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1.  BRCA1/2 Test Results Impact Risk Management Attitudes, Intentions and Uptake 
Women who receive positive or uninformative BRCA1/2 test results face a number of decisions about how to manage their cancer risk. The purpose of this study was to prospectively examine the effect of receiving a positive vs. uninformative BRCA1/2 genetic test result on the perceived pros and cons of risk-reducing mastectomy (RRM) and risk-reducing oophorectomy (RRO) and breast cancer screening. We further examined how perceived pros and cons of surgery predict intention for and uptake of surgery.
308 women (146 positive, 162 uninformative) were included in RRM and breast cancer screening analyses. 276 women were included in RRO analyses. Participants completed questionnaires at pre-disclosure baseline and 1-, 6-and 12-months post-disclosure. We used linear multiple regression to assess whether test result contributed to change in pros and cons and logistic regression to predict intentions and surgery uptake.
Receipt of a positive BRCA1/2 test result predicted stronger pros for RRM and RRO (Ps < .001), but not perceived cons of RRM and RRO. Pros of surgery predicted RRM and RRO intentions in carriers and RRO intentions in uninformatives. Cons predicted RRM intentions in carriers. Pros and cons predicted carriers’ RRO uptake in the year after testing (Ps < .001).
Receipt of BRCA1/2 mutation test results impacts how carriers see the positive aspects of RRO and RRM and their surgical intentions. Both the positive and negative aspects predict uptake of surgery.
PMCID: PMC3039480  PMID: 20383578
breast cancer; BRCA mutation; prophylactic mastectomy; prophylactic oophorectomy; screening; pros; cons
2.  Disclosure of APOE Genotype for Risk of Alzheimer's Disease 
The New England journal of medicine  2009;361(3):245-254.
The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and their family members has been discouraged. We examined the effect of genotype disclosure in a prospective, randomized, controlled trial.
We randomly assigned 162 asymptomatic adults who had a parent with Alzheimer's disease to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, and test-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure.
There were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group, P = 0.84), depression (8.8 and 8.7, respectively; P = 0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondary comparisons between the non-disclosure group and a disclosure subgroup of subjects carrying the APOE ε4 allele (which is associated with increased risk) also revealed no significant differences. However, the ε4-negative subgroup had a significantly lower level of test-related distress than did the ε4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the ε4-positive and ε4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons).
The disclosure of APOE genotyping results to adult children of patients with Alzheimer's disease did not result in significant short-term psychological risks. Test-related distress was reduced among those who learned that they were APOE ε4–negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. ( number, NCT00571025.)
PMCID: PMC2778270  PMID: 19605829
3.  Associations between self-referral and health behavior responses to genetic risk information 
Genome Medicine  2015;7(1):10.
Studies examining whether genetic risk information about common, complex diseases can motivate individuals to improve health behaviors and advance planning have shown mixed results. Examining the influence of different study recruitment strategies may help reconcile inconsistencies.
Secondary analyses were conducted on data from the REVEAL study, a series of randomized clinical trials examining the impact of genetic susceptibility testing for Alzheimer’s disease (AD). We tested whether self-referred participants (SRPs) were more likely than actively recruited participants (ARPs) to report health behavior and advance planning changes after AD risk and APOE genotype disclosure.
Of 795 participants with known recruitment status, 546 (69%) were self-referred and 249 (31%) had been actively recruited. SRPs were younger, less likely to identify as African American, had higher household incomes, and were more attentive to AD than ARPs (all P < 0.01). They also dropped out of the study before genetic risk disclosure less frequently (26% versus 41%, P < 0.001). Cohorts did not differ in their likelihood of reporting a change to at least one health behavior 6 weeks and 12 months after genetic risk disclosure, nor in intentions to change at least one behavior in the future. However, interaction effects were observed where ε4-positive SRPs were more likely than ε4-negative SRPs to report changes specifically to mental activities (38% vs 19%, p < 0.001) and diets (21% vs 12%, p = 0.016) six weeks post-disclosure, whereas differences between ε4-positive and ε4-negative ARPs were not evident for mental activities (15% vs 21%, p = 0.413) or diets (8% versus 16%, P = 0.190). Similarly, ε4-positive participants were more likely than ε4-negative participants to report intentions to change long-term care insurance among SRPs (20% vs 5%, p < 0.001), but not ARPs (5% versus 9%, P = 0.365).
Individuals who proactively seek AD genetic risk assessment are more likely to undergo testing and use results to inform behavior changes than those who respond to genetic testing offers. These results demonstrate how the behavioral impact of genetic risk information may vary according to the models by which services are provided, and suggest that how participants are recruited into translational genomics research can influence findings.
Trial registration NCT00089882 and NCT00462917
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-014-0124-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4311425  PMID: 25642295
4.  Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer’s disease 
Genetic risk for Alzheimer’s disease (AD) may be conferred by the susceptibility polymorphism apolipoprotein E (APOE), where the ε4 allele increases the risk of developing late-onset Alzheimer’s disease but is not a definitive predictor of the disease, or by autosomal dominant mutations (e.g., the presenilins), which almost inevitably result in early-onset familial Alzheimer’s disease. The purpose of this study was to compare the psychological impact of using these two different types of genetic information to disclose genetic risk for AD to family members of affected patients.
Data were compared from two separate protocols. The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study is a randomized, multi-site clinical trial that evaluated the impact of susceptibility testing for Alzheimer’s disease with APOE in 101 adult children of Alzheimer’s disease patients. A separate study, conducted at the University of Washington, assessed the impact of deterministic genetic testing by disclosing presenilin-1, presenilin-2, or TAU genotype to 22 individuals at risk for familial Alzheimer’s disease or frontotemporal dementia. In both protocols, participants received genetic counseling and completed the Impact of Event Scale (IES), a measure of test-specific distress. Scores were analyzed at the time point closest to one year post-disclosure at which IES data were available. The role of genetic test result (positive vs. negative) and type of genetic testing (deterministic vs. susceptibility) in predicting log-transformed IES scores was assessed with linear regression, controlling for age, gender, and time from disclosure.
Subjects from the REVEAL Study who learned that they were positive for the susceptibility gene APOE ε4+ experienced similar, low levels of test-specific distress compared to those who received positive results of deterministic testing in the University of Washington study (p= 0.78). APOE ε4+ individuals in the susceptibility protocol experienced more test-specific distress than those who tested ε4− in the same study (p= 0.04); however, among those receiving deterministic test disclosure, the subjects who received positive results did not experience significantly higher levels of distress when compared to those who received negative results (p= 0.88).
The findings of this preliminary study, with limited sample size, suggest that the test-related distress experienced by those receiving positive results for a deterministic mutation is similar to the distress experienced by those receiving positive results from genetic susceptibility testing, and that the majority of participants receiving genotype disclosure do not experience clinically significant distress as indicated by IES scores one year after learning of their test results.
PMCID: PMC2610442  PMID: 19012865
genetic susceptibility testing; deterministic testing; Alzheimer’s disease; APOE; genetic counseling
5.  Prevalence and correlates of treatment failure among Kenyan children hospitalised with severe community-acquired pneumonia: a prospective study of the clinical effectiveness of WHO pneumonia case management guidelines 
To determine the extent and pattern of treatment failure (TF) among children hospitalised with community-acquired pneumonia at a large tertiary hospital in Kenya.
We followed up children aged 2–59 months with WHO-defined severe pneumonia (SP) and very severe pneumonia (VSP) for up to 5 days for TF using two definitions: (i) documentation of pre-defined clinical signs resulting in change of treatment (ii) primary clinician's decision to change treatment with or without documentation of the same pre-defined clinical signs.
We enrolled 385 children. The risk of TF varied between 1.8% (95% CI 0.4–5.1) and 12.4% (95% CI 7.9–18.4) for SP and 21.4% (95% CI 15.9–27) and 39.3% (95% CI 32.5–46.4) for VSP depending on the definition applied. Higher rates were associated with early changes in therapy by clinician in the absence of an obvious clinical rationale. Non-adherence to treatment guidelines was observed for 70/169 (41.4%) and 67/201 (33.3%) of children with SP and VSP, respectively. Among children with SP, adherence to treatment guidelines was associated with the presence of wheeze on initial assessment (P = 0.02), while clinician non-adherence to guideline-recommended treatments for VSP tended to occur in children with altered consciousness (P < 0.001). Using propensity score matching to account for imbalance in the distribution of baseline clinical characteristics among children with VSP revealed no difference in TF between those treated with the guideline-recommended regimen vs. more costly broad-spectrum alternatives [risk difference 0.37 (95% CI −0.84 to 0.51)].
Before revising current pneumonia case management guidelines, standardised definitions of TF and appropriate studies of treatment effectiveness of alternative regimens are required.
Déterminer l'ampleur et les caractéristiques de l’échec du traitement (ET) chez les enfants hospitalisés avec une pneumonie acquise dans la communauté dans un grand hôpital tertiaire du Kenya.
Nous avons suivi des enfants âgés de 2 à 59 mois avec une pneumonie sévère (PS) et une pneumonie très sévère (PTS) telles que définies par l’OMS, sur un maximum de cinq jours pour l’ET, en utilisant deux définitions: (a) documentation des signes cliniques prédéfinis ayant entraîné un changement du traitement, (b) décision primaire du clinicien de changer de traitement avec ou sans documentation des mêmes signes cliniques prédéfinis.
Nous avons recruté 385 enfants. Le risque d’ET variait de 1,8% (IC95%: 0,4 à 5,1) à 12,4% (IC95%: 7,9 à 18,4) pour la PS et de 21,4% (IC95%: 15,9 à 27) à 39,3% (IC95%: 32,5 à 46,4) pour la PTS selon la définition appliquée. Des taux plus élevés étaient associés à des changements précoces du traitement par le clinicien en l'absence d'une justification clinique évidente. Le non-respect des directives de traitement a été observé pour 70/169 (41,4%) et 67/201 (33,3%) enfants avec une PS et une PTS respectivement. Chez les enfants avec une PS, le respect des directives de traitement était associé avec la présence d'une respiration sifflante au cours l’évaluation initiale (P = 0,02) tandis que le non respect par les cliniciens des traitements recommandés pour la PTS tendait à se produire chez les enfants avec une altération de la conscience (P <0,001). L'utilisation du score de propension correspondant pour tenir compte du déséquilibre dans la répartition des caractéristiques cliniques de base chez les enfants avec une PTS n'a révélé aucune différence dans l’ET entre ceux traités avec le régime recommandé par les directives et ceux traités par des alternatives plus coûteuses à large spectre (différence de risque: 0,37 (IC95%: -0,84 à 0,51).
Avant la révision des directives actuelles de prise en charge des cas de pneumonie, des définitions standard d’ET et des études appropriées de l'efficacité des traitements alternatifs sont nécessaires.
Determinar la extensión y el patrón del fallo en el tratamiento (FT) en niños hospitalizados con una neumonía adquirida en la comunidad, ingresados en un gran hospital terciario de Kenia.
Hemos seguido a niños con edades entre los 2-59 meses con una neumonía severa (NS) y neumonía muy severa (NMS) según definición de la OMS de hasta cinco días para FT utilizando dos definiciones: (a) documentación de signos clínicos pre-definidos que resultaron en un cambio de tratamiento (b) decisión del clínico principal de cambiar el tratamiento con o sin documentación de los mismos signos clínicos pre-definidos.
Incluimos a 385 niños. El riesgo de FT varió entre un 1.8% (IC 95% 0.4 a 5.1) y 12.4% (IC 95% 7.9 a 18.4) para NS y 21.4% (IC 95% 15.9 a 27) y 39.3% (IC 95% 32.5 a 46.4) para NMS dependiendo de la definición que se aplicase. Unas mayores tasas estaban asociadas con cambios tempranos en la terapia por el clínico y en ausencia de un razonamiento clínico obvio. Se observaba una no adherencia a las guías de tratamiento en 70/169 (41.4%) y 67/201 (33.3%) de los niños con NS y NMS respectivamente. Entre los niños con SP, la adherencia a las guías de tratamiento estaba asociada con la presencia de sibilancias en la evaluación inicial (P=0.02) mientras que la no adherencia del clínico a los tratamientos recomendados por las guías para NMS tendían a ocurrir en niños con un estado alterado de consciencia (P<0.001). Utilizando el pareamiento por puntaje de propensión para equilibrar los grupos en la distribución de las características clínicas de base de los niños con NMS, se observó que no existían diferencias en FT entre aquellos tratados con el régimen recomendado por las guías versus alternativas más costosas de amplio espectro (diferencias de riesgo 0.37 (IC 95% -0.84 a 0.51).
Antes de revisar las actuales guías de manejo de casos de neumonía, se requieren definiciones estandarizadas de FT y estudios apropiados de la efectividad del tratamiento de regímenes alternativos.
PMCID: PMC4241029  PMID: 25130866
treatment failure; case management; World Health Organization; pneumonia
6.  The role of disease perceptions and results sharing in psychological adaptation after genetic susceptibility testing: the REVEAL Study 
European Journal of Human Genetics  2010;18(12):1296-1301.
This study evaluates the extent to which psychological adaptation (validated measures of depressive symptoms, anxiety, and test-specific distress) after genetic susceptibility testing is influenced by changes in beliefs about Alzheimer's disease (AD) and sharing of test results with others. Adult children of AD patients (N=269) from a randomized clinical trial involving genetic testing for apolipoprotein E (APOE) provided information before, as well as 6 weeks and 12 months after results disclosure. The levels of adaptation varied highly among participants at 12-month assessment. Participants who learned that they were ɛ4 negative (lower risk) had a reduction in perceived risk and concern about developing AD compared with those who learned that they were ɛ4 positive. Those who received results through an extended educational protocol (three in-person visits) had a larger decline in AD concern than those in a condensed protocol (educational brochure and two in-person visits). Increase in AD concern 6 weeks after disclosure was associated with increase in depression scores (b=0.20, P<0.01) and anxiety levels (b=0.20, P<0.01), and higher distress associated with AD genetic testing (b=0.18, P=0.02) 1 year after testing. Increase in perceived risk (b=0.16, P=0.04) was also associated with higher AD genetic testing distress. Sharing the test results with health professionals and friends (but not family) was associated with decrease in depression (b = −0.11, P = 0.05) and anxiety levels (b=−0.16, P<0.01), respectively after a year. Enhancing discussion with regard to risks and concerns about AD during pretesting counseling and obtaining support through sharing the results after testing may help facilitate test recipients' long-term psychological adaptation.
PMCID: PMC2988099  PMID: 20664629
susceptibility genetic testing; AD; APOE; results disclosure; communication; risk perceptions
7.  The role of disease perceptions and results sharing in psychological adaptation after genetic susceptibility testing: the REVEAL Study 
This study evaluates the extent to which psychological adaptation (validated measures of depressive symptoms, anxiety, and test-specific distress) after genetic susceptibility testing is influenced by changes in beliefs about Alzheimer's disease (AD) and sharing of test results with others. Adult children of AD patients (N=269) from a randomized clinical trial involving genetic testing for apolipoprotein E (APOE) provided information before, as well as 6 weeks and 12 months after results disclosure. The levels of adaptation varied highly among participants at 12-month assessment. Participants who learned that they were ε4 negative (lower risk) had a reduction in perceived risk and concern about developing AD compared with those who learned that they were ε4 positive. Those who received results through an extended educational protocol (three in-person visits) had a larger decline in AD concern than those in a condensed protocol (educational brochure and two in-person visits). Increase in AD concern 6 weeks after disclosure was associated with increase in depression scores (b=0.20, P<0.01) and anxiety levels (b=0.20, P<0.01), and higher distress associated with AD genetic testing (b=0.18, P=0.02) 1 year after testing. Increase in perceived risk (b=0.16, P=0.04) was also associated with higher AD genetic testing distress. Sharing the test results with health professionals and friends (but not family) was associated with decrease in depression (b= −0.11, P=0.05) and anxiety levels (b= −0.16, P<0.01), respectively after a year. Enhancing discussion with regard to risks and concerns about AD during pretesting counseling and obtaining support through sharing the results after testing may help facilitate test recipients' long-term psychological adaptation.
PMCID: PMC2988099  PMID: 20664629
susceptibility genetic testing; AD; APOE; results disclosure; communication; risk perceptions
8.  Perceptions of Familial Risk in those Seeking a Genetic Risk Assessment for Alzheimer’s Disease 
Journal of genetic counseling  2008;18(2):130-136.
Perceived risk is a complex concept that influences the genetic counseling process and can affect client coping and behavior. Although the association between family history and risk perception is well recognized in the literature, no studies have explored this relationship specifically in those seeking genetic susceptibility testing for a common chronic condition. REVEAL is a randomized trial assessing the impact of APOE disclosure and genetic risk assessment for Alzheimer’s disease (AD). Using baseline REVEAL data, we hypothesized that there would be a significant association between the degree of AD family history and risk perception of AD, and that this relationship would be stronger in those who believed that genetics is a very important AD risk factor. In our sample of 293 participants, we found that a higher self-perceived risk of AD was associated with strength of family history of AD (p<0.001), belief in genetics as an important AD risk factor (p<0.001), being female (p<0.001) and being Caucasian (p=0.02). These results are the first to demonstrate the association between family history and risk perception in persons volunteering for genetic susceptibility testing for a common complex disease.
PMCID: PMC2919070  PMID: 18949541
Risk perception; Alzheimer’s disease; APOE; Genetic susceptibility testing; Risk assessment
9.  Metabolic effects of liver transplantation in cirrhotic patients. 
Journal of Clinical Investigation  1997;99(4):692-700.
To assess whether liver transplantation (LTx) can correct the metabolic alterations of chronic liver disease, 14 patients (LTx-5) were studied 5+/-1 mo after LTx, 9 patients (LTx-13) 13+/-1 mo after LTx, and 10 patients (LTx-26) 26+/-2 months after LTx. Subjects with chronic uveitis (CU) and healthy volunteers (CON) were also studied. Basal plasma leucine and branched-chain amino acids were reduced in LTx-5, LTx-13, and LTx-26 when compared with CU and CON (P < 0.01). The basal free fatty acids (FFA) were reduced in LTx-26 with respect to CON (P < 0.01). To assess protein metabolism, LTx-5, LTx-13, and LTx-26 were studied with the [1-14C]leucine turnover combined with a 40-mU/m2 per min insulin clamp. To relate changes in FFA metabolism to glucose metabolism, eight LTx-26 were studied with the [1-14C]palmitate and [3-3H]glucose turnovers combined with a two-step (8 and 40 mU/m2 per min) euglycemic insulin clamp. In the postabsorptive state, LTx-5 had lower endogenous leucine flux (ELF) (P < 0.005), lower leucine oxidation (LO) (P < 0.004), and lower non-oxidative leucine disposal (NOLD) (P < 0.03) with respect to CON (primary pool model). At 2 yr (LTx-26) both ELF (P < 0.001 vs. LTx-5) and NOLD (P < 0.01 vs. LTx-5) were normalized, but not LO (P < 0.001 vs. CON) (primary and reciprocal pool models). Suppression of ELF by insulin (delta-reduction) was impaired in LTx-5 and LTx-13 when compared with CU and CON (P < 0.01), but normalized in LTx-26 (P < 0.004 vs. LTx-5 and P = 0.3 vs. CON). The basal FFA turnover rate was decreased in LTx-26 (P < 0.01) and CU (P < 0.02) vs. CON. LTx-26 showed a lower FFA oxidation rate than CON (P < 0.02). Tissue glucose disposal was impaired in LTx-5 (P < 0.005) and LTx-13 (P < 0.03), but not in LTx-26 when compared to CON. LTx-26 had normal basal and insulin-modulated endogenous glucose production. In conclusion, LTx have impaired insulin-stimulated glucose, FFA, and protein metabolism 5 mo after surgery. Follow-up at 26 mo results in (a) normalization of insulin-dependent glucose metabolism, most likely related to the reduction of prednisone dose, and, (b) maintenance of some alterations in leucine and FFA metabolism, probably related to the functional denervation of the graft and to the immunosuppressive treatment.
PMCID: PMC507852  PMID: 9045872
10.  Explaining Behavior Change after Genetic Testing: The Problem of Collinearity between Test Results and Risk Estimates 
Genetic testing  2008;12(3):381-386.
This paper explores whether and how the behavioral impact of genotype disclosure can be disentangled from the impact of numerical risk estimates generated by genetic tests. Secondary data analyses are presented from a randomized controlled trial of 162 first-degree relatives of Alzheimer’s disease (AD) patients. Each participant received a lifetime risk estimate of AD. Control group estimates were based on age, gender, family history, and assumed ε4-negative apolipoprotein E (APOE) genotype; intervention group estimates were based upon the first three variables plus true APOE genotype, which was also disclosed. AD-specific self-reported behavior change (diet, exercise, and medication use) was assessed at 12 months. Behavior change was significantly more likely with increasing risk estimates, and also more likely, but not significantly so, in ε4-positive intervention group participants (53% changed behavior) than in control group participants (31%). Intervention group participants receiving ε4-negative genotype feedback (24% changed behavior) and control group participants had similar rates of behavior change and risk estimates, the latter allowing assessment of the independent effects of genotype disclosure. However, collinearity between risk estimates and ε4-positive genotypes, which engender high-risk estimates, prevented assessment of the independent effect of the disclosure of an ε4 genotype. Novel study designs are proposed to determine whether genotype disclosure has an impact upon behavior beyond that of numerical risk estimates.
PMCID: PMC2925186  PMID: 18666860
11.  Effect of Knowledge of APOE Genotype on Subjective and Objective Memory Performance in Healthy Older Adults 
The American journal of psychiatry  2014;171(2):201-208.
The knowledge that one carries the apolipoprotein E (APOE) ε4 allele risk factor for Alzheimer’s disease was recently found to have little short-term psychological risk. The authors investigated the impact of knowledge of carrying the risk allele on subjective ratings of memory and objective memory test performance of older adults.
Using a nested case-control design, the authors administered objective verbal and visual memory tests and self-rating scales of memory function to 144 cognitively normal older adults (ages 52–89) with known APOE genotype who knew (ε4+, N=25; ε4−, N=49) or did not know (ε4+, N=25; ε4−, N=45) their genotype and genetic risk for Alzheimer’s disease prior to neuropsychological evaluation.
Significant genotype-by-disclosure interaction effects were observed on several memory rating scales and tests of immediate and delayed verbal recall. Older adults who knew their ε4+ genotype judged their memory more harshly and performed worse on an objective verbal memory test than did ε4+ adults who did not know. In contrast, older adults who knew their ε4− genotype judged their memory more positively than did ε4− adults who did not know, but these groups did not differ in objective memory test performance.
Informing older adults that they have an APOE genotype associated with an increased risk of Alzheimer’s disease can have adverse consequences on their perception of their memory abilities and their performance on objective memory tests. The patient’s knowledge of his or her genotype and risk of Alzheimer’s disease should be considered when evaluating cognition in the elderly.
PMCID: PMC4037144  PMID: 24170170
12.  Health Behavior Changes After Genetic Risk Assessment for Alzheimer Disease: The REVEAL Study 
Risk information for Alzheimer disease (AD) may be communicated through susceptibility gene disclosure, even though this is not currently in clinical use. The REVEAL Study is the first randomized clinical trial of risk assessment for AD with apolipoprotein E (APOE) genotype and numerical risk estimate disclosure. We examined whether APOE genotype and numerical risk disclosure to asymptomatic individuals at high risk for AD alters health behaviors. One hundred sixty-two participants were randomized to either intervention (APOE disclosure) or control (no genotype disclosure) groups. Subjects in both groups received numerical lifetime risk estimates of future AD development based on sex and family history of AD. The intervention group received their APOE genotype. Subjects were informed that no proven preventive measures for AD existed and given an information sheet on preventative therapies under investigation. Participants who learned they were ε4 positive were significantly more likely than ε4 negative participants to report AD-specific health behavior change 1 year after disclosure (adjusted odds ratio: 2.73; 95% confidence interval: 1.14, 6.54; P = 0.02). Post hoc analyses revealed similar significant associations between numerical lifetime risk estimates and self-report of AD-specific health behavior change. Despite lack of preventive measures for AD, knowledge of APOE genotype, numerical lifetime risk, or both, influences health behavior.
PMCID: PMC2483341  PMID: 18317253
Alzheimer; memory; health behavior change; risk assessment
13.  APOE ε2 and ε4 influence the susceptibility for Alzheimer's disease but not other dementias 
Apolipoprotein E (APOE) genotype was determined in a population of patients with dementia, including 735 patients with Alzheimer's disease (AD), 75 with Frontotemporal Lobar Degeneration (FTLD), 97 with Vascular Dementia (VaD) and 40 with Lewy Body Dementia (LBD), as well as in 506 age- and gender-matched controls (CON). APOE ε2 allele frequency was lower in patients with AD (2.8%) than in CON (6.4%, P≤0.001, OR: 0.41). Similar results were obtained comparing AD with FTLD (6.7%, P≤0.01, OR: 0.37), at difference from VaD (5.6%, P>0.05) or LBD (5.0%, P>0.05). The frequency of the APOE ε4 allele was increased in patients with AD (25.1%) as compared with CON (8.2%, P≤0.001, OR: 4.24), FTLD (11.3%, P≤0.001, OR: 2.67), VaD (11.8%, P≤0.001, OR: 3.02), or LBD (13.8%, P=0.048, OR: 2.07). The frequency of the ε4/ε4 genotype was increased in AD patients compared with controls (6.3 versus 0.8%, P≤0.001, OR: 8.38). The presence of the ε2 allele is a protective factor for AD, whereas the ε4 allele acts as a risk factor for the disease. Both alleles do not influence the susceptibility to FTLD, LBD and VaD.
PMCID: PMC3076771  PMID: 21537391
Apolipoprotein E (APOE); Alzheimer's disease (AD); Frontotemporal Lobar Degeneraton (FTLD); Vascular dementia (VaD); Lewy body dementia (LBD); risk factor
14.  “I know what you told me, but this is what I think:” Perceived risk of Alzheimer disease among individuals who accurately recall their genetics-based risk estimate 
This study evaluates the Alzheimer disease risk perceptions of individuals who accurately recall their genetics-based Alzheimer disease risk assessment.
Two hundred forty-six unaffected first-degree relatives of patients with Alzheimer disease were enrolled in a multisite randomized controlled trial examining the effects of communicating APOE genotype and lifetime Alzheimer disease risk information.
Among the 158 participants who accurately recalled their Alzheimer disease risk assessment 6 weeks after risk disclosure, 75 (47.5%) believed their Alzheimer disease risk was more than 5% points different from the Alzheimer disease risk estimate they were given. Within this subgroup, 69.3% believed that their Alzheimer disease risk was higher than what they were told (discordant high), whereas 30.7% believed that their Alzheimer disease risk was lower (discordant low). Participants with a higher baseline risk perception were more likely to have a discordant-high risk perception (P < 0.05). Participants in the discordant-low group were more likely to be APOE ε4 positive (P < 0.05) and to score higher on an Alzheimer disease controllability scale (P < 0.05).
Our results indicate that even among individuals who accurately recall their Alzheimer disease risk assessment, many people do not take communicated risk estimates at face value. Further exploration of this clinically relevant response to risk information is warranted.
PMCID: PMC2921681  PMID: 20139767
risk recall; risk perception; Alzheimer disease; genetic susceptibility testing
15.  Effect of Kaiyu Qingwei Jianji on the morphometry and residual strain distribution of small intestine in experimental diabetic rats 
AIM: To investigate the effect of a Chinese medicine, Kaiyu Qingwei Jianji (KYQWJJ) used for diabetic treatment, on the morphometry and residual strain distribution of the small intestine in streptozotocin (STZ) -induced diabetic rats. Correlation analysis was also performed between the opening angle and residual strain with the blood glucose level.
METHODS: Forty-two male Wistar rats weighing 220-240 g were included in this study. Thirty-two STZ-induced diabetic rats were subdivided into four groups (n = 8 in each group), i.e. diabetic control group (DM); high dose of KYQWJJ (T1, 36g/kg per day); low dose of KYQWJJ (T2, 17 g/kg per day) and Gliclazide (T3, 50 mg/kg per day). Another ten rats were used as non-diabetic control (CON). The medicines were poured directly into stomach lumen by gastric lavage twice daily. The rats of CON and DM groups were only poured the physiological saline. Blood glucose and plasma insulin levels were measured. Experimental period was 35 d. At the end of experiment, three 5-cm long segments were harvested from the duodenum, jejunum and ileum. Three rings of 1-2 mm in length for no-load and zero-stress state tests were cut from the middle of different segments. The morphometric data, such as the circumferential length, the wall thickness and the opening angle were measured from the digitized images of intestinal segments in the no-load state and zero-stress state. The residual strain was computed from the morphometry data. Furthermore, the linear regression analysis was performed between blood glucose level with morphometric and biomechanical data in the different intestinal segments.
RESULTS: The blood glucose level of DM group was consistent 4-fold to 5-fold higher than those in CON group during the experiment (16.89 ± 1.11 vs 3.44 ± 0.15 mmol/L, P < 0.001). The blood glucose level in the T1 (16.89 ± 1.11 vs 11.08 ± 2.67 mmol/L, P < 0.01) and T3 groups (16.89 ± 1.11 vs 13.54 ± 1.73 mmol/L, P < 0.05), but not in T2 group (P > 0.05) was significantly lower than those in DM group. The plasma insulin levels of DM, T1, T2 and T3 groups were significantly lower than those in CON group (10.98 ± 1.02, 12.52 ± 1.42,13.54 ± 1.56,10.96 ± 0.96 vs 17.84 ± 2.34 pmol/L respectively, P < 0.05), but no significantly difference among the groups with exception of CON group. The wet weight/cm and total wall thickness of duodenum, jejunum and ileum in DM group were significantly higher than those in CON group (wet weight (g/cm): duodenum 0.209 ± 0.012 vs 0.166 ± 0.010, jejunum 0.149 ± 0.008 vs 0.121 ± 0.004, ileum 0.134 ± 0.013 vs 0.112 ± 0.007; Wall thickness (mm): duodenum 0.849 ± 0.027 vs 0.710 ± 0.026, jejunum 0.7259 ± 0.034 vs 0.627 ± 0.025, ileum 0.532 ± 0.023 vs 0.470 ± 0.010, all P < 0.05), T1 and T3 treatment could partly restore change of wall thickness, but T2 could not. The opening angle and absolute value of inner and outer residual stain were significantly smaller in duodenal segment (188 ± 11 degrees, -0.31 ± 0.02 and 0.35 ± 0.03 vs 259 ± 15 degrees, -0.40 ± 0.02 and 0.43 ± 0.05) and larger in jejunal (215 ± 20 degrees, -0.30 ± 0.03 and 0.36 ± 0.06 vs 172 ± 19 degrees, -0.25 ± 0.02 and 0.27 ± 0.02) and ileal segments (183 ± 20 degrees, -0.28 ± 0.01 and 0.34 ± 0.05 vs 153 ± 14 degrees, -0.23 ± 0.03 and 0.29 ± 0.04) in DM group than in CON group (P < 0.01). T1 and T3 treatment could partly restore this biomechanical alteration, but strong effect was found in T1 treatment (duodenum 243 ± 14 degrees, -0.36 ± 0.02 and 0.42 ± 0.06, jejunum 180 ± 15 degrees, -0.26 ± 0.03 and 0.30 ± 0.06 and ileum 163 ± 17 degrees, -0.23 ± 0.03 and 0.30 ± 0.05, compared with DM, P < 0.05). The linear association was found between the glucose level with most morphometric and biomechanical data.
CONCLUSION: KYQWJJ (high dose) treatment could partly restore the changes of blood glucose level and the remodeling of morphometry and residual strain of small intestine in diabetic rats. The linear regression analysis demonstrated that the effect of KYQWJJ on intestinal opening angle and residual strain is partially through its effect on the blood glucose level.
PMCID: PMC4087776  PMID: 17131477
Diabetes; Intestine; Kaiyu Qingwei Jianji; Residual strain; Rat
16.  Development of a Communication Protocol for Telephone Disclosure of Genetic Test Results for Cancer Predisposition 
JMIR Research Protocols  2014;3(4):e49.
Dissemination of genetic testing for disease susceptibility, one application of “personalized medicine”, holds the potential to empower patients and providers through informed risk reduction and prevention recommendations. Genetic testing has become a standard practice in cancer prevention for high-risk populations. Heightened consumer awareness of “cancer genes” and genes for other diseases (eg, cardiovascular and Alzheimer’s disease), as well as the burgeoning availability of increasingly complex genomic tests (ie, multi-gene, whole-exome and -genome sequencing), has escalated interest in and demand for genetic risk assessment and the specialists who provide it. Increasing demand is expected to surpass access to genetic specialists. Thus, there is urgent need to develop effective and efficient models of delivery of genetic information that comparably balance the risks and benefits to the current standard of in-person communication.
The aim of this pilot study was to develop and evaluate a theoretically grounded and rigorously developed protocol for telephone communication of BRCA1/2 (breast cancer) test results that might be generalizable to genetic testing for other hereditary cancer and noncancer syndromes.
Stakeholder data, health communication literature, and our theoretical model grounded in Self-Regulation Theory of Health Behavior were used to develop a telephone communication protocol for the communication of BRCA1/2 genetic test results. Framework analysis of selected audiotapes of disclosure sessions and stakeholders’ feedback were utilized to evaluate the efficacy and inform refinements to this protocol.
Stakeholder feedback (n=86) and audiotapes (38%, 33/86) of telephone disclosures revealed perceived disadvantages and challenges including environmental factors (eg, non-private environment), patient-related factors (eg, low health literacy), testing-related factors (eg, additional testing needed), and communication factors (eg, no visual cues). Resulting modifications to the communication protocol for BRCA1/2 test results included clarified patient instructions, scheduled appointments, refined visual aids, expanded disclosure checklist items, and enhanced provider training.
Analyses of stakeholders’ experiences and audiotapes of telephone disclosure of BRCA1/2 test results informed revisions to communication strategies and a protocol to enhance patient outcomes when utilizing telephone to disclose genetic test results.
PMCID: PMC4259920  PMID: 25355401
genetic testing; test result disclosure; communication; telemedicine; cancer risk assessment; self-regulation theory of health behavior
17.  Language Impairment in Children Perinatally Infected with HIV Compared to Children Who Were HIV-Exposed and Uninfected 
To investigate risk for language impairment in children perinatally infected or exposed to HIV.
We evaluated the prevalence of language impairment (LI) in 7–16 year old children with perinatal HIV infection (HIV+) compared to children HIV-exposed and uninfected (HEU), using a comprehensive standardized language test (CELF-4). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease and antiretroviral treatment (ART) factors with LI category were evaluated using univariate and multivariable logistic regression models.
Of 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ vs 87.5 (17.9) for HEU. After adjustment, Black children had higher odds of Pri-LI vs no LI (aOR=2.43, p=0.03). Children who were Black, Hispanic, had a caregiver with low education or low IQ, or a non-biological parent as caregiver had higher odds of Con-LI vs no LI. Among HIV+ children, viral load >400 copies/ml (aOR=3.04, p<0.001), CDC Class C (aOR=2.19, p=0.02) and ART initiation <6 months of age (aOR=2.12, p=0.02) were associated with higher odds of Con-LI vs. no LI.
Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI.
PMCID: PMC3310927  PMID: 22179050
Pediatric HIV infection; language impairment; antiretroviral therapy
18.  Semantic memory activation in individuals at risk for developing Alzheimer disease 
Neurology  2009;73(8):612-620.
To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE ɛ4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names.
Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no ɛ4 allele (control [CON]); 2) family history, no ɛ4 allele (FH); and 3) family history and ɛ4 allele (FH+ɛ4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only).
Cognitively intact older adults with AD risk factors (FH and FH+ɛ4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+ɛ4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression.
Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults.
= Alzheimer disease;
= Analysis of Functional NeuroImages;
= analysis of variance;
= area under the curve;
= Brodmann area;
= blood oxygen level–dependent;
= control;
= Dementia Rating Scale 2;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= episodic memory;
= family history;
= field of view;
= functional region of interest;
= hemodynamic response function;
= mild cognitive impairment;
= Mayo Older Americans Normative Studies;
= magnetic resonance;
= medial temporal lobe;
= not significant;
= Rey Auditory–Verbal Learning Test;
= semantic memory;
= supplementary motor area;
= spoiled gradient-recalled at steady state;
= echo time;
= repetition time;
= voxel-based morphometry.
PMCID: PMC2731619  PMID: 19704080
19.  Behaviour change in clients of health centre‐based voluntary HIV counselling and testing services in Kenya 
Sexually Transmitted Infections  2007;83(7):541-546.
To explore behaviour change, baseline risk behaviour, perception of risk, HIV disclosure and life events in health centre‐based voluntary counselling and testing (VCT) clients.
Design and setting
Single‐arm prospective cohort with before–after design at three (one urban and two rural) government health centres in Kenya; study duration 2 years, 1999–2001.
Consecutive eligible adult clients.
Main outcome measures
Numbers of sexual partners, partner type, condom use, reported symptoms of sexually transmitted infection, HIV disclosure and life events.
High rates of enrolment and follow‐up provided a demographically representative sample of 401 clients with mean time to follow‐up of 7.5 months. Baseline indicators showed that clients were at higher risk than the general population, but reported a poor perception of risk. Clients with multiple partners showed a significant reduction of sexual partners at follow‐up (16% to 6%; p<0.001), and numbers reporting symptoms of sexually transmitted infection decreased significantly also (from 40% to 15%; p<0.001). Condom use improved from a low baseline. Low rates of disclosure (55%) were reported by HIV‐positive clients. Overall, no changes in rates of life events were seen.
This study suggests that significant prevention gains can be recorded in clients receiving health centre‐based VCT services in Africa. Prevention issues should be considered when refining counselling and testing policies for expanding treatment programmes.
PMCID: PMC2598642  PMID: 17991688
20.  Beneficial Effects of Alternate Dietary Regimen on Liver Inflammation, Atherosclerosis and Renal Activation 
PLoS ONE  2011;6(3):e18432.
Alternate day calorie restriction (CR) has been shown to be almost as beneficial as daily CR. The question arises whether this concept is also applicable to alternating dietary composition.
To seek evidence that alternating high cholesterol (HC) - cholesterol-free (CON) Western diet can effectively diminish hepatic and renal inflammation and cardiovascular risk factors as compared with daily HC-supplemented Western diet.
Four groups of ApoE*3Leiden mice, a humanized model for atherosclerosis, were subjected to different feeding treatments for 16 weeks. Mice were fed CON diet; CON diet with 1% w/w cholesterol (HC); alternate (ALT) diet regimen of CON (4 days) and HC (3 days); or CON diet supplemented with 0.43% (w/w) cholesterol (MC), with overall dietary cholesterol intake equal to ALT. Plasma was analyzed for cardiovascular risk factors, aorta for atherosclerotic lesion formation, and liver and kidney for inflammation.
ALT diet but not MC was almost as effective as daily CON feeding in preventing disease development. Compared to HC, the ALT group showed 62% lower hepatic nuclear factor kappa B (NF-κB) activity (P<0.001), a reduction of the circulating inflammatory markers E-selectin (−20%; P<0.05), vascular cell adhesion molecule 1 (VCAM-1; −15%; P<0.05) and Serum Amyloid A (SAA; −31%; P<0.05), smaller atherosclerotic lesion sizes (−51%; 46497±10791 µm2 vs. 94664±16470 µm2; P<0.05) and diminished renal expression of specific inflammation and activation markers (VCAM-1, −27%; P<0.05; monocyte chemotactic protein-1 (MCP-1); −37%; P<0.01).
Alternate HC-CON feeding reproduced most of the beneficial effects of daily cholesterol-free diet, including strongly diminished hepatic, vascular and renal activation and inflammation; also atherosclerosis was reduced by half as compared to HC, albeit still higher compared to the CON group.
PMCID: PMC3069095  PMID: 21483792
21.  When Do HIV-Infected Women Disclose Their HIV Status to Their Male Partner and Why? A Study in a PMTCT Programme, Abidjan 
PLoS Medicine  2007;4(12):e342.
In Africa, women tested for HIV during antenatal care are counselled to share with their partner their HIV test result and to encourage partners to undertake HIV testing. We investigate, among women tested for HIV within a prevention of mother-to-child transmission of HIV (PMTCT) programme, the key moments for disclosure of their own HIV status to their partner and the impact on partner HIV testing.
Methods and Findings
Within the Ditrame Plus PMTCT project in Abidjan, 546 HIV-positive and 393 HIV-negative women were tested during pregnancy and followed-up for two years after delivery. Circumstances, frequency, and determinants of disclosure to the male partner were estimated according to HIV status. The determinants of partner HIV testing were identified according to women's HIV status. During the two-year follow-up, disclosure to the partner was reported by 96.7% of the HIV-negative women, compared to 46.2% of HIV-positive women (χ2 = 265.2, degrees of freedom [df] = 1, p < 0.001). Among HIV-infected women, privileged circumstances for disclosure were just before delivery, during early weaning (at 4 mo to prevent HIV postnatal transmission), or upon resumption of sexual activity. Formula feeding by HIV-infected women increased the probability of disclosure (adjusted odds ratio 1.54, 95% confidence interval 1.04–2.27, Wald test = 4.649, df = 1, p = 0.031), whereas household factors such as having a co-spouse or living with family reduced the probability of disclosure. The proportion of male partners tested for HIV was 23.1% among HIV-positive women and 14.8% among HIV-negative women (χ2 = 10.04, df = 1, p = 0.002). Partners of HIV-positive women who were informed of their wife's HIV status were more likely to undertake HIV testing than those not informed (37.7% versus 10.5%, χ2 = 56.36, df = 1, p < 0.001).
In PMTCT programmes, specific psychosocial counselling and support should be provided to women during the key moments of disclosure of HIV status to their partners (end of pregnancy, weaning, and resumption of sexual activity). This support could contribute to improving women's adherence to the advice given to prevent postnatal and sexual HIV transmission.
In a mother-to-child HIV prevention program in Côte d'Ivoire, Annabel Desgrées-du-Loû and colleagues identify three junctures at which women tend to disclose their HIV status to partners.
Editors' Summary
Since the first reported case of AIDS (acquired immunodeficiency syndrome) in 1981, the number of people infected with the human immunodeficiency virus (HIV), which causes AIDS, has risen steadily. By the end of 2006, nearly 40 million people were infected, 25 million of them in sub-Saharan Africa. HIV is most often spread by having unprotected sex with an infected partner. In Africa, most sexual transmission of HIV is between partners in stable relationships—many such couples do not adopt measures that prevent viral transmission, such as knowing the HIV status of both partners and using condoms if one partner is HIV-positive. HIV can also pass from a mother to her baby during pregnancy, labor, or delivery, or through breastfeeding. Mother-to-child transmission (MTCT) of HIV can be reduced by giving anti-HIV drugs to the mother during pregnancy and labor and to her newborn baby, and by avoiding breastfeeding or weaning the baby early.
Why Was This Study Done?
Many African countries have programs for prevention of MTCT (PMTCT) that offer pregnant women prenatal HIV counseling and testing. As a result, women are often the first member of a stable relationship to know their HIV status. PMTCT programs advise women to disclose their HIV test result to their partner and to encourage him to have an HIV test. But for many women, particularly those who are HIV-positive, talking to their partner about HIV/AIDS is hard because of fears of rejection (which could mean loss of housing and food) or accusations of infidelity. Knowing more about when women disclose their HIV status and what makes them decide to do so would help the people running PMTCT programs to support women during the difficult process of disclosure. In this study, the researchers have investigated when and why women participating in a PMTCT research project in Abidjan (Côte d'Ivoire) told their partner about their HIV status and the impact this disclosure had on their partner's uptake of HIV testing.
What Did the Researchers Do and Find?
At regular follow-up visits, the researchers asked women in the Abidjan PMTCT project whether they had told their partners their HIV status and whether they were breast-feeding or had resumed sexual activity. Nearly all the women who tested negative for HIV, but slightly fewer than half of the HIV-positive (infected) women had told their partner about their HIV status by two years after childbirth. Two-thirds of the HIV-positive women who disclosed their status did so before delivery. Other key times for disclosure were at early weaning (4 months after birth) for women who breast-fed their babies, and when sexual activity resumed. HIV-positive women who bottle fed their babies from birth were more likely to tell their partners of their status than women who breast-fed. Factors that prevented women disclosing their HIV status included living in a polygamous relationship or living separately from their partners. Finally, the researchers report that the partners of HIV-positive women who disclosed their HIV status were about three times more likely to take an HIV test than the partners of HIV-positive women who did not disclose.
What Do These Findings Mean?
These findings identify three key times when women who have had an HIV test during pregnancy are likely to disclose their HIV status to their partner. The main one is before delivery and relates, in part, to how the mother plans to feed her baby. To bottle feed in Abidjan, women need considerable support from their partners and this may be the impetus for disclosing their HIV status. Disclosure at early weaning may reflect the woman's need to enlist her partner's support for this unusual decision—the normal time for weaning in Abidjan is 17 months. Finally, disclosure when sexual activity resumes may be necessary so that the woman can explain why she wants to use condoms. Although these findings need confirmation in other settings, targeting counseling and support within PMTCT programs to these key moments might help HIV-positive women to tell their partners about their status. This, hopefully, would help to reduce sexual transmission of HIV within stable relationships in sub-Saharan Africa.
Additional Information.
Please access these Web sites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Women Children and HIV provides extensive information on prevention of mother-to-child transmission of HIV in developing countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS in Africa and on HIV and AIDS prevention
AIDSinfo, a service of the US Department of Health and Human Services provideshealth information for HIV-positive pregnant women (in English and Spanish)
PMCID: PMC2100145  PMID: 18052603
22.  Effects of a popular exercise and weight loss program on weight loss, body composition, energy expenditure and health in obese women 
To determine the safety and efficacy of altering the ratio of carbohydrate and protein in low-energy diets in conjunction with a popular exercise program in obese women.
Matched, prospective clinical intervention study to assess efficacy of varying ratios of carbohydrate and protein intake in conjunction with a regular exercise program.
One-hundred sixty one sedentary, obese, pre-menopausal women (38.5 ± 8.5 yrs, 164.2 ± 6.7 cm, 94.2 ± 18.8 kg, 34.9 ± 6.4 kg·m-2, 43.8 ± 4.2%) participated in this study. Participants were weight stable and not participating in additional weight loss programs.
Participants were assigned to either a no exercise + no diet control (CON), a no diet + exercise group (ND), or one of four diet + exercise groups (presented as kcals; % carbohydrate: protein: fat): 1) a high energy, high carbohydrate, low protein diet (HED) [2,600; 55:15:30%], 2) a very low carbohydrate, high protein diet (VLCHP) [1,200 kcals; 63:7:30%], 3) a low carbohydrate, moderate protein diet (LCMP) [1,200 kcals; 50:20:30%] and 4) a high carbohydrate, low protein diet (HCLP) [1,200 kcals; 55:15:30%]. Participants in exercise groups (all but CON) performed a pneumatic resistance-based, circuit training program under supervision three times per week.
Anthropometric, body composition, resting energy expenditure (REE), fasting blood samples and muscular fitness assessments were examined at baseline and weeks 2, 10 and 14.
All groups except CON experienced significant reductions (P < 0.05 – 0.001) in waist circumference over 14 weeks. VLCHP, LCHP and LPHC participants experienced similar but significant (P < 0.05 – 0.001) reductions in body mass when compared to other groups. Delta responses indicated that fat loss after 14 weeks was significantly greatest in VLCHP (95% CI: -5.2, -3.2 kg), LCMP (-4.0, -1.9 kg) and HCLP (-3.8, -2.1 kg) when compared to other groups. Subsequent reductions in % body fat were significantly greater in VLCHP, LCMP and HCLP participants. Initial dieting decreased (P < 0.05) relative REE similarly in all groups. All exercise groups significantly (P < 0.05) improved in muscular fitness, but these improvements were not different among groups. Favorable but non-significant mean changes occurred in lipid panels, glucose and HOMA-IR. Leptin levels decreased (P < 0.05) in all groups, except for CON, after two weeks of dieting and remained lower throughout the 14 week program. Exercise participation resulted in significant improvements in quality of life and body image.
Exercise alone (ND) appears to have minimal impact on measured outcomes with positive outcomes apparent when exercise is combined with a hypoenergetic diet. Greater improvements in waist circumference and body composition occurred when carbohydrate is replaced in the diet with protein. Weight loss in all diet groups (VLCHP, LCMP and HCLP) was primarily fat and stimulated improvements in markers of cardiovascular disease risk, body composition, energy expenditure and psychosocial parameters.
PMCID: PMC2693519  PMID: 19442301
23.  Disclosing the disclosure: Factors associated with communicating the results of genetic susceptibility testing for Alzheimer’s disease 
Journal of health communication  2009;14(8):768-784.
This study explored the extent to which recipients of genetic susceptibility testing for Alzheimer’s disease (AD) communicated their results to others. It also examined demographic characteristics, along with beliefs about AD, associated with such communication. Participants (N = 271) in a randomized clinical trial involving genetic testing for Apolipoprotein E (APOE) gene variants among first-degree relatives of AD patients reported their communication behaviors 6 weeks after the results disclosure. Information on beliefs about AD and genetic testing was collected at baseline. Eighty-two percent of participants receiving APOE genotype information shared their results with someone. Specifically, 64% shared with family members, 51% with spouse or significant others, 35% with friends, and 12% with health care professionals. Greater AD treatment optimism was associated with communicating results to family (OR=1.43), spouse (OR=1.62), friends (OR =1.81), and health care professionals (OR=2.20). Lower perceived risk (OR=0.98) and higher perceived importance of genetics in the development of AD (OR=1.93) were associated with results communication in general. Lower perceived drawbacks of AD genetic testing was associated with results communication to friends (OR=0.65). Beliefs about AD risks and causes, genetic testing, and development of treatments may partly determine the interpersonal communication patterns of genetic susceptibility test results.
PMCID: PMC2801901  PMID: 20029710
Susceptibility genetic testing; Alzheimer’s disease; APOE communication; disclosure
24.  A data-driven model of biomarker changes in sporadic Alzheimer's disease 
Brain  2014;137(9):2564-2577.
Young et al. reformulate an event-based model for the progression of Alzheimer's disease to make it applicable to a heterogeneous sporadic disease population. The enhanced model predicts the ordering of biomarker abnormality in sporadic Alzheimer's disease independently of clinical diagnoses or biomarker cut-points, and shows state-of-the-art diagnostic classification performance.
We demonstrate the use of a probabilistic generative model to explore the biomarker changes occurring as Alzheimer’s disease develops and progresses. We enhanced the recently introduced event-based model for use with a multi-modal sporadic disease data set. This allows us to determine the sequence in which Alzheimer’s disease biomarkers become abnormal without reliance on a priori clinical diagnostic information or explicit biomarker cut points. The model also characterizes the uncertainty in the ordering and provides a natural patient staging system. Two hundred and eighty-five subjects (92 cognitively normal, 129 mild cognitive impairment, 64 Alzheimer’s disease) were selected from the Alzheimer’s Disease Neuroimaging Initiative with measurements of 14 Alzheimer’s disease-related biomarkers including cerebrospinal fluid proteins, regional magnetic resonance imaging brain volume and rates of atrophy measures, and cognitive test scores. We used the event-based model to determine the sequence of biomarker abnormality and its uncertainty in various population subgroups. We used patient stages assigned by the event-based model to discriminate cognitively normal subjects from those with Alzheimer’s disease, and predict conversion from mild cognitive impairment to Alzheimer’s disease and cognitively normal to mild cognitive impairment. The model predicts that cerebrospinal fluid levels become abnormal first, followed by rates of atrophy, then cognitive test scores, and finally regional brain volumes. In amyloid-positive (cerebrospinal fluid amyloid-β1–42 < 192 pg/ml) or APOE-positive (one or more APOE4 alleles) subjects, the model predicts with high confidence that the cerebrospinal fluid biomarkers become abnormal in a distinct sequence: amyloid-β1–42, phosphorylated tau, total tau. However, in the broader population total tau and phosphorylated tau are found to be earlier cerebrospinal fluid markers than amyloid-β1–42, albeit with more uncertainty. The model’s staging system strongly separates cognitively normal and Alzheimer’s disease subjects (maximum classification accuracy of 99%), and predicts conversion from mild cognitive impairment to Alzheimer’s disease (maximum balanced accuracy of 77% over 3 years), and from cognitively normal to mild cognitive impairment (maximum balanced accuracy of 76% over 5 years). By fitting Cox proportional hazards models, we find that baseline model stage is a significant risk factor for conversion from both mild cognitive impairment to Alzheimer’s disease (P = 2.06 × 10−7) and cognitively normal to mild cognitive impairment (P = 0.033). The data-driven model we describe supports hypothetical models of biomarker ordering in amyloid-positive and APOE-positive subjects, but suggests that biomarker ordering in the wider population may diverge from this sequence. The model provides useful disease staging information across the full spectrum of disease progression, from cognitively normal to mild cognitive impairment to Alzheimer’s disease. This approach has broad application across neurodegenerative disease, providing insights into disease biology, as well as staging and prognostication.
PMCID: PMC4132648  PMID: 25012224
event-based model; disease progression; Alzheimer’s disease; biomarkers; biomarker ordering
25.  Willingness to Pay for Genetic Testing for Alzheimer's Disease: A Measure of Personal Utility 
Background: The increased availability of genetic tests for common, complex diseases, such as Alzheimer's disease (AD), raises questions about what people are willing to pay for these services. Methods: We studied willingness-to-pay for genetic testing in a study of AD risk assessment that included APOE genotype disclosure among 276 first-degree relatives of persons with AD. Results: Seventy-one percent reported that they would ask for such testing from their doctor if it were covered by health insurance, and 60% would ask for it even if it required self-pay. Forty-one percent were willing to pay more than $100 for testing, and more than half would have been willing to pay for the test out of pocket. Participants who learned that they were APOE ɛ4 positive and those who had higher education were less likely to want testing if covered by insurance, possibly to avoid discrimination. Conclusion: This is the first report to examine willingness to pay for susceptibility genetic testing in a sample of participants who had actually undergone such testing. These findings reveal that some participants find valuable personal utility in genetic risk information even when such information does not have proven clinical utility.
PMCID: PMC3241735  PMID: 21749214

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