Publications by authors named "Justin B Miller"

51 Publications

Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression.

Alzheimers Dement 2021 Mar 2. Epub 2021 Mar 2.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA.

Introduction: Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain.

Methods: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes.

Results: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia.

Discussion: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.
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http://dx.doi.org/10.1002/alz.12310DOI Listing
March 2021

A comprehensive analysis of the phylogenetic signal in ramp sequences in 211 vertebrates.

Sci Rep 2021 Jan 12;11(1):622. Epub 2021 Jan 12.

Department of Biology, Brigham Young University, Provo, UT, 84602, USA.

Ramp sequences increase translational speed and accuracy when rare, slowly-translated codons are found at the beginnings of genes. Here, the results of the first analysis of ramp sequences in a phylogenetic construct are presented. Ramp sequences were compared from 247 vertebrates (114 Mammalian and 133 non-mammalian), where the presence and absence of ramp sequences was analyzed as a binary character in a parsimony and maximum likelihood framework. Additionally, ramp sequences were mapped to the Open Tree of Life synthetic tree to determine the number of parallelisms and reversals that occurred, and those results were compared to random permutations. Parsimony and maximum likelihood analyses of the presence and absence of ramp sequences recovered phylogenies that are highly congruent with established phylogenies. Additionally, 81% of vertebrate mammalian ramps and 81.2% of other vertebrate ramps had less parallelisms and reversals than the mean from 1000 randomly permuted trees. A chi-square analysis of completely orthologous ramp sequences resulted in a p-value < 0.001 as compared to random chance. Ramp sequences recover comparable phylogenies as other phylogenomic methods. Although not all ramp sequences appear to have a phylogenetic signal, more ramp sequences track speciation than expected by random chance. Therefore, ramp sequences may be used in conjunction with other phylogenomic approaches if many orthologs are taken into account. However, phylogenomic methods utilizing few orthologs should be cautious in incorporating ramp sequences because individual ramp sequences may provide conflicting signals.
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http://dx.doi.org/10.1038/s41598-020-78803-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803996PMC
January 2021

CUBAP: an interactive web portal for analyzing codon usage biases across populations.

Nucleic Acids Res 2020 11;48(19):11030-11039

Department of Biology, Brigham Young University, Provo, UT 84602, USA.

Synonymous codon usage significantly impacts translational and transcriptional efficiency, gene expression, the secondary structure of both mRNA and proteins, and has been implicated in various diseases. However, population-specific differences in codon usage biases remain largely unexplored. Here, we present a web server, https://cubap.byu.edu, to facilitate analyses of codon usage biases across populations (CUBAP). Using the 1000 Genomes Project, we calculated and visually depict population-specific differences in codon frequencies, codon aversion, identical codon pairing, co-tRNA codon pairing, ramp sequences, and nucleotide composition in 17,634 genes. We found that codon pairing significantly differs between populations in 35.8% of genes, allowing us to successfully predict the place of origin for African and East Asian individuals with 98.8% and 100% accuracy, respectively. We also used CUBAP to identify a significant bias toward decreased CTG pairing in the immunity related GTPase M (IRGM) gene in East Asian and African populations, which may contribute to the decreased association of rs10065172 with Crohn's disease in those populations. CUBAP facilitates in-depth gene-specific and codon-specific visualization that will aid in analyzing candidate genes identified in genome-wide association studies, identifying functional implications of synonymous variants, predicting population-specific impacts of synonymous variants and categorizing genetic biases unique to certain populations.
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http://dx.doi.org/10.1093/nar/gkaa863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641757PMC
November 2020

Predicting Clinical Dementia Rating Using Blood RNA Levels.

Genes (Basel) 2020 06 26;11(6). Epub 2020 Jun 26.

Department of Biology, Brigham Young University, Provo, UT 84602, USA.

The Clinical Dementia Rating (CDR) is commonly used to assess cognitive decline in Alzheimer's disease patients and is included in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We divided 741 ADNI participants with blood microarray data into three groups based on their most recent CDR assessment: cognitive normal (CDR = 0), mild cognitive impairment (CDR = 0.5), and probable Alzheimer's disease (CDR ≥ 1.0). We then used machine learning to predict cognitive status using only blood RNA levels. Only one probe for chloride intracellular channel 1 () was significant after correction. However, by combining individually nonsignificant probes with -values less than 0.1, we averaged 87.87% (s = 1.02) predictive accuracy for classifying the three groups, compared to a 55.46% baseline for this study due to unequal group sizes. The best model had an overall precision of 0.902, recall of 0.895, and a receiver operating characteristic (ROC) curve area of 0.904. Although we identified one significant probe in , levels alone were not sufficient to predict dementia status and cannot be used alone in a clinical setting. Additional analyses combining individually suggestive, but nonsignificant, blood RNA levels were significantly predictive and may improve diagnostic accuracy for Alzheimer's disease. Therefore, we propose that patient features that do not individually predict cognitive status might still contribute to overall cognitive decline through interactions that can be elucidated through machine learning.
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http://dx.doi.org/10.3390/genes11060706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349260PMC
June 2020

Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants.

Neurobiol Dis 2020 09 21;143:104972. Epub 2020 Jun 21.

Department of Biology, Brigham Young University, Provo, UT 84602, USA. Electronic address:

Background: Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB).

Methods: From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives.

Results: Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values = .001 and .0001, respectively).

Discussion: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation.
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http://dx.doi.org/10.1016/j.nbd.2020.104972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461696PMC
September 2020

Codon Pairs are Phylogenetically Conserved: A comprehensive analysis of codon pairing conservation across the Tree of Life.

PLoS One 2020 13;15(5):e0232260. Epub 2020 May 13.

Department of Biology, Brigham Young University, Provo, UT, United States of America.

Identical codon pairing and co-tRNA codon pairing increase translational efficiency within genes when two codons that encode the same amino acid are translated by the same tRNA before it diffuses from the ribosome. We examine the phylogenetic signal in both identical and co-tRNA codon pairing across 23 428 species using alignment-free and parsimony methods. We determined that conserved codon pairing typically has a smaller window size than the length of a ribosome, and codon pairing tracks phylogenies across various taxonomic groups. We report a comprehensive analysis of codon pairing, including the extent to which each codon pairs. Our parsimony method generally recovers phylogenies that are more congruent with the established phylogenies than our alignment-free method. However, four of the ten taxonomic groups did not have sufficient orthologous codon pairings and were therefore analyzed using only the alignment-free methods. Since the recovered phylogenies using only codon pairing largely match phylogenies from the Open Tree of Life and the NCBI taxonomy, and are comparable to trees recovered by other algorithms, we propose that codon pairing biases are phylogenetically conserved and should be considered in conjunction with other phylogenomic techniques.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232260PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219770PMC
July 2020

Evidence of Validity for a Newly Developed Digital Cognitive Test Battery.

Front Psychol 2020 24;11:770. Epub 2020 Apr 24.

Digital Cognitive Diagnostics, Philips Healthcare, Eindhoven, Netherlands.

Clinical practice still relies heavily on traditional paper-and-pencil testing to assess a patient's cognitive functions. Digital technology has the potential to be an efficient and powerful alternative, but for many of the existing digital tests and test batteries the psychometric properties have not been properly established. We validated a newly developed digital test battery consisting of digitized versions of conventional neuropsychological tests. Two confirmatory factor analysis models were specified: a model based on traditional neuropsychological theory and expert consensus and one based on the Cattell-Horn-Carroll (CHC) taxonomy. For both models, the outcome measures of the digital tests loaded on the cognitive domains in the same way as established in the neuropsychological literature. Interestingly, no clear distinction could be made between the CHC model and traditional neuropsychological model in terms of model fit. Taken together, these findings provide preliminary evidence for the structural validity of the digital cognitive test battery.
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http://dx.doi.org/10.3389/fpsyg.2020.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194127PMC
April 2020

Failure to detect synergy between variants in transferrin and hemochromatosis and Alzheimer's disease in large cohort.

Neurobiol Aging 2020 05 12;89:142.e9-142.e12. Epub 2020 Feb 12.

Department of Biology, Brigham Young University, Provo, UT, USA. Electronic address:

Alzheimer's disease (AD) is the most common cause of dementia and, despite decades of effort, there is no effective treatment. In the last decade, many association studies have identified genetic markers that are associated with AD status. Two of these studies suggest that an epistatic interaction between variants rs1049296 in the transferrin (TF) gene and rs1800562 in the homeostatic iron regulator (HFE) gene, commonly known as hemochromatosis, is in genetic association with AD. TF and HFE are involved in the transport and regulation of iron in the brain, and disrupting these processes exacerbates AD pathology through increased neurodegeneration and oxidative stress. However, by using a significantly larger data set from the Alzheimer's Disease Genetics Consortium, we fail to detect an association between TF rs1049296 or HFE rs1800562 with AD risk (TF rs1049296 p = 0.38 and HFE rs1800562 p = 0.40). In addition, logistic regression with an interaction term and a synergy factor analysis both failed to detect epistasis between TF rs1049296 and HFE rs1800562 (SF = 0.94; p = 0.48) in AD cases. Each of these analyses had sufficient statistical power (power > 0.99), suggesting that previously reported associations may be the result of more complex epistatic interactions, genetic heterogeneity, or false-positive associations because of limited sample sizes.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206870PMC
May 2020

Codon use and aversion is largely phylogenetically conserved across the tree of life.

Mol Phylogenet Evol 2020 03 2;144:106697. Epub 2019 Dec 2.

Department of Biology, Brigham Young University, Provo, UT 84602, USA. Electronic address:

Using parsimony, we analyzed codon usages across 12,337 species and 25,727 orthologous genes to rank specific genes and codons according to their phylogenetic signal. We examined each codon within each ortholog to determine the codon usage for each species. In total, 890,814 codons were parsimony informative. Next, we compared species that used a codon with species that did not use the codon. We assessed each codon's congruence with species relationships provided in the Open Tree of Life (OTL) and determined the statistical probability of observing these results by random chance. We determined that 25,771 codons had no parallelisms or reversals when mapped to the OTL. Codon usages from orthologous genes spanning many species were 1109× more likely to be congruent with species relationships in the OTL than would be expected by random chance. Using the OTL as a reference, we show that codon usage is phylogenetically conserved within orthologous genes in archaea, bacteria, plants, mammals, and other vertebrates. We also show how to use our provided framework to test different tree hypotheses by confirming the placement of turtles as sister taxa to archosaurs.
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http://dx.doi.org/10.1016/j.ympev.2019.106697DOI Listing
March 2020

Estimating Premorbid Ability in Rehabilitation Patients Using the Test of Premorbid Functioning and Wide Range Achievement Test-Fourth Edition.

Assessment 2021 04 13;28(3):994-1003. Epub 2019 Nov 13.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

This study examined premorbid ability estimate concordance using Test of Premorbid Functioning predicted Full Scale Intelligent Quotient (TOPF-IQ) and Wide Range Achievement Test-Fourth Edition Word Reading (WRAT4-WR). The sample ( = 145) was 28% female with average age and education of 40.6 and 13.2 years, respectively. Outpatient neuropsychological evaluations were conducted in a rehabilitation setting. Measures included the TOPF, WRAT4-WR, Wechsler Adult Intelligence Scale-Fourth Edition, and other neuropsychological tests. Non-WAIS measures defined impairment groups. Analyses included tests, pairwise correlations, concordance correlation coefficients, and root mean square differences. TOPF-IQ, WRAT4-WR, and Full Scale Intelligent Quotient scores were not significantly different but were lower than normative mean. TOPF-IQ and WRAT4-WR showed acceptable agreement (concordance correlation coefficient = .92; root mean square difference = 5.9). Greater premorbid-current ability differences were observed in the impaired group. TOPF-IQ and WRAT4-WR showed lower but similar agreement with Full Scale Intelligence Quotient in the unimpaired group. Findings support the WRAT4-WR in predicting premorbid ability in rehabilitation settings.
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http://dx.doi.org/10.1177/1073191119887441DOI Listing
April 2021

Comparing the Boston Naming Test With the Neuropsychological Assessment Battery-Naming Subtest in a Neurodegenerative Disease Clinic Population.

Assessment 2019 Sep 13:1073191119872253. Epub 2019 Sep 13.

Cleveland Clinic, Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

The Boston Naming Test-Second edition (BNT-2) and the Neuropsychological Assessment Battery-Naming (NAB-N) subtest are two commonly used confrontation naming tests used to evaluate word-finding ability in individuals suspected of neurodegenerative disease. The BNT-2 and NAB-N are designed to measure the same construct; however, observations in practice suggest these two tests provide divergent estimates of naming ability. This study sought to systematically investigate the level of agreement between performance on the BNT-2 and NAB-N. Records from 105 consecutive referrals seen for neuropsychological evaluation as part of routine care in an outpatient memory disorders clinic were reviewed. Discrepancy scores, concordance correlation coefficients, and root mean squared differences were calculated between demographically adjusted -scores on the BNT-2 and NAB-N. Results indicated that estimates of word finding ability generated by the BNT-2 and NAB-N have a strong linear relationship but systematically generate scores that are inconsistent. Despite similar task demands, the BNT-2 and NAB-N provide different information about naming ability and further research is needed to understand these differences and inform clinicians on interpreting the naming estimates provided by each test.
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http://dx.doi.org/10.1177/1073191119872253DOI Listing
September 2019

Awareness of Psychiatric Symptoms in a Mixed Clinical Sample of Older Adults.

J Geriatr Psychiatry Neurol 2020 05 11;33(3):124-134. Epub 2019 Aug 11.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

Objective: This study examined the neuropsychological correlates and impact on caregiver distress of reduced awareness of mood symptoms in patients with suspected neurodegenerative disease.

Method: Records from a clinical sample of older adults were examined (N = 940).

Results: More than one-third of patient and caregiver ratings of mood symptoms did not agree (comparing patient and caregiver self-report measures); 27.9% of patients were unaware of depression (UoD) and 16.6% of patients were unaware of anxiety (UoA). The UoD group exhibited poorer verbal memory and executive abilities and the UoA group exhibited poorer verbal memory than those with preserved awareness. Unawareness was not associated with caregiver distress.

Conclusions: These findings highlight the importance of capturing informant report in clinical practice with older adults suspected of cognitive impairment. Unawareness of mood symptoms was related to memory dysfunction and-to a lesser extent-to executive abilities and may have implications for addressing patient and caregiver needs for disorders affecting these cognitive systems.
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http://dx.doi.org/10.1177/0891988719868311DOI Listing
May 2020

The Pathology of Rapid Cognitive Decline in Clinically Diagnosed Alzheimer's Disease.

J Alzheimers Dis 2019 ;70(4):983-993

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

Background: Variable rate of cognitive decline among individuals with Alzheimer's disease (AD) is an important consideration for disease management, but risk factors for rapid cognitive decline (RCD) are without consensus.

Objective: To investigate demographic, clinical, and pathological differences between RCD and normal rates of cognitive decline (NCD) in AD.

Methods: Neuropsychology test and autopsy data was pulled from the National Alzheimer's Coordinating Center database from individuals with a clinical diagnosis of AD. Individuals with average decline of 3 or more points on the Mini-Mental Status Examination (MMSE) per year over 3 years were labeled RCD; all others were NCD.

Results: Sixty individuals identified as RCD; 230 as NCD. These neuropsychology tests differed at baseline (RCD versus NCD): WMS-LM Immediate Recall (4.35[3.39] versus 6.31[3.97], p < 0.001), Animal Naming (12.1[4.83] versus 13.9[4.83], p = 0.007), TMT Part B (187[86.1] versus 159[79.0], p = 0.02), WAIS-Digit Symbol (29.5[11.3] versus 29.5[11.3], p = 0.04), and the BNT (21.5[7.05] versus 23.6[5.09], p = 0.04). RCD had more thyroid disease (30% versus 16%, p = 0.01) and greater usage of AD medication at baseline (80% versus 62%, p = 0.01). RCD had more severe cerebral amyloid angiopathy (1.62[1.0] versus 1.13[1.0], p = 0.002), more neocortical Lewy bodies (20% versus 10%, p = 0.04), and more atrophy (1.54[0.92] versus 1.17[0.83], p = 0.04). A model combining select variables was significant above chance (χ2 = 25.8, p = 0.002), but not to clinical utility (AUC < 0.70; 95% CI).

Conclusion: Individuals with RCD have more severe pathology, more comorbidities, and lower baseline neuropsychology test scores of language and executive function.
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http://dx.doi.org/10.3233/JAD-190302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306887PMC
October 2020

Does informant-based reporting of cognitive symptoms predict amyloid positivity on positron emission tomography?

Alzheimers Dement (Amst) 2019 Dec 6;11:424-429. Epub 2019 Jun 6.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV.

Introduction: Researchers are searching for clinical instruments to predict amyloid positivity for disease classification. Informant-based reports could detect disease status. This study compares subjective memory complaints captured by informant-based reports between positron emission tomography (PET)-positive and PET-negative patients and hypothesizes that amyloid PET positivity associates with increased informant-based cognitive complaints.

Methods: Ninety-eight amnestic mild cognitive impairment or mild dementia subjects were studied. Subjective report was captured by the informant-driven Alzheimer's Questionnaire (AQ) administered before PET. Differences in demographics and AQ score by diagnostic status and amyloid status were measured, and a receiver-operating characteristic curve was calculated.

Results: Sixty-five mild cognitive impairment/Alzheimer's disease amyloid PET-positive and 33 amyloid PET-negative subjects were included. AQ was significantly higher (12.51 ± 4.95) for amyloid PET-positive subjects (9.06 ± 3.65;  = .001).

Conclusions: Amyloid PET-positive subjects with Alzheimer's disease or mild cognitive impairment have more informant-based reports of cognitive decline, indicating utility for a brief informant measure.
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http://dx.doi.org/10.1016/j.dadm.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558087PMC
December 2019

CAM: an alignment-free method to recover phylogenies using codon aversion motifs.

PeerJ 2019 4;7:e6984. Epub 2019 Jun 4.

Department of Biology, Brigham Young University, Provo, UT, United States of America.

Background: Common phylogenomic approaches for recovering phylogenies are often time-consuming and require annotations for orthologous gene relationships that are not always available. In contrast, alignment-free phylogenomic approaches typically use structure and oligomer frequencies to calculate pairwise distances between species. We have developed an approach to quickly calculate distances between species based on codon aversion.

Methods: Utilizing a novel alignment-free character state, we present CAM, an alignment-free approach to recover phylogenies by comparing differences in codon aversion motifs (i.e., the set of unused codons within each gene) across all genes within a species. Synonymous codon usage is non-random and differs between organisms, between genes, and even within a single gene, and many genes do not use all possible codons. We report a comprehensive analysis of codon aversion within 229,742,339 genes from 23,428 species across all kingdoms of life, and we provide an alignment-free framework for its use in a phylogenetic construct. For each species, we first construct a set of codon aversion motifs spanning all genes within that species. We define the pairwise distance between two species, A and B, as one minus the number of shared codon aversion motifs divided by the total codon aversion motifs of the species, A or B, containing the fewest motifs. This approach allows us to calculate pairwise distances even when substantial differences in the number of genes or a high rate of divergence between species exists. Finally, we use neighbor-joining to recover phylogenies.

Results: Using the Open Tree of Life and NCBI Taxonomy Database as expected phylogenies, our approach compares well, recovering phylogenies that largely match expected trees and are comparable to trees recovered using maximum likelihood and other alignment-free approaches. Our technique is much faster than maximum likelihood and similar in accuracy to other alignment-free approaches. Therefore, we propose that codon aversion be considered a phylogenetically conserved character that may be used in future phylogenomic studies.

Availability: CAM, documentation, and test files are freely available on GitHub at https://github.com/ridgelab/cam.
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http://dx.doi.org/10.7717/peerj.6984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555396PMC
June 2019

Relationship between cortical thickness and fluency in the memory disorders clinic population.

Neuropsychologia 2019 06 2;129:294-301. Epub 2019 Apr 2.

Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.

As brain networks break down in neurodegenerative disorders such as Alzheimer's disease, language and executive function frequently decline. We aimed to quantify the relationship between fluency (both categorical and phonemic) and cortical thickness using data from a large cohort of patients who were undergoing assessment at a memory disorders clinic. In addition, we defined the pattern of these relationships across the four major lobes of the brain. A total of 590 patients underwent extensive psychometric testing, including categorical (animal-naming) and phonemic (FAS) tests of fluency. All patients also underwent structural MRI featuring a volumetric T1-weighted sequence that served as the input for postprocessing calculations using FreeSurfer, yielding cortical parcellations and thicknesses. The fluency-thickness relationships were summarized using Pearson's correlation coefficient. In a univariable analysis over all lobes, there were significant correlations using categorical fluency with both cortical thickness and age, with education less correlated; using phonemic fluency there were similar correlations with cortical thickness and age, but education was more correlated. Neither handedness nor sex was significantly correlated with either categorical or phonemic score. At a lobar level, for both fluency tests, scores were positively correlated with cortical thickness in all lobes; these relationships were strongest in the temporal lobe (p < 0.01). The correlations for categorical testing were generally stronger than the correlations for phonemic testing and were again strongest in the temporal lobe (r = 0.38 for categorical testing vs 0.22 for phonemic testing). The bilateral parietal lobes were more important for categorical testing than for phonemic testing, and the left frontal lobe was more important for phonemic testing than for categorical testing. Comparison of the homologous lobes between the two hemispheres demonstrated that only the frontal lobes were significantly different for both scores, with the left side having a stronger relationship with the scores (categorical: r = 0.21 for left; r = 0.14 for right; p < 0.01. phonemic: r = 0.13 for left; r = 0.08 for right; p < 0.01). In conclusion, these results demonstrated that structural MRI and fluency tests reveal a significant spatial pattern of correlations between cortical thickness and fluency, which varies with the type of fluency test.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.03.021DOI Listing
June 2019

Regression-based formulas for predicting change in memory test scores in healthy older adults: Comparing use of raw versus standardized scores.

J Clin Exp Neuropsychol 2019 07 5;41(5):460-468. Epub 2019 Feb 5.

a Neuropsychology , Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas , NV , USA.

Introduction: Standardized regression based (SRB) methods can be used to determine whether meaningful changes in performance on cognitive assessments occur over time. Both raw and standardized scores have been used in SRB models but it is unclear which score metric is most appropriate for predicting follow-up performance. The aim of the present study was to examine differences in SRB prediction formulas using raw versus standard scores on two memory tests commonly used in assessment of older adults.

Method: The sample consisted of 135 healthy older adults who underwent baseline and 1-year follow-up neuropsychological assessment including the Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised. Regression models were fit to predict Time 2 scores from Time 1 scores and demographic variables. Separate models were fit using raw scores and standardized scores. Akaike's information criterion (AIC) was used to determine whether models using raw or standardized scores resulted in best fit. Pearson correlation and intraclass correlation coefficients were calculated between observed and predicted scores. Mean differences between observed and predicted scores were examined using pairwise t tests. To investigate whether a similar pattern of results would be evident using prediction formulas for nonmemory tests, all analyses were also conducted for nonmemory tests.

Results: All regression models were significant, and R values for memory test raw score models were larger than those generated by standardized score models. Memory test raw score models were also a better fit based on smaller AIC values. For nonmemory tests, raw score models did not consistently outperform standardized score models. All correlations between observed and predicted Time 2 scores were significant, and none of the predicted scores significantly differed from their respective observed score.

Conclusion: For each memory measure, raw score models outperformed standardized score models. For nonmemory tests, neither score metric model consistently outperformed the other.
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http://dx.doi.org/10.1080/13803395.2019.1571169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099613PMC
July 2019

Influence of sex differences in interpreting learning and memory within a clinical sample of older adults.

Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2020 01 20;27(1):18-39. Epub 2019 Jan 20.

Neurological Institute, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, USA.

Sex is an important factor to consider when evaluating memory with older adults. This present study aimed to examine sex differences in memory within a clinical sample of older adults ( = 1084). Raw learning and recall scores on the Hopkins Verbal Learning Test, Revised (HVLT-R) and Brief Visuospatial Memory Test, Revised (BVMT-R) were compared between sexes within the entire sample and cohorts stratified by age. Within the entire sample, women outperformed men in HVLT-R learning and recall, and there were no sex differences in BVMT-R performance. These sex differences, however, were absent or reversed for those with impaired HVLT-R performance and functional deficits, indicating that women retain an early advantage in verbal memory, which is lost with greater indication of disease severity. These findings indicate that women retain an advantage in verbal learning and memory, at least before significant levels of impairment, within a sample of older adults seen at an outpatient neurology clinic, which may have implications for diagnosing memory disorders.
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http://dx.doi.org/10.1080/13825585.2019.1566433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677625PMC
January 2020

ExtRamp: a novel algorithm for extracting the ramp sequence based on the tRNA adaptation index or relative codon adaptiveness.

Nucleic Acids Res 2019 02;47(3):1123-1131

Department of Biology, Brigham Young University, Provo, UT 84602, USA.

Different species, genes, and locations within genes use different codons to fine-tune gene expression. Within genes, the ramp sequence assists in ribosome spacing and decreases downstream collisions by incorporating slowly-translated codons at the beginning of a gene. Although previously reported as occurring in some species, no previous attempt at extracting the ramp sequence from specific genes has been published. We present ExtRamp, a software package that quickly extracts ramp sequences from any species using the tRNA adaptation index or relative codon adaptiveness. Different filters facilitate the analysis of codon efficiency and enable identification of genes with a ramp sequence. We validate the existence of a ramp sequence in most species by running ExtRamp on 229 742 339 genes across 23 428 species. We evaluate differences in reported ramp sequences when we use different parameters. Using the strictest ramp sequence cut-off, we show that across most taxonomic groups, ramp sequences are approximately 20-40 codons long and occur in about 10% of gene sequences. We also show that in Drosophila melanogaster as gene expression increases, a higher proportion of genes have ramp sequences. We provide a framework for performing this analysis on other species. ExtRamp is freely available at https://github.com/ridgelab/ExtRamp.
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http://dx.doi.org/10.1093/nar/gky1193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379678PMC
February 2019

Big data and biomedical informatics: Preparing for the modernization of clinical neuropsychology.

Authors:
Justin B Miller

Clin Neuropsychol 2019 02 4;33(2):287-304. Epub 2018 Dec 4.

a Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas , Nevada , USA.

Objective: Neuropsychology is poised for a fundamental shift as we modernize the ways in which behavior is measured. The amount and complexity of data generated by these new methods will be several orders of magnitude greater than what is currently created by analog measures and will quickly adopt characteristics of "Big Data." Adequate preparation for managing the influx of data will be critical for technology integration and modernization to be successful. Drawing from information technology, mathematics, statistics, computer science, and engineering, as well as, biology, genetics, and medicine, the field of biomedical informatics has rapidly evolved from its early days in computational biology to a burgeoning independent discipline that has much to offer neuropsychology.

Method: Following a critical review of the relevant literature, the present article (1) provides an introductory overview of biomedical informatics and how these concepts are relevant to neuropsychology; (2) describes how biomedical informatics applications can be utilized to leverage existing data sources more effectively; and (3) discusses ideas for future developments designed to facilitate integration of new data derived from novel, technologically driven measurement tools. Within this context, applications intended for use by both the individual neuropsychologist to increase clinical efficiencies, as well as, larger field-wide initiatives intended to generate new information and derive new knowledge are discussed.

Conclusions: By no means a comprehensive review of biomedical informatics, the present paper highlights that our approach to data needs to become a multidisciplinary endeavor in order to develop applications capable of effectively utilizing modern data sources.
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http://dx.doi.org/10.1080/13854046.2018.1523466DOI Listing
February 2019

Statistical advances in clinical trials and clinical research.

Alzheimers Dement (N Y) 2018 14;4:366-371. Epub 2018 Jun 14.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

Introduction: New treatments for neurodegenerative disease are urgently needed, and clinical trial methods are an essential component of new drug development. Although a parallel-group study design for neurological disorder clinical trials is commonly used to test the effectiveness of a new treatment as compared to placebo, it does not efficiently use information from the on-going study to increase the success rate of a trial or to stop a trial earlier when the new treatment is indeed ineffective.

Methods: We review some recent advances in designs for clinical trials, including futility designs and adaptive designs.

Results: Futility designs and noninferiority designs are used to test the nonsuperiority and the noninferiority of a new treatment, respectively. We provide some guidance on using these two designs and analyzing data from these studies properly. Adaptive designs are increasingly used in clinical trials to improve the flexibility and efficiency of trials with the potential to reduce resources, time, and costs. We review some typical adaptive designs and new statistical methods to handle the statistical challenges from adaptive designs.

Discussion: Statistical advances in clinical trial designs may be helpful to shorten study length and benefit more patients being treated with a better treatment during the discovery of new therapies for neurological disorders. Advancing statistical underpinnings of neuroscience research is a critical aspect of the core activities supported by the Center of Biomedical Research Excellence award supporting the Center for Neurodegeneration and Translational Neuroscience.
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http://dx.doi.org/10.1016/j.trci.2018.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118095PMC
June 2018

Biomedical informatics applications for precision management of neurodegenerative diseases.

Alzheimers Dement (N Y) 2018 13;4:357-365. Epub 2018 Jun 13.

Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego, CA, USA.

Modern medicine is in the midst of a revolution driven by "big data," rapidly advancing computing power, and broader integration of technology into healthcare. Highly detailed and individualized profiles of both health and disease states are now possible, including biomarkers, genomic profiles, cognitive and behavioral phenotypes, high-frequency assessments, and medical imaging. Although these data are incredibly complex, they can potentially be used to understand multi-determinant causal relationships, elucidate modifiable factors, and ultimately customize treatments based on individual parameters. Especially for neurodegenerative diseases, where an effective therapeutic agent has yet to be discovered, there remains a critical need for an interdisciplinary perspective on data and information management due to the number of unanswered questions. Biomedical informatics is a multidisciplinary field that falls at the intersection of information technology, computer and data science, engineering, and healthcare that will be instrumental for uncovering novel insights into neurodegenerative disease research, including both causal relationships and therapeutic targets and maximizing the utility of both clinical and research data. The present study aims to provide a brief overview of biomedical informatics and how clinical data applications such as clinical decision support tools can be developed to derive new knowledge from the wealth of available data to advance clinical care and scientific research of neurodegenerative diseases in the era of precision medicine.
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http://dx.doi.org/10.1016/j.trci.2018.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118097PMC
June 2018

Neuroscience learning from longitudinal cohort studies of Alzheimer's disease: Lessons for disease-modifying drug programs and an introduction to the Center for Neurodegeneration and Translational Neuroscience.

Alzheimers Dement (N Y) 2018 11;4:350-356. Epub 2018 Jul 11.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

The development of disease-modifying therapies for Alzheimer's disease is an urgent public health emergency. Recent failures have highlighted the significant challenges faced by drug-development programs. Longitudinal cohort studies are ideal for promoting understanding of this multifactorial, slowly progressive disease. In this section of the special edition, we review several important lessons from longitudinal cohort studies which should be considered in disease-modifying therapy development. In the final section, we introduce the clinical cohort of the Center for Neurodegeneration and Translational Neuroscience. This newly established longitudinal study aims to provide new insights into the neuroimaging and biological marker (biomarkers) correlates of cognitive decline in early Alzheimer's disease and Parkinson's disease (PD).
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http://dx.doi.org/10.1016/j.trci.2018.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118098PMC
July 2018

JustOrthologs: a fast, accurate and user-friendly ortholog identification algorithm.

Bioinformatics 2019 02;35(4):546-552

Department of Biology, Brigham Young University, Provo, UT, USA.

Motivation: Orthologous gene identification is fundamental to all aspects of biology. For example, ortholog identification between species can provide functional insights for genes of unknown function and is a necessary step in phylogenetic inference. Currently, most ortholog identification algorithms require all-versus-all BLAST comparisons, which are time-consuming and memory intensive.

Results: In contrast to existing approaches, JustOrthologs exploits the conservation of gene structure by using the lengths of coding sequence regions and dinucleotide percentages to identify orthologs. In comparison to OrthoMCL, OMA and OrthoFinder, JustOrthologs decreases ortholog identification runtime by more than 96% and achieves comparable precision and recall scores. The computational speedup allowed us to conduct pairwise comparisons of 1197 complete genomes (780 eukaryotes and 417 archaea). We confirmed gene annotations for 384 120 genes, grouped 1 675 415 genes in previously unreported ortholog groups, and identified 51 429 potentially mislabeled genes across 622 843 ortholog groups.

Availability And Implementation: JustOrthologs is an open source collaborative software package available in the GitHub repository: https://github.com/ridgelab/JustOrthologs/. All test FASTA files used for comparisons are freely available at https://github.com/ridgelab/JustOrthologs/comparisonFastaFiles/. Reference genomes used in this work are available for download from the NCBI repository: ftp://ftp.ncbi.nih.gov/genomes/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378933PMC
February 2019

Comparing the Electronic and Standard Versions of the Montreal Cognitive Assessment in an Outpatient Memory Disorders Clinic: A Validation Study.

J Alzheimers Dis 2018 ;62(1):93-97

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns.
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http://dx.doi.org/10.3233/JAD-170896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817908PMC
March 2019

Assembly of 809 whole mitochondrial genomes with clinical, imaging, and fluid biomarker phenotyping.

Alzheimers Dement 2018 04 5;14(4):514-519. Epub 2018 Jan 5.

Department of Biology, Brigham Young University, Provo, UT, USA; Department of Neuroscience, Brigham Young University, Provo, UT, USA. Electronic address:

Introduction: Mitochondrial genetics are an important but largely neglected area of research in Alzheimer's disease. A major impediment is the lack of data sets.

Methods: We used an innovative, rigorous approach, combining several existing tools with our own, to accurately assemble and call variants in 809 whole mitochondrial genomes.

Results: To help address this impediment, we prepared a data set that consists of 809 complete and annotated mitochondrial genomes with samples from the Alzheimer's Disease Neuroimaging Initiative. These whole mitochondrial genomes include rich phenotyping, such as clinical, fluid biomarker, and imaging data, all of which is available through the Alzheimer's Disease Neuroimaging Initiative website. Genomes are cleaned, annotated, and prepared for analysis.

Discussion: These data provide an important resource for investigating the impact of mitochondrial genetic variation on risk for Alzheimer's disease and other phenotypes that have been measured in the Alzheimer's Disease Neuroimaging Initiative samples.
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http://dx.doi.org/10.1016/j.jalz.2017.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961720PMC
April 2018

The relationship between neuropsychological tests of visuospatial function and lobar cortical thickness.

J Clin Exp Neuropsychol 2018 06 7;40(5):518-527. Epub 2017 Nov 7.

b Department of Neuropsychology , Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas , NV , USA.

Introduction: Tests of visuospatial function are often administered in comprehensive neuropsychological evaluations. These tests are generally considered assays of parietal lobe function; however, the neural correlates of these tests, using modern imaging techniques, are not well understood. In the current study we investigated the relationship between three commonly used tests of visuospatial function and lobar cortical thickness in each hemisphere.

Method: Data from 374 patients who underwent a neuropsychological evaluation and MRI scans in an outpatient dementia clinic were included in the analysis. We examined the relationships between cortical thickness, as assessed with Freesurfer, and performance on three tests: Judgment of Line Orientation (JoLO), Block Design (BD) from the Fourth edition of the Wechsler Adult Intelligence Scale, and Brief Visuospatial Memory Test-Revised Copy Trial (BVMT-R-C) in patients who showed overall average performance on these tasks. Using a series of multiple regression models, we assessed which lobe's overall cortical thickness best predicted test performance.

Results: Among the individual lobes, JoLO performance was best predicted by cortical thickness in the right temporal lobe. BD performance was best predicted by cortical thickness in the right parietal lobe, and BVMT-R-C performance was best predicted by cortical thickness in the left parietal lobe.

Conclusions: Performance on constructional tests of visuospatial function appears to correspond best with underlying cortical thickness of the parietal lobes, while performance on visuospatial judgment tests appears to correspond best to temporal lobe thickness. Future research using voxel-wise and connectivity techniques and including more diverse samples will help further understanding of the regions and networks involved in visuospatial tests.
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http://dx.doi.org/10.1080/13803395.2017.1384799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310069PMC
June 2018

Kmer-SSR: a fast and exhaustive SSR search algorithm.

Bioinformatics 2017 Dec;33(24):3922-3928

Department of Biology, BYU, Provo, UT 84602, USA.

Motivation: One of the main challenges with bioinformatics software is that the size and complexity of datasets necessitate trading speed for accuracy, or completeness. To combat this problem of computational complexity, a plethora of heuristic algorithms have arisen that report a 'good enough' solution to biological questions. However, in instances such as Simple Sequence Repeats (SSRs), a 'good enough' solution may not accurately portray results in population genetics, phylogenetics and forensics, which require accurate SSRs to calculate intra- and inter-species interactions.

Results: We present Kmer-SSR, which finds all SSRs faster than most heuristic SSR identification algorithms in a parallelized, easy-to-use manner. The exhaustive Kmer-SSR option has 100% precision and 100% recall and accurately identifies every SSR of any specified length. To identify more biologically pertinent SSRs, we also developed several filters that allow users to easily view a subset of SSRs based on user input. Kmer-SSR, coupled with the filter options, accurately and intuitively identifies SSRs quickly and in a more user-friendly manner than any other SSR identification algorithm.

Availability And Implementation: The source code is freely available on GitHub at https://github.com/ridgelab/Kmer-SSR.

Contact: perry.ridge@byu.edu.
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http://dx.doi.org/10.1093/bioinformatics/btx538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860095PMC
December 2017

Dissociation of Executive and Attentional Elements of the Digit Span Task in a Population of Older Adults: A Latent Class Analysis.

Assessment 2019 10 16;26(7):1386-1398. Epub 2017 Jun 16.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

The prevailing model for working memory proposes the existence of a "central executive" responsible for coordinating and prioritizing incoming information from sensory and association cortices. The Digit Span task is commonly used by clinicians to parse attentional and executive components of working memory; however, the interrelatedness of these constructs in the context of advanced age and neurodegenerative disease remains an area of active investigation. The current study details a procedure and rationale for the use of latent class analysis, a data-driven, person-centered method, in the investigation of older adults and dementia. Class analysis of digit span performance in older adults ( = 874) drawn from a specialty clinic revealed four classes with distinct performance across task subcomponents. In three of the classes, attentional and executive elements demonstrated similar performance. The fourth class and implications of class structure are discussed in the context of aging.
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http://dx.doi.org/10.1177/1073191117714556DOI Listing
October 2019

The Technology Crisis in Neuropsychology.

Arch Clin Neuropsychol 2017 Aug;32(5):541-554

NYU, School of Medicine, New York, NY, USA.

Neuropsychology has fallen reliant on outdated and labor intensive methods of data collection that are slow, highly inefficient, and expensive, and provide relatively data-poor estimates of human behavior despite rapid technological advance in most other fields of medicine. Here we present a brief historical overview of current testing practices in an effort to frame the current crisis, followed by an overview of different settings in which technology can and should be integrated. Potential benefits of laboratory based assessments, remote assessments, as well as passive and high-frequency data collection tools rooted in technology are discussed, along with several relevant examples and how these technologies might be deployed. Broader issues of data security and privacy are discussed, as well as additional considerations to be addressed within each setting. Some of the historical barriers to adoption of technology are also presented, along with a brief discussion of the remaining uncertainties. While by no means intended as a comprehensive review or prescriptive roadmap, our goal is to show that there are a tremendous number of advantages to technologically driven data collection methods, and that technology should be embraced by the field. Our predictions are that the comprehensive assessments of the future will likely entail a combination of lab-based assessments, remote assessments, and passive data capture, and leading the development of these efforts will cement the role of neuropsychology at the forefront of cognitive and behavioral science.
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http://dx.doi.org/10.1093/arclin/acx050DOI Listing
August 2017