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2.  How could disclosing incidental information from whole-genome sequencing affect patient behavior? 
Personalized medicine  2013;10(4):10.2217/pme.13.24.
In this article, we argue that disclosure of incidental findings from whole-genome sequencing has the potential to motivate individuals to change health behaviors through psychological mechanisms that differ from typical risk assessment interventions. Their ability to do so, however, is likely to be highly contingent upon the nature of the incidental findings and how they are disclosed, the context of the disclosure and the characteristics of the patient. Moreover, clinicians need to be aware that behavioral responses may occur in unanticipated ways. This article argues for commentators and policy makers to take a cautious but optimistic perspective while empirical evidence is collected through ongoing research involving whole-genome sequencing and the disclosure of incidental information.
doi:10.2217/pme.13.24
PMCID: PMC3852635  PMID: 24319470
contextual factor; health behavior; incidental finding; whole-genome sequencing
3.  Genomic Medicine in Primary Care: Barriers and Assets 
Postgraduate medical journal  2013;89(1057):615-616.
doi:10.1136/postgradmedj-2013-132093
PMCID: PMC3951755  PMID: 24129030
individualized medicine; genomics; primary health care
4.  Variations in predicted risks in personal genome testing for common complex diseases 
Purpose
The promise of personalized genomics for common complex diseases depends, in part, on the ability to predict genetic risks on the basis of single nucleotide polymorphisms. We examined and compared the methods of three companies (23andMe, deCODEme, and Navigenics) that have offered direct-to-consumer personal genome testing.
Methods
We simulated genotype data for 100,000 individuals on the basis of published genotype frequencies and predicted disease risks using the methods of the companies. Predictive ability for six diseases was assessed by the AUC.
Results
AUC values differed among the diseases and among the companies. The highest values of the AUC were observed for age related macular degeneration, celiac disease, and Crohn disease. The largest difference among the companies was found for celiac disease: the AUC was 0.73 for 23andMe and 0.82 for deCODEme. Predicted risks differed substantially among the companies as a result of differences in the sets of single nucleotide polymorphisms selected and the average population risks selected by the companies, and in the formulas used for the calculation of risks.
Conclusion
Future efforts to design predictive models for the genomics of common complex diseases may benefit from understanding the strengths and limitations of the predictive algorithms designed by these early companies.
doi:10.1038/gim.2013.80
PMCID: PMC3883880  PMID: 23807614
5.  Personalized Genetic Risk Counseling to Motivate Diabetes Prevention 
Diabetes Care  2012;36(1):13-19.
OBJECTIVE
To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors.
RESEARCH DESIGN AND METHODS
We conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top and bottom score quartiles received individual genetic counseling before being enrolled with untested control participants in a 12-week, validated, diabetes prevention program. Middle-risk quartile participants were not studied further. We examined the effect of this genetic counseling intervention on patient self-reported attitudes, program attendance, and weight loss, separately comparing higher-risk and lower-risk result recipients with control participants.
RESULTS
The 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 ± 10.6 years, 61% were men, and average BMI was 34.8 kg/m2, with no differences among randomization groups. Participants attended 6.8 ± 4.3 group sessions and lost 8.5 ± 10.1 pounds, with 33 of 108 (30.6%) losing ≥5% body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects (P > 0.05 for all but one comparison).
CONCLUSIONS
Diabetes genetic risk counseling with currently available variants does not significantly alter self-reported motivation or prevention program adherence for overweight individuals at risk for diabetes.
doi:10.2337/dc12-0884
PMCID: PMC3526219  PMID: 22933432
6.  ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing 
In clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing, which emphasized the importance of disclosing the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. We recommend that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the ‘normal’ of tumor-normal subtractive analyses in all subjects, irrespective of age, but excluding fetal samples. We recognize that there are insufficient data on clinical utility to fully support these recommendations and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.
doi:10.1038/gim.2013.73
PMCID: PMC3727274  PMID: 23788249
secondary findings; incidental findings; genome; genomic medicine; personalized medicine; whole-exome; whole-genome; sequencing
7.  Management of Incidental Findings in Clinical Genomic Sequencing 
Genomic sequencing is becoming accurate, fast, and inexpensive, and is rapidly being incorporated into clinical practice. Incidental findings, which result in large numbers from genomic sequencing, are a potential barrier to the utility of this new technology due to their high prevalence and the lack of evidence or guidelines available to guide their clinical interpretation. This unit reviews the definition, classification, and management of incidental findings from genomic sequencing. The unit focuses on the clinical aspects of handling incidental findings, with an emphasis on the key role of clinical context in defining incidental findings and determining their clinical relevance and utility.
doi:10.1002/0471142905.hg0923s77
PMCID: PMC3763715  PMID: 23595601
8.  Diagnostic Accuracy Statistics for Seven Neuropsychological Assessment Battery (NAB) Test Variables in the Diagnosis of Alzheimer’s Disease 
Applied neuropsychology. Adult  2012;19(2):10.1080/09084282.2011.643947.
Neuropsychological tests are useful for diagnosing Alzheimer’s disease (AD), yet for many tests, diagnostic accuracy statistics are unavailable. We present diagnostic accuracy statistics for seven variables from the Neuropsychological Assessment Battery (NAB) that were administered to a large sample of elderly adults (n = 276) participating in a longitudinal research study at a national AD Center. Tests included Driving Scenes, Bill Payment, Daily Living Memory, Screening Visual Discrimination, Screening Design Construction, and Judgment. Clinical diagnosis was made independent of these tests, and for the current study, participants were categorized as AD (n = 65) or non-AD (n = 211). Receiver operating characteristics curve analysis was used to determine each test’s sensitivity and specificity at multiple cut points, which were subsequently used to calculate positive and negative predictive values at a variety of base rates. Of the tests analyzed, the Daily Living Memory test provided the greatest accuracy in the identification of AD and the two Screening measures required a significant tradeoff between sensitivity and specificity. Overall, the seven NAB subtests included in the current study are capable of excellent diagnostic accuracy, but appropriate understanding of the context in which the tests are used is crucial for minimizing errors.
doi:10.1080/09084282.2011.643947
PMCID: PMC3857936  PMID: 23373577
9.  The Structure and Validity of Self-reported Affect in Mild Cognitive Impairment and Mild Alzheimer’s Disease 
International psychogeriatrics / IPA  2011;23(6):10.1017/S104161021100041X.
Background
This study determined the reliability, validity, and factor structure of self-report emotions in persons with mild Alzheimer’s disease (AD) and mild cognitive impairment (MCI) relative to controls.
Methods
Participants (mild AD, n = 73; MCI, n = 159; controls, n = 96) rated current emotions with the Visual Analogue Mood Scales (Stern, 1997).
Results
Internal consistency reliabilities were comparable across groups, as were the factor structures of emotion. Persons with AD reported more negative affect (NA) than persons with MCI and controls. The emotion that most differentiated groups was confusion. NA and PA may be more bipolar in persons with AD than for persons with MCI and controls.
Conclusions
The underlying structure of affect was similar in persons with mild AD, MCI, and controls. Further, persons with MCI appeared to be “transitional” between cognitive health and dementia with regard to mood and affect. That is, participants with MCI tended to have affect scores that were intermediate between those with AD and controls. Implications for interventions to improve emotional well-being in AD and MCI are discussed.
doi:10.1017/S104161021100041X
PMCID: PMC3827970  PMID: 21429280
visual analogue scales; positive affect; negative affect; factor structure; emotion; self-report; dementia
11.  Research Results: Preserving Newborn Blood Samples 
Science translational medicine  2012;4(159):159cm12.
doi:10.1126/scitranslmed.3004474
PMCID: PMC3763707  PMID: 23136040
12.  The future of direct-to-consumer clinical genetic tests 
Nature reviews. Genetics  2011;12(7):511-515.
In light of the meeting of the US Food and Drug Administration (FDA) in March 2011 to discuss the regulation of clinical direct-to-consumer (DTC) genetic tests, we have invited five experts to consider the best means of overseeing the ordering and interpretation of these tests. Should these tests be regulated? If so, who, if anyone, should communicate results to consumers?
doi:10.1038/nrg3026
PMCID: PMC3763708  PMID: 21629275
13.  The Beliefs, Motivations, and Expectations of Parents Who Have Enrolled Their Children in a Genetic Biorepository 
Purpose
Little is known about parental attitudes toward return of individual research results (IRRs) in pediatric genomic research. The aim of this study was to understand the views of the parents who enrolled their children in a genomic repository in which IRRs will be returned.
Methods
We conducted focus groups with parents of children with developmental disorders enrolled in the Gene Partnership (GP), a genomic research repository that offers to return IRRs, to learn about their understanding of the GP, motivations for enrolling their children, and expectations regarding the return of IRRs.
Results
Parents hoped to receive IRRs that would help them better understand their children’s condition(s). They understood that this outcome was unlikely, but hoped that their children’s participation in the GP would contribute to scientific knowledge. Most parents wanted to receive all IRRs about their child, even for diseases that were severe and untreatable, citing reasons of personal utility. Parents preferred electronic delivery of the results and wanted to designate their preferences regarding what information they would receive.
Conclusion
It is important for researchers to understand participant expectations in enrolling in a research repository that offers to disclose children’s IRRs in order to effectively communicate the implications to parents during the consenting process.
doi:10.1038/gim.2011.25
PMCID: PMC3763713  PMID: 22241099
biorepository research; individual research results; parent perspectives; pediatric biobank; pediatric genetic research; returning research results
14.  Exploring Concordance and Discordance for Return of Incidental Findings from Clinical Sequencing 
Purpose
To explore specific conditions and types of genetic variants that specialists in genetics recommend should be returned as incidental findings in clinical sequencing.
Methods
Sixteen specialists in clinical genetics and/or molecular medicine selected variants in 99 common conditions to return to the ordering physician if discovered incidentally through whole genome sequencing. For most conditions, the specialists independently considered 3 molecular scenarios for both adults and minor children: a known pathogenic mutation, a truncating variant presumed pathogenic (where other truncating variants were known to be pathogenic), or a missense variant predicted in silico to be pathogenic.
Results
On average, for adults and children respectively, each specialist selected 83.5 and 79.0 conditions or genes out of 99 in the known pathogenic mutation categories, 57.0 and 53.5 out of 72 in the truncating variant categories, and 33.4 and 29.7 out of 72 in the missense variant categories. Concordance in favor of disclosure within the adult/known pathogenic mutation category was 100% for 21 conditions or genes and 80% or higher for 64 conditions or genes.
Conclusion
Specialists were highly concordant for the return of findings in 64 conditions or genes if discovered incidentally during whole exome or whole genome sequencing.
doi:10.1038/gim.2012.21
PMCID: PMC3763716  PMID: 22422049
whole genome sequencing; incidental findings
15.  Successful Recruitment of Centenarians for Post-Mortem Brain Donation: Results from the Georgia Centenarian Study 
Objective
Brain donation and neuropathological examination of brain tissues is the only way to obtain definitive diagnostic information on research subjects enrolled in aging studies. We investigated predictors of brain donation in a population-based study of centenarians in Phase III of the Georgia Centenarian Study (GCS).
Methods
Sixty-six individuals (mean age = 100.6 years, 91% female, 20% African American) were successfully recruited from the core sample of 244 individuals residing in 44 counties of Northeast Georgia to provide brain donation.
Results
Bivariate (t-tests, chi-square tests) and multivariate analyses (logistic regression) showed no significant differences between donors and non-donors across a wide range of demographic, religious, personality, cognitive and physical functioning characteristics.
Conclusions
We succeeded in recruiting a diverse, population-based sample of centenarians for brain donation. Our findings also suggest that barriers to brain donation reported in other studies may have less impact in these exceptional survivors.
PMCID: PMC3763720  PMID: 24013849
16.  Design of a Randomized Trial of Diabetes Genetic Risk Testing to Motivate Behavior Change: The Genetic Counseling/Lifestyle Change (GC/LC) Study to Prevent Diabetes 
Background
The efficacy of genetic testing for diabetes risk to motivate behavior change for diabetes prevention is currently unknown.
Purpose
This paper presents key issues in the design and implementation of one of the first randomized trials (the Genetic Counseling/Lifestyle Change for Diabetes Prevention Study) to test whether knowledge of diabetes genetic risk can motivate patients to adopt healthier behaviors.
Methods
Because individuals may react differently to receiving ‘higher’ vs ‘lower’ genetic risk results, we designed a 3-arm parallel group study to separately test the hypotheses that: (1) patients receiving ‘higher’ diabetes genetic risk results will increase healthy behaviors compared to untested controls, and (2) patients receiving ‘lower’ diabetes genetic risk results will decrease healthy behaviors compared to untested controls. In this paper we describe several challenges to implementing this study, including: (1) the application of a novel diabetes risk score derived from genetic epidemiology studies to a clinical population, (2) the use of the principle of Mendelian randomization to efficiently exclude ‘average’ diabetes genetic risk patients from the intervention, and (3) the development of a diabetes genetic risk counseling intervention that maintained the ethical need to motivate behavior change in both ‘higher’ and ‘lower’ diabetes genetic risk result recipients.
Results
Diabetes genetic risk scores were developed by aggregating the results of 36 diabetes-associated single nucleotide polymorphisms. Relative risk for type 2 diabetes was calculated using Framingham Offspring Study outcomes, grouped by quartiles into ‘higher’, ‘average (middle two quartiles)’ and ‘lower’ genetic risk. From these relative risks, revised absolute risks were estimated using the overall absolute risk for the study group. For study efficiency, we excluded all patients receiving ’average’ diabetes risk results from the subsequent intervention. This post randomization allocation strategy was justified because genotype represents a random allocation of parental alleles (‘Mendelian randomization’). Finally, because it would be unethical to discourage participants to participate in diabetes prevention behaviors, we designed our two diabetes genetic risk counseling interventions (for ‘higher’ and ‘lower’ result recipients) so that both groups would be motivated despite receiving opposing results.
Limitations
For this initial assessment of the clinical implementation of genetic risk testing we assessed intermediate outcomes of attendance at a 12-week diabetes prevention course and changes in self-reported motivation. If effective, longer term studies with larger sample sizes will be needed to assess whether knowledge of diabetes genetic risk can help patients prevent diabetes.
Conclusions
We designed a randomized clinical trial designed to explore the motivational impact of disclosing both higher than average and lower than average genetic risk for type 2 diabetes. This design allowed exploration of both increased risk and false reassurance, and has implications for future studies in translational genomics.
doi:10.1177/1740774511414159
PMCID: PMC3763721  PMID: 22013171
17.  Navigating a research partnership between academia and industry to assess the impact of personalized genetic testing 
Purpose
To describe the process of structuring a partnership between academic researchers and two personalized genetic testing companies that would manage conflicts of interest while allowing researchers to study the impact of this nascent industry.
Methods
We developed a transparent process of ongoing communication about the interests of all research partners to address challenges in establishing study goals, survey development, data collection, analysis, and manuscript preparation. Using the existing literature on conflicts of interest and our experience, we created a checklist for academic and industry researchers seeking to structure research partnerships.
Results
Our checklist includes questions about the risk to research participants, sponsorship of the study, control of data analysis, freedom to publish results, the impact of the research on industry customers, openness to input from all partners, sharing results before publication, and publication of industry-specific data. Transparency is critical to building trust between partners. Involving all partners in the research development enhanced the quality of our research and provided an opportunity to manage conflicts early in the research process.
Conclusion
Navigating relationships between academia and industry is complex and requires strategies that are transparent and responsive to the concerns of all. Employing a checklist of questions prior to beginning a research partnership may help to manage conflicts of interest.
doi:10.1038/gim.2011.59
PMCID: PMC3763722  PMID: 22241103
conflicts of interest; direct-to-consumer; partnership; personalized genetic testing; personalized medicine
18.  Effectiveness of a condensed protocol for disclosing APOE genotype and providing risk education for Alzheimer disease 
Purpose
Brief, effective models of patient genetic education are needed for common, complex diseases. Using Alzheimer disease as a model, we compared participants’ risk knowledge and recall in extended versus condensed education protocols.
Methods
A four-site randomized clinical trial enrolled 280 first-degree relatives of individuals with Alzheimer disease (mean age = 58 years, 71% female); each received lifetime Alzheimer disease risk information (range: 13–74%) that incorporated apolipoprotein E genotype. In the condensed protocol, participants received an educational brochure in place of an in-person education session. Outcomes were assessed at 6 weeks and 6 months following risk disclosure.
Results
The condensed protocol required less clinician time than the extended protocol (mean = 34 min vs. 77 min). The groups did not differ on recall of apolipoprotein E genotype or lifetime risk, and most participants in both groups recalled and retained this information over time. Both groups showed improvement from baseline in Alzheimer disease risk knowledge (e.g., understanding the magnitude of apolipoprotein E genotype effect on risk).
Conclusion
A condensed protocol for communicating genetic risk for Alzheimer disease achieved similar educational results as an extended protocol in this study. Further research should explore the efficacy of brief genetic education protocols for complex diseases in diverse populations.
doi:10.1038/gim.2012.37
PMCID: PMC3718049  PMID: 22498844
Alzheimer disease; APOE; genetic counseling; health education; risk communication
19.  Education effects on cognitive function in a healthy aged Arab population 
Background
The Minimental State Examination (MMSE) has not been validated in Arabic speaking populations. The Brookdale Cognitive Screening Test (BCST) has been developed for use in low schooling populations. We investigated the influence of gender, education and occupation in a cognitively normal community sample assessed with an Arabic translation of the MMSE and the BCST.
Methods
Cognitively normal subjects (n=266, 59.4 % males, mean age (SD): 72.4 (5.5) years) from an Arab community in northern Israel (Wadi Ara) were evaluated. Education was categorized into levels: 1=0–4 years, 2=5–8 years, 3=9–12 years. Effects of gender, education and occupation on MMSE and BCST were analyzed by ANOVA, taking age as a covariate.
Results
The mean MMSE score of males [26.3 (4.1)] was higher than that of females [23.6 (4.2) points]. Two-way ANOVA showed a significant interaction between gender and education on MMSE (p=0.0017) and BCST scores (p=0.0002). The effect of gender on MMSE and BCST was significant in education level 1 (p<0.0001, both tests) and level 2 (p<0.05, both tests). For education level 1, MMSE and BCST scores were higher for males, while both scores were higher for females in education level 2. The effect of occupation was not significant for both genders.
Conclusion
Education and gender influence performance on the Arabic translation of the MMSE and BCST in cognitively normal elderly. Cognitively normal females with 0–4 years of education score lower than males. These results should be taken into consideration in the daily use of these instruments in Arabic.
doi:10.1017/S1041610206004327
PMCID: PMC3695483  PMID: 17052375
Minimental state examination; MMSE; cognitive; Arabic; elderly; gender; education
20.  Relationship between Serum and Brain Carotenoids, α-Tocopherol, and Retinol Concentrations and Cognitive Performance in the Oldest Old from the Georgia Centenarian Study 
Journal of Aging Research  2013;2013:951786.
Oxidative stress is involved in age-related cognitive decline. The dietary antioxidants, carotenoids, tocopherols, and vitamin A may play a role in the prevention or delay in cognitive decline. In this study, sera were obtained from 78 octogenarians and 220 centenarians from the Georgia Centenarian Study. Brain tissues were obtained from 47 centenarian decedents. Samples were analyzed for carotenoids, α-tocopherol, and retinol using HPLC. Analyte concentrations were compared with cognitive tests designed to evaluate global cognition, dementia, depression and cognitive domains (memory, processing speed, attention, and executive functioning). Serum lutein, zeaxanthin, and β-carotene concentrations were most consistently related to better cognition (P < 0.05) in the whole population and in the centenarians. Only serum lutein was significantly related to better cognition in the octogenarians. In brain, lutein and β-carotene were related to cognition with lutein being consistently associated with a range of measures. There were fewer significant relationships for α-tocopherol and a negative relationship between brain retinol concentrations and delayed recognition. These findings suggest that the status of certain carotenoids in the old may reflect their cognitive function. The protective effect may not be related to an antioxidant effect given that α-tocopherol was less related to cognition than these carotenoids.
doi:10.1155/2013/951786
PMCID: PMC3690640  PMID: 23840953
21.  Serum paraoxonase activity is associated with variants in the PON gene cluster and risk of Alzheimer disease 
Neurobiology of Aging  2010;33(5):1015.e7-1015.e23.
Previous studies have shown association of single nucleotide polymorphisms (SNPs) in three contiguous genes (PON1, PON2 and PON3) encoding paraoxonase with risk of Alzheimer disease (AD). We evaluated the association of serum paraoxonase activity measured by phenyl acetate (PA) and thiobutyl butyrolactone (TBBL) with risk of AD and with 26 SNPs spanning the PON gene cluster in 266 AD cases and 306 sibling controls from the MIRAGE Study. The odds of AD (adjusted for age, gender and ethnicity) increased 20% for each standard deviation decrease in PA or TBBL activity. There were association signals with activity in all three genes. Haplotypes including SNPs spanning the PON genes were generally more significant than haplotypes comprising SNPs from one gene. Significant interactions were observed between SNP pairs located across the PON cluster with either serum activity measure as the outcome, and between several PON SNPs and PA activity with AD status as the outcome. Our results suggest that low serum paraoxonase activity is a risk factor for AD. Furthermore, multiple variants in PON influence serum paraoxonase activity and their effects may be synergistic.
doi:10.1016/j.neurobiolaging.2010.08.003
PMCID: PMC3034817  PMID: 20980077
22.  Effects of FDA approved medications for Alzheimer’s disease on clinical progression 
Background
Observational studies suggest cholinesterase inhibitors and/or memantine may delay clinical progression of Alzheimer’s disease (AD) in 40% of individuals taking the medications. Given this response and existence of side effects, we sought to quantify medication use and benefits in a population-based study of incident AD cases.
Methods
The Cache County Dementia Progression study (DPS) enrolled and followed a cohort of 327 incident AD cases up to 9 years. Drug exposure was expressed using a persistency index (PI), calculated as total years of drug use divided by total years of observation. Linear mixed effects models examined PI, and interactions with sex and APOE ε4, as predictors of clinical progression on the Mini-Mental State Exam (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-Sum).
Results
Sixty-nine participants (21.1%) ever used cholinesterase inhibitors or memantine. There was a strong three-way interaction between PI, sex, and time. Among women, a higher PI (i.e. greater duration of use) of cholinesterase inhibitors was associated with slower progression on the MMSE and CDR-Sum, particularly among those with an APOE ε4 allele. In contrast, higher PI was associated with faster progression in males.
Conclusion
A low percentage of individuals with AD in the community are taking cholinesterase inhibitors or memantine. This study suggests that women, particularly those with an APOE ε4 allele, may receive the most benefit from these medications. With the newly approved increased dose of donepezil, it will be imperative to determine whether a higher dose is needed in men or whether other factors warrant consideration.
doi:10.1016/j.jalz.2011.02.011
PMCID: PMC3341471  PMID: 22301194
Cholinesterase inhibitor; Memantine; Incident Alzheimer’s disease; Population-based; Disease progression; Sex; APOE
23.  The Framingham Brain Donation Program: Neuropathology Along the Cognitive Continuum 
Current Alzheimer research  2012;9(6):673-686.
The Framingham Heart Study has enrolled 3 generations of participants, the Original cohort (Gen 1) enrolled in 1948, the Offspring cohort (Gen 2) enrolled in 1971 and the Third Generation enrolled in 2002. Participants have been undergoing prospective surveillance for incident stroke and dementia and embedded within this cohort is the voluntary Framingham Brain Donation Program that was begun in 1997. Participants who register to become brain donors have had one or more brain MR and cognitive test batteries administered. In addition, they undergo neurological evaluation as indicated, record review and post-mortem next-of-kin interview to determine the presence, type and extent of antemortem, clinical neurological diagnoses and to assign a retrospective Clinical Dementia Rating (CDR) Scale score. Between 1997 and 2009 there were 1806 deaths, 186 of which were among registered brain donors and of these 139 brains could be examined. 58% were deemed cognitively normal at death. We present results for 3 projects; the first was to examine the sensitivity and specificity of our clinical diagnosis against the gold standard of pathological AD in 59 persons who underwent detailed cognitive assessment in the two years prior to death; we observed a 77.3% sensitivity (2 persons with AD were diagnosed clinically as Lewy body dementia) and a 91.9% specificity. The second examined the correlation of regional Alzheimer-type pathology to cognitive status at death among 34 persons who were over the age of 75 and without any significant vascular or alternative neurodegenerative pathology and found that neurofibrillary tangle counts distinguished between persons who were controls, had mild cognitive impairment, mild or moderate dementia; tangles in dorsolateral frontal cortex best distinguished MCI and controls. The third project examined the extent and severity of vascular pathology, again in a larger sample of varying cognitive abilities and in a subsample of persons with either amnestic or non-amnestic MCI. We observed that an aggregate ischemic injury score was significantly higher in persons with a CDR score of 0.5 than in normal controls.
PMCID: PMC3622706  PMID: 22471865
Brain; autopsy; epidemiology; alzheimer's disease; brain ischemia
24.  Effects of General Medical Health on Alzheimer Progression: the Cache County Dementia Progression Study 
International psychogeriatrics / IPA  2012;24(10):1561-1570.
Background
Several observational studies suggested a link between health status and rate of decline among individuals with Alzheimer’s disease (AD). We sought to quantify the relationship in a population-based study of incident AD, and to compare global comorbidity ratings to counts of comorbid conditions and medications as predictors of AD progression.
Methods
Design
Case-only cohort study arising from population-based longitudinal study of memory and aging.
Setting
Cache County, Utah
Participants
335 individuals with incident AD followed for up to 11 years.
Measurements
Patient descriptors included sex, age, education, dementia duration at baseline, and APOE genotype. Measures of health status made at each visit included the GMHR (General Medical Health Rating), number of comorbid medical conditions, and number of non-psychiatric medications. Dementia outcomes included the Mini-Mental State Exam (MMSE), Clinical Dementia Rating – sum of boxes (CDR-sb), and the Neuropsychiatric Inventory (NPI).
Results
Health Status tended to fluctuate over time within individuals. None of the baseline medical variables (GMHR, comorbidities, non-psychiatric medications) were associated with differences in rates of decline in longitudinal linear mixed effects models. Over time, low GMHR ratings, but not comorbidities or medications, were associated with poorer outcomes (MMSE: β=−1.07 p=0.01; CDR-sb: β=1.79 p<0.001; NPI: β=4.57 p=0.01)
Conclusions
Given that time-varying GMHR, but not baseline GMHR, was associated with the outcomes, there is likely a dynamic relationship between medical and cognitive health. GMHR is a more sensitive measure of health than simple counts of comorbidities or medications. Since health status is a potentially modifiable risk factor, further study is warranted.
doi:10.1017/S104161021200049X
PMCID: PMC3573852  PMID: 22687143
Alzheimer; comorbidity; GMHR; disease progression; rate of decline; medical care; cohort study
25.  Genetic susceptibility testing for chronic disease and intention for behavior change in healthy young adults 
Journal of Community Genetics  2013;4(2):263-271.
Genetic testing for chronic disease susceptibility may motivate young adults for preventive behavior change. This nationally representative survey gave 521 young adults hypothetical scenarios of receiving genetic susceptibility results for heart disease, type 2 diabetes, and stroke and asked their (1) interest in such testing, (2) anticipated likelihood of improving diet and physical activity with high- and low-risk test results, and (3) readiness to make behavior change. Responses were analyzed by presence of established disease-risk factors. Respondents with high phenotypic diabetes risk reported increased likelihood of improving their diet and physical activity in response to high-risk results compared with those with low diabetes risk (odds ratio (OR), 1.82 (1.03, 3.21) for diet and OR, 2.64 (1.24, 5.64) for physical activity). In contrast, poor baseline diet (OR, 0.51 (0.27, 0.99)) and poor physical activity (OR, 0.53 (0.29, 0.99)) were associated with decreased likelihood of improving diet. Knowledge of genetic susceptibility may motivate young adults with higher personal diabetes risk for improvement in diet and exercise, but poor baseline behaviors are associated with decreased intention to make these changes. To be effective, genetic risk testing in young adults may need to be coupled with other strategies to enable behavior change.
Electronic supplementary material
The online version of this article (doi:10.1007/s12687-013-0140-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s12687-013-0140-6
PMCID: PMC3666830  PMID: 23435806
Genetic testing; Young adults; Chronic disease; Health behaviors; Prevention

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