Regression of high dimensional data is particularly difficult when the number of observations is ... more Regression of high dimensional data is particularly difficult when the number of observations is limited. Principal Component Analysis, canonical correlation analysis and factor analysis are commonly used methods to reduce data dimensions, but usually cannot find the most significant linear combination. The goal is usually to find a particular partition of the space X consisting of all independent factors. In this paper, we propose an approach to high dimensional regression for applications where N>K or N<K, where N is the sample size, k is the dimension of space X. The approach starts by finding the most significant linear combination and one of the most insignificant directions to decompose the sample space into two subspaces and reduce the dimension. Further, we examine the contributions of individual variables to those most significant vectors by the coefficients of the combinations to reduce the total number of variables in the selected space without losing the power of t...
There are limited data describing the epidemiology of adult-onset schizophrenic disorders in the ... more There are limited data describing the epidemiology of adult-onset schizophrenic disorders in the United States. Although the military is not proportionately comparable in all demographic characteristics to the civilian population, it is drawn from all racial/ethnic subgroups, and members range in age from 17 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;60 years. We describe the incidence of hospitalization for new onset schizophrenic disorders among military members by sex, race, and age. Using military inpatient data, we evaluated patterns of initial hospitalizations for schizophrenic disorders among military personnel for 2000-2009, focusing on sex, race, and age. No individual-level data were available. From 2000-2009, 1976 military personnel had a first schizophrenic disorder hospitalization, with an overall incidence rate of 0.14/1000 person-years. There were no consistent changes in rates over time. While overall incidence rates were similar for men and women (incidence rate ratio (IRR)=1.10), rates were higher among men than women below age 25; after 25-30 rates were higher among women. Incidence was higher among blacks and other racial groups, with IRR=2.0 and 1.3, respectively. Medical screening of military applicants prevents persons with overt or a reported history of psychosis, and most with serious behavior problems, from enlisting; therefore, first hospitalization is likely to reflect new illness. No pre-military socioeconomic data were available, however, essentially all study subjects were high school graduates; unmeasured differences in socioeconomic status were unlikely to explain the observed results. This report may provide lower bound estimates of the schizophrenic disorder incidence in the United States.
We describe the validation of a serum-based test developed by Rules-Based Medicine which can be u... more We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls.
Background: The Department of Defense Hearing Conservation Program requires that a reference audi... more Background: The Department of Defense Hearing Conservation Program requires that a reference audiogram be performed at initial entry training (IET), before noise exposure. In the Army, only Fort Sill, home of the field artillery, and Fort Benning, home of the infantry, are in compliance. All military applicants receive a screening audiogram at a military entrance processing station (MEPS) to qualify for service. This audiogram does not meet the Defense Occupational and Environmental Health Readiness System-Hearing Conservation (DOEHRS-HC) standard. Nevertheless, it has been proposed that the MEPS screen be used as the reference because of limited resources and time during IET medical in-processing. Methods: A total of 11,816 individual reference audiograms performed at Fort Sill 95th Adjutant General Recruit Reception Center in 2000 were identified in the DOEHRS-HC database. Results of the MEPS screening audiograms were found for 11,311 (96%) of these individuals. The two audiograms were compared by frequency and ear and by using the two Department of Defense criteria for threshold shift. Results: A total of 14.49% (95% confidence interval, 14.48-14.50%) of audiograms using the three-frequency average difference and 23.19% (95% confidence interval, 23.18-23.20%) using the four-frequency difference in either ear demonstrated a threshold shift. The mean difference in intensity between the two audiograms ranged from 5 to 12 dB and varied by frequency and ear, with the greatest differences being seen at 500 and 6,000 kHz and in the left ear, compared with the right ear. The mean threshold level was higher for each frequency in the DOEHRS-HC audiogram, compared with the MEPS audiogram. Conclusions: Approximately 15% of soldiers at Fort Sill in 2000 showed a clinically significant threshold difference between their MEPS screening and the DOEHRS-HC baseline audiogram. Methodological variations in testing and interval noise-induced hearing loss could account for these differences. The results do not support the use of the MEPS screening audiogram as the reference audiogram. Compliance with the Hearing Conservation Program in the Army would require either improving MEPS testing to DOEHRS-HC standards or performing baseline audiograms at all five IET sites.
IMPORTANCE Unrecognized demyelinating events often precede the clinical onset of multiple scleros... more IMPORTANCE Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease. OBJECTIVE To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding. EXPOSURES Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa). MAIN OUTCOMES AND MEASUREMENTS Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models. RESULTS Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for Ն5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009). CONCLUSIONS AND RELEVANCE The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.
A biomarker is a measurable indicator of the severity or presence of some disease. A biomarker is... more A biomarker is a measurable indicator of the severity or presence of some disease. A biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism. The space Decomposition-Gradient-Regression (DGR) method has been developed (Li et al., 2012; Li et al., 2015) to select biomarkers for schizophrenia. This study performs the DGR approach on data for bipolar disorder patients, which contains 56 biomarkers and 8 infectious agent’s antibodies. Serum specimens were collected from 132 United States military service members (118 males and 14 females) with a diagnosis of bipolar disorder from 1992 to 2005 and their matched healthy controls.. Trefoil Factor3 (TFF3), Gliadin, prolactin (PRL), Apolipoprotein A-II (Apo A-II) and Immunoglobulin A (IGA) were found to be significant predictors of Bipolar Disorder (BD) in males. Macrophage-Derived Chemokine (MDC), Alpha-1-Antitrypsin (AAT), Gliadin, Beta-2-Microglobulin (B2M) and ...
Recent research efforts have progressively shifted towards preventative psychiatry and prognostic... more Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset ...
Regression of high dimensional data is particularly difficult when the number of observations is ... more Regression of high dimensional data is particularly difficult when the number of observations is limited. Principal Component Analysis, canonical correlation analysis and factor analysis are commonly used methods to reduce data dimensions, but usually cannot find the most significant linear combination. The goal is usually to find a particular partition of the space X consisting of all independent factors. In this paper, we propose an approach to high dimensional regression for applications where N>K or N<K, where N is the sample size, k is the dimension of space X. The approach starts by finding the most significant linear combination and one of the most insignificant directions to decompose the sample space into two subspaces and reduce the dimension. Further, we examine the contributions of individual variables to those most significant vectors by the coefficients of the combinations to reduce the total number of variables in the selected space without losing the power of t...
There are limited data describing the epidemiology of adult-onset schizophrenic disorders in the ... more There are limited data describing the epidemiology of adult-onset schizophrenic disorders in the United States. Although the military is not proportionately comparable in all demographic characteristics to the civilian population, it is drawn from all racial/ethnic subgroups, and members range in age from 17 to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;60 years. We describe the incidence of hospitalization for new onset schizophrenic disorders among military members by sex, race, and age. Using military inpatient data, we evaluated patterns of initial hospitalizations for schizophrenic disorders among military personnel for 2000-2009, focusing on sex, race, and age. No individual-level data were available. From 2000-2009, 1976 military personnel had a first schizophrenic disorder hospitalization, with an overall incidence rate of 0.14/1000 person-years. There were no consistent changes in rates over time. While overall incidence rates were similar for men and women (incidence rate ratio (IRR)=1.10), rates were higher among men than women below age 25; after 25-30 rates were higher among women. Incidence was higher among blacks and other racial groups, with IRR=2.0 and 1.3, respectively. Medical screening of military applicants prevents persons with overt or a reported history of psychosis, and most with serious behavior problems, from enlisting; therefore, first hospitalization is likely to reflect new illness. No pre-military socioeconomic data were available, however, essentially all study subjects were high school graduates; unmeasured differences in socioeconomic status were unlikely to explain the observed results. This report may provide lower bound estimates of the schizophrenic disorder incidence in the United States.
We describe the validation of a serum-based test developed by Rules-Based Medicine which can be u... more We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls.
Background: The Department of Defense Hearing Conservation Program requires that a reference audi... more Background: The Department of Defense Hearing Conservation Program requires that a reference audiogram be performed at initial entry training (IET), before noise exposure. In the Army, only Fort Sill, home of the field artillery, and Fort Benning, home of the infantry, are in compliance. All military applicants receive a screening audiogram at a military entrance processing station (MEPS) to qualify for service. This audiogram does not meet the Defense Occupational and Environmental Health Readiness System-Hearing Conservation (DOEHRS-HC) standard. Nevertheless, it has been proposed that the MEPS screen be used as the reference because of limited resources and time during IET medical in-processing. Methods: A total of 11,816 individual reference audiograms performed at Fort Sill 95th Adjutant General Recruit Reception Center in 2000 were identified in the DOEHRS-HC database. Results of the MEPS screening audiograms were found for 11,311 (96%) of these individuals. The two audiograms were compared by frequency and ear and by using the two Department of Defense criteria for threshold shift. Results: A total of 14.49% (95% confidence interval, 14.48-14.50%) of audiograms using the three-frequency average difference and 23.19% (95% confidence interval, 23.18-23.20%) using the four-frequency difference in either ear demonstrated a threshold shift. The mean difference in intensity between the two audiograms ranged from 5 to 12 dB and varied by frequency and ear, with the greatest differences being seen at 500 and 6,000 kHz and in the left ear, compared with the right ear. The mean threshold level was higher for each frequency in the DOEHRS-HC audiogram, compared with the MEPS audiogram. Conclusions: Approximately 15% of soldiers at Fort Sill in 2000 showed a clinically significant threshold difference between their MEPS screening and the DOEHRS-HC baseline audiogram. Methodological variations in testing and interval noise-induced hearing loss could account for these differences. The results do not support the use of the MEPS screening audiogram as the reference audiogram. Compliance with the Hearing Conservation Program in the Army would require either improving MEPS testing to DOEHRS-HC standards or performing baseline audiograms at all five IET sites.
IMPORTANCE Unrecognized demyelinating events often precede the clinical onset of multiple scleros... more IMPORTANCE Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease. OBJECTIVE To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding. EXPOSURES Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa). MAIN OUTCOMES AND MEASUREMENTS Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models. RESULTS Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for Ն5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009). CONCLUSIONS AND RELEVANCE The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.
A biomarker is a measurable indicator of the severity or presence of some disease. A biomarker is... more A biomarker is a measurable indicator of the severity or presence of some disease. A biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism. The space Decomposition-Gradient-Regression (DGR) method has been developed (Li et al., 2012; Li et al., 2015) to select biomarkers for schizophrenia. This study performs the DGR approach on data for bipolar disorder patients, which contains 56 biomarkers and 8 infectious agent’s antibodies. Serum specimens were collected from 132 United States military service members (118 males and 14 females) with a diagnosis of bipolar disorder from 1992 to 2005 and their matched healthy controls.. Trefoil Factor3 (TFF3), Gliadin, prolactin (PRL), Apolipoprotein A-II (Apo A-II) and Immunoglobulin A (IGA) were found to be significant predictors of Bipolar Disorder (BD) in males. Macrophage-Derived Chemokine (MDC), Alpha-1-Antitrypsin (AAT), Gliadin, Beta-2-Microglobulin (B2M) and ...
Recent research efforts have progressively shifted towards preventative psychiatry and prognostic... more Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset ...
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Papers by David Niebuhr