Fitting ACE Structural Equation Models to Case-Control Family Data

Investigators interested in whether a disease aggregates in families often collect case-control family data, which consist of disease status and covariate information for families selected via case or control probands. Here, we focus on the use of case-control family data to investigate the relative contributions to the disease of additive genetic effects (A), shared family environment (C), and unique environment (E). To this end, we describe a ACE model for binary family data and then introduce an approach to fitting the model to case-control family data. The structural equation model, which has been described previously, combines a general-family extension of the classic ACE twin model with a (possibly covariate-specific) liability-threshold model for binary outcomes. Our likelihood-based approach to fitting involves conditioning on the proband’s disease status, as well as setting prevalence equal to a pre-specified value that can be estimated from the data themselves if necessary. Simulation experiments suggest that our approach to fitting yields approximately unbiased estimates of the A, C, and E variance components, provided that certain commonly-made assumptions hold. These assumptions include: the usual assumptions for the classic ACE and liability-threshold models; assumptions about shared family environment for relative pairs; and assumptions about the case-control family sampling, including single ascertainment. When our approach is used to fit the ACE model to Austrian case-control family data on depression, the resulting estimate of heritability is very similar to those from previous analyses of twin data

MDMA (“Ecstasy”) Abuse and High-Risk Sexual Behaviors Among 169 Gay and Bisexual Men

OBJECTIVE: The authors explored the association between abuse of 3,4-methylenedioxymethamphetamine (MDMA, or “Ecstasy”) and high-risk sexual behaviors among gay and bisexual men. METHOD: An anonymous questionnaire was completed by 169 gay and bisexual men at three New York City dance clubs. The questionnaire covered demographic indices, use of MDMA and other drugs, and history of high-risk sexual behaviors. RESULTS: About one-third of the respondents reported MDMA use at least monthly. MDMA use was strongly and significantly associated with a history of recent unprotected anal intercourse. This association remained equally strong even after controlling for age, ethnicity, and all other forms of drug use, including alcohol. CONCLUSIONS: MDMA abuse, and its strong association with high-risk sexual behaviors, appears to represent important unexplored public health problems among some gay or bisexual men

Estimating the Prevalence of Disease Using Relatives of Case and Control Probands

We introduce a method for estimating the prevalence of disease using data from a case-control family study performed to investigate the aggregation of disease in families. The families are sampled via case and control probands, and the resulting data consist of information on disease status and covariates for the probands and their relatives. We introduce estimators for overall prevalence and for covariate stratum-specific prevalence (e.g., sex-specific prevalence) that yield approximately unbiased estimates of their population counterparts. We also introduce corresponding confidence intervals that have good coverage properties even for small prevalences. The estimators and intervals address the over-representation of diseased individuals in case-control family data by using only the relatives (of the probands) and by taking into account whether each relative was selected via a case or a control proband. Finally, we describe a simulation experiment in which the estimators and intervals were applied to case-control family datasets sampled from a fictional population that resembled the catchment area for an Austrian family study of major depressive disorder. The resulting estimates varied closely and symmetrically around their population counterparts, and the resulting intervals had good coverage properties

Duloxetine in the Treatment of Major Depressive Disorder: An Open-Label Study

Background: Major depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined. Methods: Patients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score ≥18 and a Clinical Global Impression of Severity (CGI-S) score ≥4 at baseline. Efficacy measures included the HAMD17 total score, HAMD17 subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale. Results: The rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by ≥10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD17, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment. Conclusion: In this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD. Trial registration: NCT00036309

The model of mortality with incident cirrhosis (MoMIC) and the model of long-term outlook of mortality in dcirrhosis (LOMiC)

The purpose of this study was to produce two statistical survival models in those with cirrhosis utilising only routine parameters, including non-liver-related clinical factors that influence survival. The first model identified and utilised factors impacting short-term survival to 90-days post incident diagnosis, and a further model characterised factors that impacted survival following this acute phase. Data were from the Clinical Practice Research Datalink linked with Hospital Episode Statistics. Incident cases in patients ≥18 years were identified between 1998 and 2014. Patients that had prior history of cancer or had received liver transplants prior were excluded. Model-1 used a logistic regression model to predict mortality. Model-2 used data from those patients who survived 90 days, and used an extension of the Cox regression model, adjusting for time-dependent covariables. At 90 days, 23% of patients had died. Overall median survival was 3.7 years. Model-1: numerous predictors, prior comorbidities and decompensating events were incorporated. All comorbidities contributed to increased odds of death, with renal disease having the largest adjusted odds ratio (OR = 3.35, 95%CI 2.97–3.77). Model-2: covariables included cumulative admissions for liver disease-related events and admissions for infections. Significant covariates were renal disease (adjusted hazard ratio (HR = 2.89, 2.47–3.38)), elevated bilirubin levels (aHR = 1.38, 1.26–1.51) and low sodium levels (aHR = 2.26, 1.84–2.78). An internal validation demonstrated reliability of both models. In conclusion: two survival models that included parameters commonly recorded in routine clinical practice were generated that reliably forecast the risk of death in patients with cirrhosis: in the acute, post diagnosis phase, and following this critical, 90 day phase. This has implications for practice and helps better forecast the risk of mortality from cirrhosis using routinely recorded parameters without inputs from specialists

Placebo response in binge eating disorder

Objective: Placebo response in studies of binge eating disorder (BED) has raised concern about its diagnostic stability. The aims of this study were (1) to compare placebo responders (PRs) with nonresponders (NRs); (2) to investigate the course of BED following placebo response; and (3) to examine attributions regarding placebo response. Method: The baseline placebo run-in phase (BL) was part of a RCT investigating sibutramine hydrochloride for BED; it included 451 participants, ages 19–63, diagnosed with BED. Follow-up (FU) included 33 PRs. Results: In this study, 32.6% of participants responded to placebo (PRs = 147; NRs = 304). PRs exhibited significantly less symptom severity. At FU (n = 33), many PRs reported continued symptoms. Conclusion: PRs exhibited significantly less severe pathology than NRs. Placebo response in BED may transitory or incomplete. The results of this study suggest variable stability in the BED diagnosis

Predators reduce extinction risk in noisy metapopulations

Background Spatial structure across fragmented landscapes can enhance regional population persistence by promoting local “rescue effects.” In small, vulnerable populations, where chance or random events between individuals may have disproportionately large effects on species interactions, such local processes are particularly important. However, existing theory often only describes the dynamics of metapopulations at regional scales, neglecting the role of multispecies population dynamics within habitat patches. Findings By coupling analysis across spatial scales we quantified the interaction between local scale population regulation, regional dispersal and noise processes in the dynamics of experimental host-parasitoid metapopulations. We find that increasing community complexity increases negative correlation between local population dynamics. A potential mechanism underpinning this finding was explored using a simple population dynamic model. Conclusions Our results suggest a paradox: parasitism, whilst clearly damaging to hosts at the individual level, reduces extinction risk at the population level

Coherent quantum LQG control

Based on a recently developed notion of physical realizability for quantum linear stochastic systems, we formulate a quantum LQG optimal control problem for quantum linear stochastic systems where the controller itself may also be a quantum system and the plant output signal can be fully quantum. Such a control scheme is often referred to in the quantum control literature as "coherent feedback control.'' It distinguishes the present work from previous works on the quantum LQG problem where measurement is performed on the plant and the measurement signals are used as input to a fully classical controller with no quantum degrees of freedom. The difference in our formulation is the presence of additional non-linear and linear constraints on the coefficients of the sought after controller, rendering the problem as a type of constrained controller design problem. Due to the presence of these constraints our problem is inherently computationally hard and this also distinguishes it in an important way from the standard LQG problem. We propose a numerical procedure for solving this problem based on an alternating projections algorithm and, as initial demonstration of the feasibility of this approach, we provide fully quantum controller design examples in which numerical solutions to the problem were successfully obtained. For comparison, we also consider the case of classical linear controllers that use direct or indirect measurements, and show that there exists a fully quantum linear controller which offers an improvement in performance over the classical ones.Comment: 25 pages, 1 figure, revised and corrected version (mainly to Section 8). To be published in Automatica, Journal of IFAC, 200

Association between frequency of telephonic contact and clinical testing for a large, geographically diverse diabetes disease management population

Diabetes disease management (DM) programs strive to promote healthy behaviors, including obtaining hemoglobin A1c (A1c) and low-density lipoprotein (LDL) tests as part of standards of care. The purpose of this study was to examine the relationship between frequency of telephonic contact and A1c and LDL testing rates. A total of 245,668 members continuously enrolled in diabetes DM programs were evaluated for performance of an A1c or LDL test during their first 12 months in the programs. The association between the number of calls a member received and clinical testing rates was examined. Members who received four calls demonstrated a 24.1% and 21.5% relative increase in A1c and LDL testing rates, respectively, compared to members who received DM mailings alone. Response to the telephonic intervention as part of the diabetes DM programs was influenced by member characteristics including gender, age, and disease burden. For example, females who received four calls achieved a 27.7% and 23.6% increase in A1c and LDL testing, respectively, compared to females who received mailings alone; by comparison, males who were called achieved 21.2% and 19.9% relative increase in A1c and LDL testing, respectively, compared to those who received mailings alone. This study demonstrates a positive association between frequency of telephonic contact and increased performance of an A1c or LDL test in a large, diverse diabetes population participating in DM programs. The impact of member characteristics on the responsiveness to these programs provides DM program designers with knowledge for developing strategies to promote healthy behaviors and improve diabetes outcomes

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance