Simplifying alcohol assessment: two questions to identify alcohol use disorders

BACKGROUND: Previous work has validated a single question to screen for hazardous or harmful drinking, but identifying those patients who have an alcohol use disorder (AUD) among those who screen positive is still time consuming. We therefore sought to develop and validate a brief assessment instrument using DSM-IV criteria for use in primary care medical practice. METHODS: Four cross-sectional surveys of past-year drinkers. The developmental sample included patients presenting to emergency departments with an acute injury. The second sample, from the same study, was recruited by random-digit dialing. The third sample was recruited in 5 family medicine practices in Georgia. The fourth sample was the National Epidemiologic Survey on Alcohol and Related Conditions. Interviews with the first 3 samples used the Diagnostic Interview Schedule. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) used the Alcohol Use Disorder and Associated Disabilities Interview Schedule. RESULTS: Two constructs with promising test characteristics were identified: recurrent drinking in hazardous situations and drinking more than intended. Among those who screened positive with the single question in the developmental sample (N=959), if either of the 2 items was positive, the sensitivity for current AUD was 95% and the specificity was 77%. In the second (N=494) and third (N=280) samples, the sensitivity was 94 and 95% and the specificity was 62 and 66%, respectively, among those with a positive screen. In the NESARC sample, including those with at least 1 occasion in the past year of drinking 5 or more drinks (N=7,890), the sensitivity and specificity were 77 and 86%, respectively. CONCLUSIONS: The sensitivity and specificity of these 2 items across 4 samples suggest that they could be formulated into 2 questions, potentially providing busy primary care clinicians with an efficient, reasonably accurate assessment instrument to identify AUD among those patients who screen positive with the single screening question.     

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite-the deadliest of those that cause malaria-is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites' in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.     

Genome-wide association scans identify multiple confirmed susceptibility loci for Crohn's disease: lessons for study design

The last 12 months have seen unprecedented progress in identifying the susceptibility genes that predispose to common disease in general and Crohn's disease in particular. Success has derived from the new technique of genome-wide association scanning in large panels of cases and controls. This has itself been made possible by the sequencing of the human genome,12 development of a map of common human haplotype structure (HapMap),3 and advances in genotyping technologies permitting ascertainment of hundreds of thousands of genetic variants in multiple individuals. Several previously unsuspected pathways particularly relating to innate immunity and the early host response to bacteria have been revealed as key determinants of Crohn's disease susceptibility. These will provide a solid foundation for directed functional and translational research. Further, the wealth of confirmed association data coming from unbiased surveys of the genome provided by genome-wide association scans provide several key pointers regarding design and analysis of inflammatory bowel disease genetics studies in the future.     

Adolescent alcohol and tobacco use: onset,persistence and trajectories of use across two samples

Aims We examined the alcohol‐tobacco relationship using two prospective, ethnically diverse samples. Trajectories of alcohol and tobacco use are portrayed overall and by sex and ethnicity. Using prospective analyses, we examine directional influences between alcohol and tobacco use, and we characterize initiation versus persistence of drinking and smoking as a function of use of the other substance. Design, setting Data were from the National Longitudinal Study of Adolescent Health (AddHealth) and the Adolescent Health Risk Study (AHRS). Follow‐up intervals for AddHealth and AHRS were 1 and 5 years, respectively. Participants AddHealth respondents (n = 4831) were on average 14.8 years old (48% male, 23% black, 61% white) and AHRS respondents (n = 1814) were on average 16.7 years old (47% male, 44% black, 49% white). Measurements Two alcohol consumption variables and two smoking variables were used: drinking frequency and heavy drinking frequency, and regular (current) smoking and daily number of cigarettes. Findings Alcohol and tobacco use exhibited monotonic increases over adolescence and young adulthood. Men and white respondents reported more use than women and black respondents. Alcohol and tobacco were moderately associated at both times. Analyses revealed that prior alcohol use predicted tobacco use more strongly than the converse. Initiation of smoking was a function of prior drinking; to a lesser extent, initiation of drinking was a function of prior smoking. Persistence of smoking was a function of prior drinking and persistence of drinking was a function of prior smoking. Conclusions Provisional support exists for the claim that alcohol use predicts tobacco use more strongly than the converse. For both drinking and smoking, onset and persistence are predicted by prior use of the other substance, and these associations were robust across sex and ethnicity.     

Development and validation of PRISM: A survey tool to identify diabetes self-management barriers

Aims

Although most children with type 1 diabetes do not achieve optimal glycemic control, no systematic method exists to identify and address self-management barriers. This study develops and validates PRISM (Problem Recognition in Illness Self-Management), a survey-based tool for efficiently identifying self-management barriers experienced by children/adolescents with diabetes and their parents.

Methods

Adolescents 13 years and older and parents of children 8 years and older visiting for routine diabetes management (n = 425) were surveyed about self-management barriers. HbA1c was abstracted from the electronic health record. To develop PRISM, exploratory and confirmatory factor analyses were used. To assess validity, the association of PRISM scores with HbA1c was examined using linear regression.

Results

Factor analyses of adolescent and parent data yielded well-fitting models of self-management barriers, reflecting the following domains: (1) Understanding and Organizing Care, (2) Regimen Pain and Bother, (3) Denial of Disease and Consequences, and (4) Healthcare Team, (5) Family, or (6) Peer Interactions. All models exhibited good fit, with χ² ratios < 2.21, root mean square errors of approximation < 0.09, Confirmatory Fit Indices and Tucker–Lewis Indices both >0.92, and weighted root mean square residuals < 1.71. Greater PRISM barrier scores were significantly associated with higher HbA1cs.

Conclusions

Our findings suggest at least six different domains exist within self-management barriers, nearly all of which are significantly related to HbA1c. PRISM could be used in clinical practice to identify each child and family's unique self-management barriers, allowing existing self-management resources to be tailored to the family's barriers, ultimately improving effectiveness of such services.     

Sequence-tagged connectors: A sequence approach to mapping and scanning the human genome

The sequence-tagged connector (STC) strategy proposes to generate sequence tags densely scattered (every 3.3 kilobases) across the human genome by arraying 450,000 bacterial artificial chromosomes (BACs) with randomly cleaved inserts, sequencing both ends of each, and preparing a restriction enzyme fingerprint of each. The STC resource, containing end sequences, fingerprints, and arrayed BACs, creates a map where the interrelationships of the individual BAC clones are resolved through their STCs as overlapping BAC clones are sequenced. Once a seed or initiation BAC clone is sequenced, the minimum overlapping 5' and 3' BAC clones can be identified computationally and sequenced. By reiterating this "sequence-then-map by computer analysis against the STC database" strategy, a minimum tiling path of clones can be sequenced at a rate that is primarily limited by the sequencing throughput of individual genome centers. As of February 1999, we had deposited, together with The Institute for Genomic Research (TIGR), into GenBank 314,000 STCs ( approximately 135 megabases), or 4.5% of human genomic DNA. This genome survey reveals numerous genes, genome-wide repeats, simple sequence repeats (potential genetic markers), and CpG islands (potential gene initiation sites). It also illustrates the power of the STC strategy for creating minimum tiling paths of BAC clones for large-scale genomic sequencing. Because the STC resource permits the easy integration of genetic, physical, gene, and sequence maps for chromosomes, it will be a powerful tool for the initial analysis of the human genome and other complex genomes.     

风湿病的遗传学研究：全基因组关联研究和后全基因组关联研究时代

风湿病（其中大多属于自身免疫性结缔组织病）是一类可危害全身各种结缔组织的复杂的炎症性疾病。因其种类繁多、疾病病因及发病机制不明而致误诊、误治时有发生。同时,可有效缓解风湿病的药物较少,获批的药物也多以对症治疗为主或者价格昂贵,药物作用缺乏特异性,易引起不良反应。     

Sexual assault and harassment,perceived vulnerability,and association with alcohol use in a student population: a cross-sectional survey

BackgroundThe prevalence of sexual assault and harassment at universities is unclear because of under-reporting. Furthermore, student perceptions of vulnerability to sexual assault and how these relate to alcohol consumption are unknown. The present study assesses the prevalence of sexual assault and harassment in a student sample, and how this relates to issues of vulnerability and alcohol use.MethodsParticipants were recruited via a weekly email of notices that is sent to all students attending a town-based Scottish university of about 7200 students. The study was approved by the university ethics committee, and all participants gave informed consent before participating. The online survey was available in November, 2013, and included validated scales examining personal experience of sexual harassment and assault, perception of own and peers' vulnerability to sexual assault, and the Alcohol Use Disorder Identification Test (AUDIT). Data were analysed with χ² and t tests.FindingsThe survey was completed by 135 female and 40 male students, aged 17–56 years (mean 21·9, SD 5·4), 84 (48%) of whom were in their first year of study. There was no significant difference in the proportion of male students (22·5%) and female students (37·0%) who reported having experienced some form of sexual harassment or assault at the university. Participants perceived themselves as significantly less vulnerable than same-sex peers (t(df 160)=6·10, 95% CI ?1·09 to ?0·55; p<0·0001) and judged peers to significantly underestimate their own vulnerability (t(df 159)=4·86, 0·40 to 0·95; p<0·0001). Controlling for sex, AUDIT did not predict judgments of own vulnerability (β=0·02, 95% CI ?0·03 to 0·06, p=0·49), but hazardous drinkers were more likely to report experiences of sexual harassment than non-hazardous drinkers (χ²(df 2)=20·98, p<0·0001).InterpretationPrevalence rates for experiencing sexual harassment or assault were high, and participants underestimated their own vulnerability compared with peers. Although hazardous drinkers were more likely to report experiencing sexual harassment or assault than non-hazardous drinkers, this finding was not shown in their judged vulnerability, again suggesting a misperception. The role of alcohol and vulnerability misperceptions should be considered in future interventions. The study was limited by oversampling female first-year students, thereby producing a non-representative sample.FundingNone.     

A serosurvey to identify the window of vulnerability to wild-type measles among infants in rural Mali

As infants lose maternally derived antibody, they experience a period when antibody levels are insufficient to protect against measles yet may interfere with immunization. In Kangaba Mali, sera were collected from 89 2-8-month-old infants and 32 9-10-month-old infants without a history of measles or vaccination; post-vaccination sera were collected from 24 of the 9-10-month-old infants 3-5 weeks after receiving measles vaccine. Measles antibody was measured by plaque reduction neutralization (PRN) and enzyme linked immunosorbent assay. At two months of age, 30% had protective PRN titers; among six-month-old infants, none had protective titers. Prior to vaccination, 16% of 9-10-month-old infants exhibited protective titers; all demonstrated protective titers post-vaccination. The early onset of the window of vulnerability in Kangaba infants likely reflects the changing ecology of measles in Africa. Ways to protect these vulnerable infants against measles must be devised.     

Neutralizing antibodies against two HIV-1 strains in consecutively collected serum samples: cross neutralization and association to HIV-1 related disease.

97 sera collected during a 10-year period from 10 HIV-1 infected individuals were tested for neutralizing capacity against a virus isolate FICPH-22 obtained from a Danish AIDS patient, and the laboratory strain HTLV-IIIB. Three patterns of serum neutralizing activity were demonstrated: (a) patients developing high neutralizing activity against both HIV strains; (b) patients developing high neutralizing activity against the Danish virus isolate; and (c) patients developing only low titers of neutralizing antibodies (NA) against both HIV strains. The HTLV-IIIB strain was less sensitive to serum neutralization than the FICPH-22 isolate and the appearance of NA against HTLV-IIIB was typically lacking several years behind that against FICPH-22 indicating a broadening of the NA response over time. No difference in clinical outcome was observed comparing patients reaching high titers of NA and patients with low titers. Development of AIDS among patients reaching high titers of NA was preceded by a decline in NA titers, indicating an association of high titers of NA with the healthy carrier state and of declining or low titers of NA with disease progression. The majority of the neutralizing activity was mediated by IgG, but some neutralizing activity was demonstrated in the IgG depleted serum, indicating the presence of additional neutralizing substances in serum.     

Development and validation of a questionnaire to identify patients with sleep apnea in Mexican population

Purpose  

To develop and validate a questionnaire to identify patients with obstructive sleep apnea (OSA) in Mexican population.     

Derivation and validation of a simple model to identify venous thromboembolism risk in medical patients

Background

Fewer than half of eligible hospitalized medical patients receive appropriate venous thromboembolism (VTE) prophylaxis. One reason for this low rate is the complexity of existing risk assessment models. A simple set of easily identifiable risk factors that are highly predictive of VTE among hospitalized medical patients may enhance appropriate thromboprophylaxis.

Methods

Electronic medical record interrogation was performed to identify medical admissions from January 1, 2000-December 31, 2007 (n = 143,000), and those patients with objectively confirmed VTE during hospitalization or within 90 days following discharge. Putative risk factors most predictive of VTE were identified, and a risk assessment model (RAM) was derived; 46,000 medicine admissions from January 1, 2008-December 31, 2009 served as a validation cohort to test the predictive ability of the RAM. The newly derived RAM was compared with a published VTE assessment tool (Kucher Score).

Results

Four risk factors: previous VTE; an order for bed rest; peripherally inserted central venous catheterization line; and a cancer diagnosis, were the minimal set most predictive of hospital-associated VTE (area under the receiver operating characteristic curve [AUC] = 0.874; 95% confidence interval [CI], 0.869-0.880). These risk factors upon validation in a separate population (validation cohort) retained an AUC = 0.843; 95% CI, 0.833-0.852. The ability of the 4-element RAM to identify patients at risk of developing VTE within 90 days was superior to the Kucher Score.

Conclusions

The 4-element RAM identified in this study may be used to identify patients at risk for VTE and improve rates of thromboprophylaxis. This simple and accurate RAM is an alternative to more complicated published VTE risk assessment tools that currently exist.     

Linkage to nodal osteoarthritis: quantitative and qualitative analyses of data from a whole-genome screen identify trait-dependent susceptibility loci

OBJECTIVE: To identify susceptibility loci for nodal osteoarthritis. METHODS: A genome screen at an average marker spacing of 9.29 cM was carried out on 558 people from 202 families, of whom 491 had nodal osteoarthritis. All genotyped people were graded for the incidence and severity of distal interphalangeal (DIP) nodes, and radiographs from 354 people were graded for joint-space narrowing (JSN) and osteophytes (OSTs). Age-regressed indices for DIP nodes, JSN and OSTs were calculated using these phenotypic data. Affected sibling pair (ASP) and quantitative trait analyses were carried out using MERLIN. RESULTS: The data analysis identified suggestive linkage to loci on chromosomes 3 (for JSN and OST), 4 (for JSN), 8 (for DIP), 11 (for radiographic osteoarthritis) and 16 (for JSN). Both the ASP and quantitative analyses identified the loci on chromosomes 4 and 11. The loci on chromosomes 3 and 16 overlap with those previously identified for large-joint osteoarthritis. Of the loci identified by the quantitative analyses with the logarithm of the odds of linkage >1.5, two were linked to more than one trait, whereas nine were linked to single traits: one for DIP, six for JSN and two for OST. CONCLUSION: The ASP and quantitative analyses of the cohort with nodal osteoarthritis suggest that multiple susceptibility loci for osteoarthritis influence the traits, which combine to form the osteoarthritis phenotype, and that these loci may not act exclusively on the joints of the hand.     

Genome-wide association mapping to candidate polymorphism resolution in the unsequenced barley genome

Although commonplace in human disease genetics, genome-wide association (GWA) studies have only relatively recently been applied to plants. Using 32 phenotypes in the inbreeding crop barley, we report GWA mapping of 15 morphological traits across ～500 cultivars genotyped with 1,536 SNPs. In contrast to the majority of human GWA studies, we observe high levels of linkage disequilibrium within and between chromosomes. Despite this, GWA analysis readily detected common alleles of high penetrance. To investigate the potential of combining GWA mapping with comparative analysis to resolve traits to candidate polymorphism level in unsequenced genomes, we fine-mapped a selected phenotype (anthocyanin pigmentation) within a 140-kb interval containing three genes. Of these, resequencing the putative anthocyanin pathway gene HvbHLH1 identified a deletion resulting in a premature stop codon upstream of the basic helix-loop-helix domain, which was diagnostic for lack of anthocyanin in our association and biparental mapping populations. The methodology described here is transferable to species with limited genomic resources, providing a paradigm for reducing the threshold of map-based cloning in unsequenced crops.