pre-Treatment Loss to Care after HIV Diagnosis at Two PEPFAR Sites in Durban, South Africa
(Public Library of Science, 2010-3-4) Losina, Elena; Bassett, Ingrid V.; Giddy, Janet; Chetty, Senica; Regan, Susan; Walensky, Rochelle P.; Ross, Douglas; Scott, Callie A.; Uhler, Lauren M.; Katz, Jeffrey N.; Holst, Helga; Freedberg, Kenneth A.
BACKGROUND. Although loss to follow-up after antiretroviral therapy (ART) initiation is increasingly recognized, little is known about pre-treatment losses to care (PTLC) after an initial positive HIV test. Our objective was to determine PTLC in newly identified HIV-infected individuals in South Africa. METHODOLOGY/PRINCIPAL FINDINGS. We assembled the South African Test, Identify and Link (STIAL) Cohort of persons presenting for HIV testing at two sites offering HIV and CD4 count testing and HIV care in Durban, South Africa. We defined PTLC as failure to have a CD4 count within 8 weeks of HIV diagnosis. We performed multivariate analysis to identify factors associated with PTLC. From November 2006 to May 2007, of 712 persons who underwent HIV testing and received their test result, 454 (64%) were HIV-positive. Of those, 206 (45%) had PTLC. Infected patients were significantly more likely to have PTLC if they lived =10 kilometers from the testing center (RR=1.37; 95% CI: 1.11-1.71), had a history of tuberculosis treatment (RR=1.26; 95% CI: 1.00-1.58), or were referred for testing by a health care provider rather than self-referred (RR=1.61; 95% CI: 1.22-2.13). Patients with one, two or three of these risks for PTLC were 1.88, 2.50 and 3.84 times more likely to have PTLC compared to those with no risk factors. CONCLUSIONS/SIGNIFICANCE. Nearly half of HIV-infected persons at two high prevalence sites in Durban, South Africa, failed to have CD4 counts following HIV diagnosis. These high rates of pre-treatment loss to care highlight the urgent need to improve rates of linkage to HIV care after an initial positive HIV test.
Assessing the Performance of a Computer-Based Policy Model of HIV and AIDS
(Public Library of Science, 2010-9-9) Rydzak, Chara E.; Cotich, Kara L.; Sax, Paul E.; Hsu, Heather E.; Wang, Bingxia; Losina, Elena; Freedberg, Kenneth A.; Weinstein, Milton C.; Goldie, Sue J.
BACKGROUND. Model-based analyses, conducted within a decision analytic framework, provide a systematic way to combine information about the natural history of disease and effectiveness of clinical management strategies with demographic and epidemiological characteristics of the population. Among the challenges with disease-specific modeling include the need to identify influential assumptions and to assess the face validity and internal consistency of the model. METHODS AND FINDINGS. We describe a series of exercises involved in adapting a computer-based simulation model of HIV disease to the Women's Interagency HIV Study (WIHS) cohort and assess model performance as we re-parameterized the model to address policy questions in the U.S. relevant to HIV-infected women using data from the WIHS. Empiric calibration targets included 24-month survival curves stratified by treatment status and CD4 cell count. The most influential assumptions in untreated women included chronic HIV-associated mortality following an opportunistic infection, and in treated women, the 'clinical effectiveness' of HAART and the ability of HAART to prevent HIV complications independent of virologic suppression. Good-fitting parameter sets required reductions in the clinical effectiveness of 1st and 2nd line HAART and improvements in 3rd and 4th line regimens. Projected rates of treatment regimen switching using the calibrated cohort-specific model closely approximated independent analyses published using data from the WIHS. CONCLUSIONS. The model demonstrated good internal consistency and face validity, and supported cohort heterogeneities that have been reported in the literature. Iterative assessment of model performance can provide information about the relative influence of uncertain assumptions and provide insight into heterogeneities within and between cohorts. Description of calibration exercises can enhance the transparency of disease-specific models.
Does Modality of Survey Administration Impact Data Quality: Audio Computer Assisted Self Interview (ACASI) Versus Self-Administered Pen and Paper?
(Public Library of Science, 2010-1-15) Reichmann, William M.; Losina, Elena; Seage, George R.; Arbelaez, Christian; Safren, Steven A.; Katz, Jeffrey N.; Hetland, Adam; Walensky, Rochelle P.
BACKGROUND. In the context of a randomized controlled trial (RCT) on HIV testing in the emergency department (ED) setting, we evaluated preferences for survey modality and data quality arising from each modality. METHODS. Enrolled participants were offered the choice of answering a survey via audio computer assisted self-interview (ACASI) or pen and paper self-administered questionnaire (SAQ). We evaluated factors influencing choice of survey modality. We defined unusable data for a particular survey domain as answering fewer than 75% of the questions in the domain. We then compared ACASI and SAQ with respect to unusable data for domains that address sensitive topics. RESULTS. Of 758 enrolled ED patients, 218 (29%) chose ACASI, 343 chose SAQ (45%) and 197 (26%) opted not to complete either. Results of the log-binomial regression indicated that older (RR=1.08 per decade) and less educated participants (RR=1.25) were more likely to choose SAQ over ACASI. ACASI yielded substantially less unusable data than SAQ. CONCLUSIONS. In the ED setting there may be a tradeoff between increased participation with SAQ versus better data quality with ACASI. Future studies of novel approaches to maximize the use of ACASI in the ED setting are needed.
Population-Based Rates of Revision of Primary Total Hip Arthroplasty: A Systematic Review
(Public Library of Science, 2010-10-20) Corbett, Kelly L.; Losina, Elena; Nti, Akosua A.; Prokopetz, Julian J. Z.; Katz, Jeffrey N.
BACKGROUND. Most research on failure leading to revision total hip arthroplasty (THA) is reported from single centers. We searched PubMed between January 2000 and August 2010 to identify population- or community-based studies evaluating ten-year revision risks. We report ten-year revision risk using the Kaplan-Meier method, stratifying by age and fixation technique. RESULTS. Thirteen papers met the inclusion criteria. Cemented prostheses had Kaplan-Meier estimates of revision-free implant survival of ten years ranging from 88% to 95%; uncemented prostheses had Kaplan-Meier estimates from 80% to 85%. Estimates ranged from 72% to 86% in patients less than 60 years old and from 90 to 96% in older patients. CONCLUSION. Data reported from national registries suggest revision risks of 5 to 20% ten years following primary THA. Revision risks are lower in older THA recipients. Uncemented implants may have higher ten-year rates of revision, regardless of age.
Routine HIV Screening in France: Clinical Impact and Cost-Effectiveness
(Public Library of Science, 2010-10-1) Yazdanpanah, Yazdan; Sloan, Caroline E.; Charlois-Ou, Cécile; Le Vu, Stéphane; Semaille, Caroline; Costagliola, Dominique; Pillonel, Josiane; Poullié, Anne-Isabelle; Scemama, Olivier; Deuffic-Burban, Sylvie; Losina, Elena; Walensky, Rochelle P.; Freedberg, Kenneth A.; Paltiel, A. David
BACKGROUND. In France, roughly 40,000 HIV-infected persons are unaware of their HIV infection. Although previous studies have evaluated the cost-effectiveness of routine HIV screening in the United States, differences in both the epidemiology of infection and HIV testing behaviors warrant a setting-specific analysis for France. METHODS/PRINCIPAL FINDINGS. We estimated the life expectancy (LE), cost and cost-effectiveness of alternative HIV screening strategies in the French general population and high-risk sub-populations using a computer model of HIV detection and treatment, coupled with French national clinical and economic data. We compared risk-factor-based HIV testing ("current practice") to universal routine, voluntary HIV screening in adults aged 18-69. Screening frequencies ranged from once to annually. Input data included mean age (42 years), undiagnosed HIV prevalence (0.10%), annual HIV incidence (0.01%), test acceptance (79%), linkage to care (75%) and cost/test (€43). We performed sensitivity analyses on HIV prevalence and incidence, cost estimates, and the transmission benefits of ART. "Current practice" produced LEs of 242.82 quality-adjusted life months (QALM) among HIV-infected persons and 268.77 QALM in the general population. Adding a one-time HIV screen increased LE by 0.01 QALM in the general population and increased costs by €50/person, for a cost-effectiveness ratio (CER) of €57,400 per quality-adjusted life year (QALY). More frequent screening in the general population increased survival, costs and CERs. Among injection drug users (prevalence 6.17%; incidence 0.17%/year) and in French Guyana (prevalence 0.41%; incidence 0.35%/year), annual screening compared to every five years produced CERs of €51,200 and €46,500/QALY. CONCLUSIONS/SIGNIFICANCE. One-time routine HIV screening in France improves survival compared to "current practice" and compares favorably to other screening interventions recommended in Western Europe. In higher-risk groups, more frequent screening is economically justifiable.
Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels
(Public Library of Science, 2010-8-5) Meyer, Tamra E.; Verwoert, Germaine C.; Hwang, Shih-Jen; Glazer, Nicole L.; Smith, Albert V.; Van Rooij, Frank J. A.; Ehret, Georg B.; Boerwinkle, Eric; Felix, Janine F.; Leak, Tennille S.; Harris, Tamara B.; Yang, Qiong; Dehghan, Abbas; Aspelund, Thor; Katz, Ronit; Homuth, Georg; Kocher, Thomas; Rettig, Rainer; Ried, Janina S.; Gieger, Christian; Prucha, Hanna; Pfeufer, Arne; Meitinger, Thomas; Coresh, Josef; Hofman, Albert; Sarnak, Mark J.; Chen, Yii-Der Ida; Uitterlinden, André G.; Chakravarti, Aravinda; Psaty, Bruce M.; Van Duijn, Cornelia M.; Kao, W. H. Linda; Witteman, Jacqueline C. M.; Gudnason, Vilmundur; Siscovick, David S.; Fox, Caroline S.; Köttgen, Anna
Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ∼2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10−8) or suggestive associations (p<4×10−7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10−7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels. Author Summary Magnesium, potassium, and sodium are involved in important physiological processes. To better understand how common genetic variation may contribute to inter-individual differences in serum concentrations of these electrolytes, we evaluated single nucleotide polymorphisms (SNPs) across the genome in association with serum magnesium, potassium, and sodium levels in 15,366 participants of European descent from the CHARGE Consortium. We then verified the associations in an additional 8,463 study participants. Six different genomic regions contain variants that are reproducibly associated with serum magnesium levels, and only one of the regions had been previously known to influence serum magnesium concentrations in humans. The identified SNPs also show association with clinically defined hypomagnesemia, and some of them with traits that have been linked to serum magnesium levels, including kidney function, fasting glucose, and bone mineral density. We further provide evidence for a physiological role of magnesium transporters in humans which have previously only been studied in model systems. None of the SNPs evaluated in our study are significantly associated with serum levels of sodium or potassium. Additional studies are needed to investigate the underlying molecular mechanisms in order to help us understand the contribution of these newly identified regions to magnesium homeostasis.
Transmissibility of the Influenza Virus in the 1918 Pandemic
(Public Library of Science, 2008-1-30) White, Laura Forsberg; Pagano, Marcello
BACKGROUND. With a heightened increase in concern for an influenza pandemic we sought to better understand the 1918 Influenza pandemic, the most devastating epidemic of the previous century. METHODOLOGY/PRINCIPAL FINDINGS. We use data from several communities in Maryland, USA as well as two ships that experienced well-documented outbreaks of influenza in 1918. Using a likelihood-based method and a nonparametric method, we estimate the serial interval and reproductive number throughout the course of each outbreak. This analysis shows the basic reproductive number to be slightly lower in the Maryland communities (between 1.34 and 3.21) than for the enclosed populations on the ships (R0=4.97, SE=3.31). Additionally the effective reproductive number declined to sub epidemic levels more quickly on the ships (within around 10 days) than in the communities (within 30-40 days). The mean serial interval for the ships was consistent (3.33, SE=5.96 and 3.81, SE=3.69), while the serial intervals in the communities varied substantially (between 2.83, SE=0.53 and 8.28, SE=951.95). CONCLUSIONS/SIGNIFICANCE. These results illustrate the importance of considering the population dynamics when making statements about the epidemiological parameters of Influenza. The methods that we employ for estimation of the reproductive numbers and the serial interval can be easily replicated in other populations and with other diseases.
Cost-Effectiveness of Preventing Loss to Follow-up in HIV Treatment Programs: A Côte d'Ivoire Appraisal
(Public Library of Science, 2009-10-27) Losina, Elena; Touré, Hapsatou; Uhler, Lauren M.; Anglaret, Xavier; Paltiel, A. David; Balestre, Eric; Walensky, Rochelle P.; Messou, Eugène; Weinstein, Milton C.; Dabis, François; Freedberg, Kenneth A.
Based on data from West Africa, Elena Losina and colleagues predict that interventions to reduce dropout rates from HIV treatment programs (such as eliminating copayments) will be cost-effective. BACKGROUND. Data from HIV treatment programs in resource-limited settings show extensive rates of loss to follow-up (LTFU) ranging from 5% to 40% within 6 mo of antiretroviral therapy (ART) initiation. Our objective was to project the clinical impact and cost-effectiveness of interventions to prevent LTFU from HIV care in West Africa. METHODS AND FINDINGS. We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International model to project the clinical benefits and cost-effectiveness of LTFU-prevention programs from a payer perspective. These programs include components such as eliminating ART co-payments, eliminating charges to patients for opportunistic infection-related drugs, improving personnel training, and providing meals and reimbursing for transportation for participants. The efficacies and costs of these interventions were extensively varied in sensitivity analyses. We used World Health Organization criteria of >3× gross domestic product per capita (3× GDP per capita = US$2,823 for Côte d'Ivoire) as a plausible threshold for "cost-effectiveness." The main results are based on a reported 18% 1-y LTFU rate. With full retention in care, projected per-person discounted life expectancy starting from age 37 y was 144.7 mo (12.1 y). Survival losses from LTFU within 1 y of ART initiation ranged from 73.9 to 80.7 mo. The intervention costing US$22/person/year (e.g., eliminating ART co-payment) would be cost-effective with an efficacy of at least 12%. An intervention costing US$77/person/year (inclusive of all the components described above) would be cost-effective with an efficacy of at least 41%. CONCLUSIONS. Interventions that prevent LTFU in resource-limited settings would substantially improve survival and would be cost-effective by international criteria with efficacy of at least 12%–41%, depending on the cost of intervention, based on a reported 18% cumulative incidence of LTFU at 1 y after ART initiation. The commitment to start ART and treat HIV in these settings should include interventions to prevent LTFU.
Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis
(Public Library of Science, 2009-11-20) Chasman, Daniel I.; Paré, Guillaume; Mora, Samia; Hopewell, Jemma C.; Peloso, Gina; Clarke, Robert; Cupples, L. Adrienne; Hamsten, Anders; Kathiresan, Sekar; Mälarstig, Anders; Ordovas, José M.; Ripatti, Samuli; Parker, Alex N.; Miletich, Joseph P.; Ridker, Paul M.
While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle concentrations according to class (LDL, HDL, and VLDL) and particle size (small, medium, and large). The concentrations of these lipoprotein sub-fractions may be related to risk of cardiovascular disease and related metabolic disorders. We performed a genome-wide association study of 17 lipoprotein measures determined by NMR together with LDL-C, HDL-C, triglycerides, ApoA1, and ApoB in 17,296 women from the Women's Genome Health Study (WGHS). Among 36 loci with genome-wide significance (P<5×10−8) in primary and secondary analysis, ten (PCCB/STAG1 (3q22.3), GMPR/MYLIP (6p22.3), BTNL2 (6p21.32), KLF14 (7q32.2), 8p23.1, JMJD1C (10q21.3), SBF2 (11p15.4), 12q23.2, CCDC92/DNAH10/ZNF664 (12q24.31.B), and WIPI1 (17q24.2)) have not been reported in prior genome-wide association studies for plasma lipid concentration. Associations with mean lipoprotein particle size but not cholesterol content were found for LDL at four loci (7q11.23, LPL (8p21.3), 12q24.31.B, and LIPG (18q21.1)) and for HDL at one locus (GCKR (2p23.3)). In addition, genetic determinants of total IDL and total VLDL concentration were found at many loci, most strongly at LIPC (15q22.1) and APOC-APOE complex (19q13.32), respectively. Associations at seven more loci previously known for effects on conventional plasma lipid measures reveal additional genetic influences on lipoprotein profiles and bring the total number of loci to 43. Thus, genome-wide associations identified novel loci involved with lipoprotein metabolism—including loci that affect the NMR-based measures of concentration or size of LDL, HDL, and VLDL particles—all characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay. Author Summary Genome-wide association studies (GWAS) of plasma lipoprotein fractions hold great promise for understanding lipid metabolism and its central role in cardiovascular disease and related disorders. Conventional assays for lipoprotein status determine total cholesterol content of low- or high-density lipoprotein particles (LDL-C or HDL-C, respectively) or total plasma triglyceride content (as an estimate of very-low density lipoprotein particle concentration [VLDL]). All three measures have been targets for recent GWAS. However, a more precise target for GWAS of lipoprotein metabolism would be the concentration of the individual lipoprotein particles according to class (LDL, HDL, VLDL) and size (small, medium, and large), all of which can be measured by NMR-based methods. In a population of 17,296 women of European ancestry from the Women's Genome Health Study, we have performed a GWAS for 22 lipoprotein measures derived from NMR-based and conventional assays. We find 43 genetic loci involved in lipoprotein metabolism, including 10 novel loci. The results offer a clearer picture of common genetic influences on lipoprotein metabolism than available previously, including genetic effects on the distribution of LDL, HDL, and VLDL particle size, as well as on IDL and VLDL particle concentration, neither of which can be assessed by conventional measures.
An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits
(Public Library of Science, 2010-6-10) Hsu, Yi-Hsiang; Zillikens, M. Carola; Wilson, Scott G.; Farber, Charles R.; Demissie, Serkalem; Soranzo, Nicole; Bianchi, Estelle N.; Grundberg, Elin; Liang, Liming; Richards, J. Brent; Estrada, Karol; Zhou, Yanhua; van Nas, Atila; Moffatt, Miriam F.; Zhai, Guangju; Hofman, Albert; van Meurs, Joyce B.; Pols, Huibert A. P.; Price, Roger I.; Nilsson, Olle; Pastinen, Tomi; Cupples, L. Adrienne; Lusis, Aldons J.; Schadt, Eric E.; Ferrari, Serge; Uitterlinden, André G.; Rivadeneira, Fernando; Spector, Timothy D.; Karasik, David; Kiel, Douglas P.
Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6×10−8), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6×10−13; SOX6, p = 6.4×10−10) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation. Author Summary BMD and hip geometry are two major predictors of osteoporotic fractures, the most severe consequence of osteoporosis in elderly persons. We performed sex-specific genome-wide association studies (GWAS) for BMD at the lumbar spine and femor neck skeletal sites as well as hip geometric indices (NSA, NL, and NW) in the Framingham Osteoporosis Study and then replicated the top findings in two independent studies. Three novel loci were significant: in women, including chromosome 1p13.2 (RAP1A) for NW; in men, 2q11.2 (TBC1D8) for NSA and 18q11.2 (OSBPL1A) for NW. We confirmed a previously reported region on 8q24.12 (TNFRSF11B/OPG) for lumbar spine BMD in women. In addition, we integrated GWAS signals with eQTL in several tissues and publicly available expression signature profiling in cellular and whole-animal models, and prioritized 16 candidate genes/loci based on their potential involvement in skeletal metabolism. Among three prioritized loci (GPR177, SOX6, and CASR genes) associated with BMD in women, GPR177 and SOX6 have been successfully replicated later in a large-scale meta-analysis, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of using expression profiling to support the candidacy of suggestive GWAS signals that may contain important genes of interest.
A genome-wide association study reveals variants in ARL15 that influence adiponectin levels
(Public Library of Science, 2009-12-11) Richards, J. Brent; Waterworth, Dawn; O'Rahilly, Stephen; Hivert, Marie-France; Loos, Ruth J. F.; Perry, John R. B.; Tanaka, Toshiko; Timpson, Nicholas John; Semple, Robert K.; Soranzo, Nicole; Song, Kijoung; Rocha, Nuno; Grundberg, Elin; Dupuis, Josée; Florez, Jose C.; Langenberg, Claudia; Prokopenko, Inga; Saxena, Richa; Sladek, Robert; Aulchenko, Yurii; Evans, David; Waeber, Gerard; Erdmann, Jeanette; Burnett, Mary-Susan; Sattar, Naveed; Devaney, Joseph; Willenborg, Christina; Hingorani, Aroon; Witteman, Jaquelin C. M.; Vollenweider, Peter; Glaser, Beate; Hengstenberg, Christian; Ferrucci, Luigi; Melzer, David; Stark, Klaus; Deanfield, John; Winogradow, Janina; Grassl, Martina; Hall, Alistair S.; Egan, Josephine M.; Thompson, John R.; Ricketts, Sally L.; König, Inke R.; Reinhard, Wibke; Grundy, Scott; Wichmann, H-Erich; Barter, Phil; Mahley, Robert; Kesaniemi, Y. Antero; Rader, Daniel J.; Reilly, Muredach P.; Epstein, Stephen E.; Stewart, Alexandre F. R.; Van Duijn, Cornelia M.; Schunkert, Heribert; Burling, Keith; Deloukas, Panos; Pastinen, Tomi; Samani, Nilesh J.; McPherson, Ruth; Davey Smith, George; Frayling, Timothy M.; Wareham, Nicholas J.; Meigs, James B.; Mooser, Vincent; Spector, Tim D.
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk. Author Summary Through a meta-analysis of genome-wide association studies of 14,733 individuals, we identified common base-pair variants in the genome which influence circulating adiponectin levels. Since adiponectin is an adipocyte-derived circulating protein which has been inversely associated with risk of obesity-related diseases such as type 2 diabetes (T2D) and coronary heart disease (CHD), we next sought to understand if the identified variants influencing adiponectin levels also influence risk of T2D, CHD, and several metabolic traits. In addition to confirming that variation at the ADIPOQ locus influences adiponectin levels, our analyses point to a variant in the ARL15 (ADP-ribosylation factor-like 15) locus which decreases adiponectin levels and increases risk of CHD and T2D. Further, this same variant was associated with increased fasting insulin levels and glycated hemoglobin. While the function of ARL15 is not known, we provide insight into the tissue specificity of ARL15 expression. These results thus provide novel insights into the physiology of the adiponectin pathway and obesity-related diseases.
Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm
(Public Library of Science, 2008-2-15) Kimura, Masayuki; Cherkas, Lynn F.; Kato, Bernet S.; Demissie, Serkalem; Hjelmborg, Jacob B.; Brimacombe, Michael; Cupples, Adrienne; Hunkin, Janice L.; Gardner, Jefferey P.; Lu, Xiaobin; Cao, Xiaojian; Sastrasinh, Malinee; Province, Michael A.; Hunt, Steven C.; Christensen, Kaare; Levy, Daniel; Spector, Tim D.; Aviv, Abraham
Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18–94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (>30 years) and older (<50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study. Author Summary. Leukocyte telomere length becomes shorter with age and is apparently a biomarker of aging and a forecaster of longevity in humans. Leukocyte telomere length is heritable, longer in women than in men, and is relatively shorter in persons who suffer from aging-related diseases, cardiovascular diseases in particular. This study found in four different populations that leukocyte telomere length in adult offspring was positively correlated with paternal age at the time of birth of the offspring. Analysis of telomeres in sperm of young (>30 years) and older (<50 years) donors revealed the emergence in the older donors of a subset of sperm with elongated telomeres. The mechanisms behind this enigmatic, age-dependent elongation in telomere length of sperm are unknown but may relate to epigenetic factors or the survival of a subset of germ-line stem cells, resilient against aging. It is also unknown how older fathers endow their offspring with longer telomeres in their leukocytes. The potential impact of paternal age on leukocyte telomere length and, conceivably, aging-related diseases and longevity in the offspring is of relevance because offspring of older fathers comprise an increasing proportion of society.
Patterns of Co-Expression for Protein Complexes by Size in Saccharomyces Cerevisiae
(Nucleic Acids Research, 2009-2) Liu, Ching-Ti; Yuan, Shinsheng; Li, Ker-Chau
Many successful functional studies by gene expression profiling in the literature have led to the perception that profile similarity is likely to imply functional association. But how true is the converse of the above statement? Do functionally associated genes tend to be co-regulated at the transcription level? In this paper, we focus on a set of well-validated yeast protein complexes provided by Munich Information Center for Protein Sequences (MIPS). Using four well-known large-scale microarray expression data sets, we computed the correlations between genes from the same complex. We then analyzed the relationship between the distribution of correlations and the complex size (the number of genes in a protein complex). We found that except for a few large protein complexes, such as mitochondrial ribosomal and cytoplasmic ribosomal proteins, the correlations are on the average not much higher than that from a pair of randomly selected genes. The global impact of large complexes on the expression of other genes in the genome is also studied. Our result also showed that the expression of over 85% of the genes are affected by six large complexes: the cytoplasmic ribosomal complex, mitochondrial ribosomal complex, proteasome complex, F0/F1 ATP synthase (complex V) (size 18), rRNA splicing (size 24) and H+- transporting ATPase, vacular (size 15).
Prognostic Outcomes of Tall Cell Variant Papillary Thyroid Cancer: A Meta-Analysis
(SAGE-Hindawi Access to Research, 2010-7-26) Jalisi, Scharukh; Ainsworth, Tiffiny; LaValley, Michael
Objective. To evaluate the prognosis of tall cell variant (TCV) compared to usual variant (UV) papillary thyroid cancer by comparing disease-related mortality and recurrence data from published studies. Methods. Ovid MEDLINE keyword search using "tall cell variant papillary thyroid cancer" was used to identify studies published in English that calculated disease-related mortality and recurrence rates for both TCV and UV. Results. A total of 131 cases of tall cell variant papillary thyroid cancer were reviewed. The combined odds ratio of recurrence for TCV compared to UV is 4.50 with a 95% confidence interval from 2.90 to 6.99. For disease-related mortality, the combined odds ratio for TCV was compared to UV of 14.28 with a 95% confidence interval from 8.01 to 25.46. Conclusion. Currently published data suggests that TCV is a negative prognostic indicator in papillary thyroid cancer and requires aggressive therapy. This meta-analysis provides the largest prognostic data series on TCV in the literature and clearly identifies the need for accurate pathological identification of TCV and its further study as an independent prognostic factor.
Caregiving, Metabolic Syndrome Indicators, and 1-year Decline in Walking Speed: Results of Caregiver-SOF
(Oxford University Press, 2010-3-29) Fredman, Lisa; Doros, Gheorghe; Cauley, Jane A.; Hillier, Teresa A.; Hochberg, Marc C.
BACKGROUND Chronic stress may lead to health decline through metabolic syndrome. Thus, persons in stressful caregiving situations who also have more indicators of metabolic syndrome may experience more decline than other caregivers or noncaregivers. METHODS The sample included 921 women (338 caregivers and 583 noncaregivers) from the Caregiver-Study of Osteoporotic Fractures study. Participants had home-based baseline and 1-year follow-up interviews between 1999 and 2003. At baseline, caregivers were categorized as long term (³4 years) versus short term (<4 years), and caring for someone with Alzheimer's disease/dementia or not. A metabolic risk composite score was the sum of four indicators: body mass index ³30, and diagnosis or using medications for hypertension, diabetes, or high cholesterol. Walking speed (m/second) was measured at both interviews. RESULTS Walking speed declined for the total sample (adjusted mean = −0.005 m/second, ±0.16) over an average of 1.04 years (±0.16). Overall, caregiving was not associated with decline. Increasing metabolic risk score was associated with greater decline for the total sample and long-term and dementia caregivers, but not other caregivers or noncaregivers. Metabolic risk score modified the adjusted associations between years of caregiving and dementia caregiving with walking speed decline (p values for interaction terms were 0.039 and 0.057, respectively). The biggest declines were in long-term caregivers and dementia caregivers who also had 3–4 metabolic indicators (−0.10 m/second and −0.155 m/second, respectively). CONCLUSIONS Walking speed declined the most among older women who had both stressful caregiving situations and more metabolic syndrome indicators, suggesting these caregiver subgroups may have increased risk of health decline.

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