Performance of a Paired-End Sequencing-Based Noninvasive Prenatal Screening Test in the Detection of Genome-Wide Fetal Chromosomal Anomalies.

BACKGROUND: Noninvasive prenatal tests (NIPTs) detect fetal chromosomal anomalies with high clinical sensitivity and specificity. We examined the performance of a paired-end sequencing-based NIPT in the detection of genome-wide fetal chromosomal anomalies including common trisomies, sex chromosomal aneuploidies (SCA), rare autosomal aneuploidies (RAAs), and partial deletions/duplications ≥7 Mb. METHODS: Frozen plasma samples from pregnant women were tested using the VeriSeq NIPT Solution v2 assay. All samples were previously tested with a laboratory-developed NIPT and had known clinical outcomes. Individuals performing the sequencing were blinded to clinical outcome data. Clinical sensitivity and specificity were determined for basic (chromosomes 21, 18, 13, X, and Y) and genome-wide screening modes. RESULTS: Of 2335 samples that underwent genome-wide analysis, 28 did not meet QC requirements, resulting in a first-pass assay failure rate of 1.2%. Basic screening analysis, excluding known mosaics, correctly classified 130/130 trisomy 21 samples (sensitivity >99.9%, 95% confidence interval [CI] 97.1%-100%), 41/41 trisomy 18 samples (sensitivity >99.9%, 95% CI 91.4%-100%), and 26/26 trisomy 13 samples (sensitivity >99.9%, 95% CI 87.1%-100%) with 6 false-positive results; specificities ≥99.90% were reported for all 3 trisomies. Concordance for SCAs ranged from 90.5%-100%. Genome-wide screening analysis including known mosaics correctly classified 27/28 RAAs and 20/27 partial deletions/duplications with a specificity of 99.80% for both anomalies, and an overall genome-wide specificity for all anomalies of 99.34%. CONCLUSIONS: The VeriSeq NIPT Solution v2 assay enables accurate identification of fetal aneuploidy, allowing detection of genome-wide fetal chromosomal anomalies with high clinical sensitivities and specificities and a low assay failure rate.Clinical Trial Notification [CTN] identification number [ID]: CT-2018-CTN-01585-1 v1, Protocol: NIPT T05 002.

Prediction of pain outcomes in a randomized controlled trial of dose-response of spinal manipulation for the care of chronic low back pain.

BACKGROUND: No previous studies have created and validated prediction models for outcomes in patients receiving spinal manipulation for care of chronic low back pain (cLBP). We therefore conducted a secondary analysis alongside a dose-response, randomized controlled trial of spinal manipulation. METHODS: We investigated dose, pain and disability, sociodemographics, general health, psychosocial measures, and objective exam findings as potential predictors of pain outcomes utilizing 400 participants from a randomized controlled trial. Participants received 18 sessions of treatment over 6-weeks and were followed for a year. Spinal manipulation was performed by a chiropractor at 0, 6, 12, or 18 visits (dose), with a light-massage control at all remaining visits. Pain intensity was evaluated with the modified von Korff pain scale (0-100). Predictor variables evaluated came from several domains: condition-specific pain and disability, sociodemographics, general health status, psychosocial, and objective physical measures. Three-quarters of cases (training-set) were used to develop 4 longitudinal models with forward selection to predict individual "responders" (≥50% improvement from baseline) and future pain intensity using either pretreatment characteristics or post-treatment variables collected shortly after completion of care. The internal validity of the predictor models were then evaluated on the remaining 25% of cases (test-set) using area under the receiver operating curve (AUC), R(2), and root mean squared error (RMSE). RESULTS: The pretreatment responder model performed no better than chance in identifying participants who became responders (AUC = 0.479). Similarly, the pretreatment pain intensity model predicted future pain intensity poorly with low proportion of variance explained (R(2) = .065). The post-treatment predictor models performed better with AUC = 0.665 for the responder model and R(2) = 0.261 for the future pain model. Post-treatment pain alone actually predicted future pain better than the full post-treatment predictor model (R(2) = 0.350). The prediction errors (RMSE) were large (19.4 and 17.5 for the pre- and post-treatment predictor models, respectively). CONCLUSIONS: Internal validation of prediction models showed that participant characteristics preceding the start of care were poor predictors of at least 50% improvement and the individual's future pain intensity. Pain collected shortly after completion of 6 weeks of study intervention predicted future pain the best.

A path analysis of the effects of the doctor-patient encounter and expectancy in an open-label randomized trial of spinal manipulation for the care of low back pain.

BACKGROUND: The doctor-patient encounter (DPE) and associated patient expectations are potential confounders in open-label randomized trials of treatment efficacy. It is therefore important to evaluate the effects of the DPE on study outcomes. METHODS: Four hundred participants with chronic low back pain (LBP) were randomized to four dose groups: 0, 6, 12, or 18 sessions of spinal manipulation from a chiropractor. Participants were treated three times per week for six weeks. They received light massage control at visits when manipulation was not scheduled. Treating chiropractors were instructed to have equal enthusiasm for both interventions. A path analysis was conducted to determine the effects of dose, patient expectations of treatment success, and DPE on LBP intensity (100-point scale) at the end of care (6 weeks) and primary endpoint (12 weeks). Direct, indirect, and total standardized effects (ßtotal) were computed. Expectations and DPE were evaluated on Likert scales. The DPE was assessed as patient-rated perception of chiropractor enthusiasm, confidence, comfort with care, and time spent. RESULTS: The DPE was successfully balanced across groups, as were baseline expectations. The principal finding was that the magnitude of the effects of DPE on LBP at 6 and 12 weeks (|ß|total = 0.22 and 0.15, p < .05) were comparable to the effects of dose of manipulation at those times (|ß|total = 0.11 and 0.12, p < .05). In addition, baseline expectations had no notable effect on follow-up LBP. Subsequent expectations were affected by LBP, DPE, and dose (p < .05). CONCLUSIONS: The DPE can have a relatively important effect on outcomes in open-label randomized trials of treatment efficacy. Therefore, attempts should be made to balance the DPE across treatment groups and report degree of success in study publications. We balanced the DPE across groups with minimal training of treatment providers. TRIAL REGISTRATION: ClinicalTrials.gov NCT00376350.

Cost analysis related to dose-response of spinal manipulative therapy for chronic low back pain: outcomes from a randomized controlled trial.

OBJECTIVE: The purpose of this analysis is to report the incremental costs and benefits of different doses of spinal manipulative therapy (SMT) in patients with chronic low back pain (LBP). METHODS: We randomized 400 patients with chronic LBP to receive a dose of 0, 6, 12, or 18 sessions of SMT. Participants were scheduled for 18 visits for 6 weeks and received SMT or light massage control from a doctor of chiropractic. Societal costs in the year after study enrollment were estimated using patient reports of health care use and lost productivity. The main health outcomes were the number of pain-free days and disability-free days. Multiple regression was performed on outcomes and log-transformed cost data. RESULTS: Lost productivity accounts for most societal costs of chronic LBP. Cost of treatment and lost productivity ranged from $3398 for 12 SMT sessions to $3815 for 0 SMT sessions with no statistically significant differences between groups. Baseline patient characteristics related to increase in costs were greater age (P = .03), greater disability (P = .01), lower quality-adjusted life year scores (P = .01), and higher costs in the period preceding enrollment (P < .01). Pain-free and disability-free days were greater for all SMT doses compared with control, but only SMT 12 yielded a statistically significant benefit of 22.9 pain-free days (P = .03) and 19.8 disability-free days (P = .04). No statistically significant group differences in quality-adjusted life years were noted. CONCLUSIONS: A dose of 12 SMT sessions yielded a modest benefit in pain-free and disability-free days. Care of chronic LBP with SMT did not increase the costs of treatment plus lost productivity.

Spinal manipulation for the treatment of hypertension: a systematic qualitative literature review.

OBJECTIVE: Spinal manipulative therapy (SMT) has been reported to successfully treat hypertension (HTN). The purpose of this study was to perform a qualitative literature review on the efficacy of SMT for treating HTN. METHODS: The literature was systematically searched in PubMed, Medline, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature, and Index of Chiropractic Literature. Included articles were rated for bias using the Cochrane Collaboration's tool for assessing risk of bias. Studies reporting differing methodologies, types of SMT, frequency of treatment, and time of follow-up were considered too dissimilar for meta-analysis. RESULTS: Of 208 articles identified, 10 were selected as relevant and were assessed. Risk of bias scores revealed 2 studies with low risk, 3 studies with unclear risk, and 5 studies with high risk. The maximum improvement observed in any SMT group, in low risk of bias studies was -9.7 (95% confidence interval [CI], -21.1 to 1.8) systolic improvement and -9.0 (95% CI, -16.8 to -1.2) diastolic; and in unclear risk of bias studies, it was -17.2 (95% CI, -20.7 to -13.7) systolic and -13.0 (95% CI, -15.4 to -10.6) diastolic. Statistically significant decreases in blood pressure were not observed in clinical trials with low bias when SMT was compared with effleurage massage and a 5-minute wait. The studies with more risk of bias showed a greater treatment effect. CONCLUSION: There is currently a lack of low bias evidence to support the use of SMT as a therapy for the treatment of HTN. Future investigations may clarify if SMT is effective for treating HTN, either by itself or as an adjunctive therapy, and by which physiologic mechanism this occurs.

Evaluation of the effects of an evidence-based practice curriculum on knowledge, attitudes, and self-assessed skills and behaviors in chiropractic students.

OBJECTIVE: The purpose of this study was to evaluate the effects of an evidence-based practice (EBP) curriculum incorporated throughout a chiropractic doctoral program on EBP knowledge, attitudes, and self-assessed skills and behaviors in chiropractic students. METHODS: In a prospective cohort design, students from the last entering class under an old curriculum were compared with students in the first 2 entering classes under a new EBP curriculum during the 9th and 11th quarters of the 12-quarter doctoral program at the University of Western States in Portland, OR (n = 370 students at matriculation). Analysis of variance (ANOVA) was performed using a 3-cohort × 2-quarter repeated cross-sectional factorial design to assess the effect of successive entering classes and stage of the students' education. RESULTS: For the knowledge exam (primary outcome), there was a statistically significant cohort effect with each succeeding cohort showing better performance (P < .001); students also performed slightly better in the 11th quarter than in the 9th quarter (P < .05). A similar pattern in cohort and quarter effects was found with behavior self-appraisal for greater time accessing databases such as PubMed. Student self-appraisal of their skills was higher in the 11th than the 9th quarter. All cohorts rejected a set of sentinel misconceptions about application of scientific literature (practice attitudes). CONCLUSIONS: The implementation of the EBP curriculum at this institution resulted in acquisition of knowledge necessary to access and interpret scientific literature, the retention and improvement of skills over time, and the enhancement of self-reported behaviors favoring use of quality online resources.

A preliminary path analysis of expectancy and patient-provider encounter in an open-label randomized controlled trial of spinal manipulation for cervicogenic headache.

OBJECTIVE: The purpose of this article was to present a preliminary model to identify the effects of expectancy of treatment success and the patient-provider encounter (PPE) on outcomes in an open-label randomized trial. METHODS: Eighty participants with chronic cervicogenic headache (CGH) were randomized to 4 groups: 2 levels of treatment dose (8 or 16) and 2 levels of therapy from a chiropractor (spinal manipulation or light massage). Providers were instructed to have equal enthusiasm for all care. Structural equation modeling with standardized path coefficients (beta) was used in a path analysis to identify the effects of patient expectancy and the PPE on CGH pain. The model included monthly pain from baseline to 12 weeks. Expectancy and PPE were evaluated on Likert scales. The patient-provider encounter was measured as patient perception of chiropractor enthusiasm, confidence, and comfort with care. RESULTS: Baseline patient expectancy was balanced across groups. The PPE measures were balanced across groups and consistent over the 8-week treatment period. Treatment and baseline pain had the strongest effects on pain outcomes (|beta| = .46-.59). Expectations had little effect on pain (abs value(beta) < .15). The patient-provider encounter had a weak effect on pain (abs value(beta)= .03-.27) and on subsequent confidence in treatment success (abs value(beta)= .09 and .12). CONCLUSIONS: Encouraging equipoise in the PPE and balancing expectancy across treatment groups may protect against some confounding related to the absence of blinding in a randomized controlled trial of pain. In this trial, their effects were found to be small relative to the effects of treatment and baseline values.

Physical examination and self-reported pain outcomes from a randomized trial on chronic cervicogenic headache.

OBJECTIVE: Objective clinical measures for use as surrogate markers of cervicogenic headache (CGH) pain have not been established. In this analysis, we investigate relationships between objective physical examination (PE) measures with self-reported CGH outcomes. METHODS: This is an exploratory analysis of data generated by attention control PE from an open-label randomized clinical trial. Of 80 subjects, 40 were randomized to 8 treatments (spinal manipulative therapy or light massage control) and 8 PE over 8 weeks. The remaining subjects received no PE. Physical examination included motion palpation of the cervical and upper thoracic regions, active cervical range of motion (ROM) and associated pain, and algometric pain threshold evaluated over articular pillars. Self-reported outcomes included CGH and neck pain and disability, number of CGH headaches, and related disability days. Associations between PE and self-reported outcomes were evaluated using generalized linear models, adjusting for sociodemographic differences and study group. RESULTS: At baseline, number of CGH and disability days were strongly associated with cervical active ROM (P < .001 to .037). Neck pain and disability were strongly associated with ROM-elicited pain (P < .001 to .035) but not later in the study. After the final treatment, pain thresholds were strongly associated with week 12 neck pain and disability and CGH disability and disability days (P < or = .001 to .048). CONCLUSIONS: Cervical ROM was most associated with the baseline headache experience. However, 4 weeks after treatment, algometric pain thresholds were most associated. No one PE measure remained associated with the self-reported headache outcomes over time.

Illustrating risk difference and number needed to treat from a randomized controlled trial of spinal manipulation for cervicogenic headache.

BACKGROUND: The number needed to treat (NNT) for one participant to benefit is considered a useful, clinically meaningful way of reporting binary outcomes from randomized trials. Analysis of continuous data from our randomized controlled trial has previously demonstrated a significant and clinically important difference favoring spinal manipulation over a light massage control. METHODS: Eighty participants were randomized to receive spinal manipulation or a light massage control (n = 40/group). Improvements in cervicogenic headache pain (primary outcome), disability, and number in prior four weeks were dichotomized into binary outcomes at two thresholds: 30% representing minimal clinically important change and 50% representing clinical success. Groups were compared at 12 and 24-week follow-up using binomial regression (generalized linear models) to compute the adjusted risk difference (RD) between groups and number needed to treat (NNT) after adjusting for baseline differences between groups. Results were compared to logistic regression results. RESULTS: For headache pain, clinically important improvement (30% or 50%) was more likely for spinal manipulation: adjusted RD = 17% to 27% and NNT = 3.8 to 5.8 (p = .005 to .028). Some statistically significant results favoring manipulation were found for headache disability and number. CONCLUSION: Spinal manipulation demonstrated a benefit in terms of a clinically important improvement of cervicogenic headache pain. The use of adjusted NNT is recommended; however, adjusted RD may be easier to interpret than NNT. The study demonstrated how results may depend on the threshold for dichotomizing variables into binary outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NLM identifier NCT00246350.

Visual hallucinations in dementia: a prospective community-based study with autopsy.

OBJECTIVE: Several studies have demonstrated that specific neuropathologic features may be associated with the presence of visual hallucinations in dementia patients, but the clinical usefulness of these studies has been limited because their subjects were selected on the basis of neuropathologic findings rather than clinical presentations. This study seeks to investigate the demographic, clinical, and neuropathologic features of community-based dementia subjects with and without visual hallucations. DESIGN: A prospective examination of the clinical and neuropathologic correlates of visual hallucinations in community-based dementia subjects. PARTICIPANTS: One hundred forty-eight subjects with sufficient clinical and neuropathologic data from a community-based incident dementia autopsy case series. RESULTS: Subjects were classified according to the presence or absence of visual hallucinations and subjects with visual hallucinations (N = 27) were younger at intake and more likely to exhibit agitation, delusions, and apathy than subjects without visual hallucinations (N = 121). Subjects with visual hallucinations were also more likely than subjects without visual hallucinations to have Lewy-related pathology (LRP) (78% versus 45%). In addition, a higher frequency of visual hallucinations was observed in subjects with neocortical LRP than subjects with limbic-, amygdala-, or brainstem-predominant LRP. Although Alzheimer disease with concomitant LRP was the most common neuropathologic subtype in the visual hallucinations-positive group (59%), the frequency of subjects with Alzheimer disease pathology did not differ significantly between those with and without visual hallucinations (74% versus 62%). CONCLUSIONS: Subjects with visual hallucinations were more likely to have concomitant postural and gait disturbance, additional neuropsychiatric symptoms, and neocortical LRP than subjects without visual hallucinations. Visual hallucinations accompanying dementia have distinct clinical and neuropathologic characteristics that are important for prognosis and clinical management.

Cognitive impairment in older adults without dementia: clinical and pathologic outcomes in a community-based sample.

This study examines clinical and neuropathologic characteristics of 37 participants in a community-based dementia series who had cognitive complaints at enrollment but did not meet dementia criteria. Participants had neuropsychological testing, were followed until death, and underwent autopsy. Twenty-four participants progressed to dementia, and their baseline characteristics were analyzed. Of the 24, 13 met criteria for neuropathologic Alzheimer disease (AD). The 13 participants who progressed to neuropathologic AD (mean intake age 78.5 +/- 7.7, mean enrollment 6.4 +/- 2.1 years) performed worse than the 11 who progressed to neuropathologic non-AD dementias (mean intake age 79.0 +/- 6.0, mean enrollment 6.0 +/- 3.2 years) on baseline Wechsler Memory Scale (WMS) delayed logical memory (3.4 +/- 2.9 vs 6.3 +/- 3.9, P = .05) and delayed visual reproduction (1.4 +/- 2.1 vs 3.1 +/- 2.7, P = .02). These observations are consistent with the view that nondemented patients with underlying AD may be more likely to present with memory than nonmemory cognitive impairment.

The impact of microbial surveys on disinfection protocols in a chiropractic college environment.

OBJECTIVE: A baseline microbial survey was conducted to identify the microbes present on the headpieces of chiropractic adjusting tables from across the Western States Chiropractic College, Portland, Ore, facilities. This included the instructional adjustive technique laboratories, the student health center, the campus outpatient clinic, and an off-site clinic. The objective of this study was to evaluate the effect of disinfection protocols over time at a chiropractic college. METHODS: Four samplings were done for a 12-month period. A total of 69 treatment tables were tested. Sampling was done directly to blood agar (5% sheep blood) plates. Data obtained from the clinic locations were analyzed using linear regression models. RESULTS: Identification of microbes by differential staining and biochemical analysis yielded a variety of gram-positive bacteria in all 4 surveys. The numbers of bacterial colonies decreased in the second survey after changes to disinfection protocols. The number of colonies continued to remain below baseline in the third and fourth surveys. Methicillin-resistant Staphylococcus aureus was found in the clinics in 3 of 4 surveys. Methicillin-resistant S aureus was not detected in the technique laboratories. CONCLUSIONS: Various microbes were identified on the headpieces of adjusting tables in the college instructional technique laboratories and college clinics. Changing the disinfection protocols reduced the number of bacteria found in the second survey. In addition, the third and fourth surveys showed fewer bacterial colonies than baseline, suggesting that compliance with disinfection protocols continued over time.

Empiric refinement of the pathologic assessment of Lewy-related pathology in the dementia patient.

Lewy-related pathology (LRP) is a common pathologic finding at autopsy in dementia patients. Recently criteria for categorizing types of LRP in dementia patients were published, though these criteria have yet to be systematically applied to large dementia samples. We examined a large (n = 208) referral-based autopsy sample for LRP, and applied the published criteria for LRP categorization to these cases. We found almost half (49%) of LRP positive cases from this sample were not classifiable. However, modifying the published criteria by reducing the number of regions requiring examination, allowing more variability in LRP severity scores within specific brain regions, and adding an amygdala predominant category permitted classification of 97% of LRP positive cases from the referral-based sample. Application of the modified criteria to an unrelated community-based autopsy sample (n = 226) allowed classification of 96% of LRP positive cases. Modest modifications in the published criteria permit a significantly greater number of dementia cases with LRP to be classified. In addition, this modification allows for more limited sampling of brain regions for classification of LRP. We propose that these modified criteria for the categorization of LRP be utilized in patients with a history of dementia.

Dose-response and efficacy of spinal manipulation for care of cervicogenic headache: a dual-center randomized controlled trial.

BACKGROUND CONTEXT: The optimal number of visits for the care of cervicogenic headache (CGH) with spinal manipulative therapy (SMT) is unknown. PURPOSE: The present study aimed to identify the dose-response relationship between visits for SMT and chronic CGH outcomes and to evaluate the efficacy of SMT by comparison with a light-massage control. STUDY DESIGN/SETTING: This is a two-site, open-label randomized controlled trial. PATIENT SAMPLE: Participants were 256 adults with chronic CGH. OUTCOME MEASURES: The primary outcome was days with CGH in the previous 4 weeks evaluated at the 12- and 24-week primary end points. Secondary outcomes included CGH days at remaining end points, pain intensity, disability, perceived improvement, medication use, and patient satisfaction. METHODS: Participants were randomized to four dose levels of chiropractic SMT: 0, 6, 12, or 18 sessions. They were treated three times per week for 6 weeks and received a focused light-massage control at sessions when SMT was not assigned. Linear dose effects and comparisons with the no-manipulation control group were evaluated at 6, 12, 24, 39, and 52 weeks. The present study was funded by the National Center for Complementary and Integrative Health (R01AT006330) and is registered at ClinicalTrials.gov (NCT01530321). The authors declare no conflicts of interest. RESULTS: A linear dose-response was observed for all follow-ups, a reduction of approximately 1 CGH day/4 weeks per additional 6 SMT visits (p<.05); a maximal effective dose could not be determined. Cervicogenic headache days/4 weeks were reduced from about 16 to 8 for the highest and most effective dose of 18 SMT visits. Mean differences in CGH days/4 weeks between 18 SMT visits and control were -3.3 (p=.004) and -2.9 (p=.017) at the primary end points, and were similar in magnitude at the remaining end points (p<.05). Differences between other SMT doses and control were smaller in magnitude (p>.05). Cervicogenic headache intensity showed no important improvement nor differed by dose. Other secondary outcomes were generally supportive of the primary outcome. CONCLUSIONS: There was a linear dose-response relationship between SMT visits and days with CGH. For the highest and most effective dose of 18 SMT visits, CGH days were reduced by half and about 3 more days per month than for the light-massage control.

Clinical validation of the next-generation sequencing-based Extended RAS Panel assay using metastatic colorectal cancer patient samples from the phase 3 PRIME study.

PURPOSE: To validate a next-generation sequencing (NGS)-based companion diagnostic using the MiSeqDx® sequencing instrument to simultaneously detect 56 RAS mutations in DNA extracted from formalin-fixed paraffin-embedded metastatic colorectal cancer (mCRC) tumor samples from the PRIME study. The test's ability to identify patients with mCRC likely to benefit from panitumumab treatment was assessed. METHODS: Samples from PRIME, which compared first-line panitumumab + FOLFOX4 with FOLFOX4, were processed according to predefined criteria using a multiplex assay that included input DNA qualification, library preparation, sequencing, and the bioinformatics reporting pipeline. NGS mutational analysis of KRAS and NRAS exons 2, 3, and 4 was performed and compared with Sanger sequencing. RESULTS: In 441 samples, positive percent agreement of the Extended RAS Panel with Sanger sequencing was 98.7% and negative percent agreement was 97.6%. For clinical validation (n = 528), progression-free survival (PFS) and overall survival (OS) were compared between patients with RAS mutations (RAS Positive) and those without (RAS Negative). Panitumumab + FOLFOX4 improved PFS in RAS Negative patients (P = 0.02). Quantitative interaction testing indicated the treatment effect (measured by the hazard ratio of panitumumab + FOLFOX4 versus FOLFOX4) differed for RAS Negative versus RAS Positive for PFS (P = 0.0038) and OS (P = 0.0323). CONCLUSIONS: NGS allows for broad, rapid, highly specific analyses of genomic regions. These results support use of the Extended RAS Panel as a companion diagnostic for selecting patients for panitumumab, and utilization is consistent with recent clinical guidelines regarding mCRC RAS testing. Overall, approximately 13% more patients were detected with the Extended RAS Panel versus KRAS exon 2 alone. CLINICAL TRIAL REGISTRY IDENTIFIER: NCT00364013 (ClinicalTrials.gov).

Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease.

Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare autosomal trisomies (RATs) to improve understanding of feto-placental biology. We analyzed two independent cohorts from clinical laboratories, both of which used a similar quality control parameter, normalized chromosome denominator quality. The entire data set included 89,817 samples. Samples flagged for analysis and classified as abnormal were 328 of 72,932 (0.45%) and 71 of 16,885 (0.42%) in cohorts 1 and 2, respectively. Clinical outcome data were available for 57 of 71 (80%) of abnormal cases in cohort 2. Visual analysis of WGS data demonstrated RATs, copy number variants, and extensive genome-wide imbalances. Trisomies 7, 15, 16, and 22 were the most frequently observed RATs in both cohorts. Cytogenetic or pregnancy outcome data were available in 52 of 60 (87%) of cases with RATs in cohort 2. Cases with RATs detected were associated with miscarriage, true fetal mosaicism, and confirmed or suspected uniparental disomy. Comparing the trisomic fraction with the fetal fraction allowed estimation of possible mosaicism. Analysis and reporting of aneuploidies in all chromosomes can clarify cases in which cfDNA findings on selected "target" chromosomes (21, 18, and 13) are discordant with the fetal karyotype and may identify pregnancies at risk of miscarriage and other complications.

Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid.

BACKGROUND: Treatment with HMG-CoA reductase inhibitors ("statins") has been variably associated with a reduced risk of Alzheimer's disease (AD) in epidemiologic studies and reduced amyloid-beta (Abeta) deposition in animal models of AD. Putative neuroprotective effects of statins may vary in relation to their ability to penetrate into the central nervous system (CNS). METHODS: We measured levels of cerebrospinal fluid (CSF) AD biomarkers following 14 weeks of treatment with simvastatin (a CNS permeant statin; n=10) at 40 mg/day or pravastatin (a CNS impermeant statin; n=13) at 80 mg/day in hypercholesterolemic subjects without dementia. RESULTS: Simvastatin, but not pravastatin, reduced CSF levels of phospho-tau-181 (p-tau181) in all subjects. There were no differences in CSF levels of total tau, Abeta42, Abeta40, soluble amyloid beta protein precursor (sAbetaPP) alpha or beta, or F2-isoprostanes. CONCLUSIONS: Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD.

Dose-response of spinal manipulation for cervicogenic headache: study protocol for a randomized controlled trial.

BACKGROUND: Cervicogenic headache is a prevalent and costly pain condition commonly treated by chiropractors. There is evidence to support the effectiveness for spinal manipulation, but the dose of treatment required to achieve maximal relief remains unknown. The purpose of this paper is to describe the methodology for a randomized controlled trial evaluating the dose-response of spinal manipulation for chronic cervicogenic headache in an adult population. METHODS/DESIGN: This is a mixed-methods, two-site, prospective, parallel groups, observer-blind, randomized controlled trial conducted at university-affiliated research clinics in the Portland, OR and Minneapolis, MN areas. The primary outcome is patient reported headache frequency. Other outcomes include self-reported headache intensity, disability, quality of life, improvement, neck pain intensity and frequency, satisfaction, medication use, outside care, cervical motion, pain pressure thresholds, health care utilization, health care costs, and lost productivity. Qualitative interviews are also conducted to evaluate patients' expectations of treatment. DISCUSSION: With growing concerns regarding the costs and side effects of commonly used conventional treatments, greater numbers of headache sufferers are seeking other approaches to care. This is the first full-scale randomized controlled trial assessing the dose-response of spinal manipulation therapy on outcomes for cervicogenic headache. The results of this study will provide important evidence for the management of cervicogenic headache in adults. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01530321).

Comparative study of outcome measures and analysis methods for traumatic brain injury trials.

Batteries of functional and cognitive measures have been proposed as alternatives to the Extended Glasgow Outcome Scale (GOSE) as the primary outcome for traumatic brain injury (TBI) trials. We evaluated several approaches to analyzing GOSE and a battery of four functional and cognitive measures. Using data from a randomized trial, we created a "super" dataset of 16,550 subjects from patients with complete data (n=331) and then simulated multiple treatment effects across multiple outcome measures. Patients were sampled with replacement (bootstrapping) to generate 10,000 samples for each treatment effect (n=400 patients/group). The percentage of samples where the null hypothesis was rejected estimates the power. All analytic techniques had appropriate rates of type I error (≤5%). Accounting for baseline prognosis either by using sliding dichotomy for GOSE or using regression-based methods substantially increased the power over the corresponding analysis without accounting for prognosis. Analyzing GOSE using multivariate proportional odds regression or analyzing the four-outcome battery with regression-based adjustments had the highest power, assuming equal treatment effect across all components. Analyzing GOSE using a fixed dichotomy provided the lowest power for both unadjusted and regression-adjusted analyses. We assumed an equal treatment effect for all measures. This may not be true in an actual clinical trial. Accounting for baseline prognosis is critical to attaining high power in Phase III TBI trials. The choice of primary outcome for future trials should be guided by power, the domain of brain function that an intervention is likely to impact, and the feasibility of collecting outcome data.

Dose-response and efficacy of spinal manipulation for care of chronic low back pain: a randomized controlled trial.

BACKGROUND CONTEXT: There have been no full-scale trials of the optimal number of visits for the care of any condition with spinal manipulation. PURPOSE: To identify the dose-response relationship between visits to a chiropractor for spinal manipulation and chronic low back pain (cLBP) outcomes and to determine the efficacy of manipulation by comparison with a light massage control. STUDY DESIGN/SETTING: Practice-based randomized controlled trial. PATIENT SAMPLE: Four hundred participants with cLBP. OUTCOME MEASURES: The primary cLBP outcomes were the 100-point modified Von Korff pain intensity and functional disability scales evaluated at the 12- and 24-week primary end points. Secondary outcomes included days with pain and functional disability, pain unpleasantness, global perceived improvement, medication use, and general health status. METHODS: One hundred participants with cLBP were randomized to each of four dose levels of care: 0, 6, 12, or 18 sessions of spinal manipulation from a chiropractor. Participants were treated three times per week for 6 weeks. At sessions when manipulation was not assigned, they received a focused light massage control. Covariate-adjusted linear dose effects and comparisons with the no-manipulation control group were evaluated at 6, 12, 18, 24, 39, and 52 weeks. RESULTS: For the primary outcomes, mean pain and disability improvement in the manipulation groups were 20 points by 12 weeks and sustainable to 52 weeks. Linear dose-response effects were small, reaching about two points per six manipulation sessions at 12 and 52 weeks for both variables (p<.025). At 12 weeks, the greatest differences from the no-manipulation control were found for 12 sessions (8.6 pain and 7.6 disability points, p<.025); at 24 weeks, differences were negligible; and at 52 weeks, the greatest group differences were seen for 18 visits (5.9 pain and 8.8 disability points, p<.025). CONCLUSIONS: The number of spinal manipulation visits had modest effects on cLBP outcomes above those of 18 hands-on visits to a chiropractor. Overall, 12 visits yielded the most favorable results but was not well distinguished from other dose levels.