Whole mitochondrial genomes assembled from thermally altered forensic bones and teeth.

The recovery and analysis of genetic material obtained from thermally altered human bones and teeth are increasingly important to forensic investigations, especially in cases where soft-tissue identification is no longer possible. Although little is known about how these fire-related processes affect DNA degradation over time, next-generation sequencing technology in combination with traditional osteobiographical applications may provide us clues to these questions. In this study, we compare whole mitochondrial genome data generated using two different DNA extraction methods from 27 thermally altered samples obtained from fire victims (Maricopa County, Arizona) . DNA extracts were converted to double-stranded DNA libraries and enriched for whole mitochondrial DNA (mtDNA) using synthetic biotinylated RNA baits, then sequenced on an Illumina MiSeq. We processed the mitochondrial data using an in-house computational pipeline (MitoPipe1.0) composed of ancient DNA and modern genomics applications, then compared the resulting information across the two extraction types and five burn categories. Our analysis shows that DNA fragmentation increases with temperature, but that the acute insult from fire combined with the lack of water is insufficient to produce 5' and 3' terminal deamination characteristic of ancient DNA. Our data also suggest an acute and significant point of DNA degradation between 350 °C and 550 °C, and that the likelihood of generating high quality mtDNA haplogroup calls decreases significantly at temperatures > 550 °C. This research is part of a concerted effort to understand how fire affects our ability to generate genetic profiles suitable for forensic identification purposes.

Reconstructing full and partial STR profiles from severely burned human remains using comparative ancient and forensic DNA extraction techniques.

Thermal degeneration of the DNA molecule presents a special challenge to medico-legal investigations since low DNA yields, fragmented DNA molecules, and damaged nucleotide bases hinder accurate STR genotyping. As a consequence, fragments of severely burned human remains are often not amenable to standard DNA recovery. However, current ancient DNA (aDNA) extraction methods have proven highly effective at obtaining ultrashort DNA fragments (∼50 bp) from degraded palaeontological and archaeological specimens. In this study, we compare DNA yields and STR results obtained from two established aDNA and forensic DNA extraction protocols by sampling multiple skeletal elements recovered from victims (n = 23) involved in fire-related incidents. DNA yields and STR results suggest an inverse correlation between DNA yield and STR quality and increasing temperature. Despite the rapid thermal destruction of DNA at high temperatures, we generated higher quality full and partial STR profiles using the aDNA extraction protocol across all burn categories than the forensic total bone demineralization extraction method. Our analysis suggests adopting aDNA extraction methods as an alternative to current forensic practices to improve DNA yields from challenging human remains.

Adult psychosocial outcome of prepubertal major depressive disorder.

OBJECTIVE: To compare adult psychosocial functioning (PSF) of subjects with prepubertal major depressive disorder (PMDD) to a normal comparison (NC) group. METHOD: PSF of subjects with PMDD (n = 72) and of NC subjects (n = 28) was compared after prospective follow-up to adulthood. These 100 subjects were 90.9% of the baseline 110 subjects who participated in the "Nortriptyline in Childhood Depression: Follow-up Study." Research nurses who were blind to group status conducted telephone interviews using the Longitudinal Interval Follow-up Evaluation (LIFE) to obtain PSF data. RESULTS: At follow-up, the PMDD group was 20.7+/-2.0 and the NC subjects were 20.9+/-2.2 years old. The PMDD subjects were 10.3+/-1.5 years old at baseline. Time between baseline and follow-up was 9.9+/-1.5 years. In the PMDD group, subjects with MDD, bipolar disorder, or substance use disorders during the previous 5 years had significantly worse PSF than NC subjects. These PSF impairments included significantly worse relationships with parents, siblings, and friends; significantly worse functioning in household, school, and work settings; and worse overall quality of life and global social adjustment. CONCLUSIONS: Although combined treatments for PMDD have little scientific basis, multimodality regimens seem prudent until definitive treatment data become available.

Reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections.

OBJECTIVE: To investigate the reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections. METHOD: The 1986 version of the KSADS was modified and expanded to include onset and offset of each symptom for both current and lifetime episodes, expanded prepubertal mania and rapid cycling sections, and categories for attention-deficit/hyperactivity disorder and other DSM-IV diagnoses. To optimize diagnostic research, skip-outs were minimized. Subjects participated in the ongoing "Phenomenology and Course of Pediatric Bipolar Disorder" study. Mothers and children were interviewed separately by research nurses who were blind to diagnostic group status. In addition, ratings of off-site child psychiatrists, made from the narrative documentation given for each WASH-U-KSADS item, were compared with research nurse ratings. This work was performed between 1995 and 2000. RESULTS: There was 100% interrater reliability, five consecutive times, as both interviewer and observer after 10 to 15 trials. The kappa values of comparisons between research nurse and off-site blind best-estimate ratings of mania and rapid cycling sections were excellent (0.74-1.00). High 6-month stability for mania diagnoses (85.7%) and for individual mania items and validity against parental and teacher reports were previously reported. CONCLUSIONS: The WASH-U-KSADS mania and rapid cycling sections have acceptable reliability.

One-year recovery and relapse rates of children with a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: The study examined 1-year recovery and relapse rates for mania in subjects who met criteria for a prepubertal and early adolescent bipolar disorder phenotype. METHOD: Outpatients identified by consecutive new-case ascertainment were assessed by means of separate child and parent interviews, consensus conferences, and blind best estimates. The definition of the prepubertal and early adolescent bipolar disorder phenotype was DSM-IV mania with elation and/or grandiosity as one criterion. RESULTS: Of 93 subjects seen at baseline, 89 were seen at 1 year (95.7% retention). The rate of recovery from mania was 37.1%, and the rate of relapse after recovery was 38.3%. No covariates were significantly associated with recovery or relapse. CONCLUSIONS: The low recovery and high relapse rates supported the study hypothesis of poor outcomes, which was made on the basis of similarity between the characteristics of the prepubertal and early adolescent bipolar disorder phenotype (long episode duration and high prevalence of mixed mania, psychosis, and rapid cycling) and those of severe bipolar disorder in adults.

Bipolar disorder at prospective follow-up of adults who had prepubertal major depressive disorder.

OBJECTIVE: The authors' goal was to conduct an adult follow-up of subjects who had participated in a study of nortriptyline for childhood depression. METHOD: The study group represented 100 (90. 9%) of the original 110 subjects and included 72 subjects who had a prepubertal diagnosis of major depressive disorder and 28 normal comparison subjects. Subjects were assessed with semistructured research interviews given by research nurses who were blind to the subjects' original diagnoses. RESULTS: In the original study, the mean age of the children with prepubertal major depressive disorder was 10.3 years (SD=1.5); at adult follow-up the mean age of these subjects was 20.7 years (SD=2.0). At follow-up, significantly more of the subjects who had prepubertal diagnoses of major depressive disorder (N=24 [33.3%]) than normal comparison subjects (none) had bipolar I disorder. Subjects who had prepubertal diagnoses of major depressive disorder also had significantly higher rates of any bipolar disorder than normal subjects (48.6% [N=35] versus 7.1% [N=2]), major depressive disorder (36.1% [N=26] versus 14.3% [N=4]), substance use disorders (30.6% [N=22] versus 10.7% [N=3]), and suicidality (22.2% [N=16] versus 3.6% [N=1]). Parental and grandparental mania predicted bipolar I disorder outcomes. CONCLUSIONS: High rates of switching to mania have implications for the treatment of depressed children. The authors discuss the reasons for their finding a higher rate of bipolar disorder in this outcome study than was found in the one other adult outcome study of prepubertal major depressive disorder.

Psychosocial functioning in a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: To compare psychosocial functioning (PF) in a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) sample to two comparison groups, i.e., attention-deficit/hyperactivity disorder (ADHD) and community controls (CC). METHOD: There were 93 PEA-BP (with or without comorbid ADHD), 81 ADHD, and 94 CC subjects who were participants in an ongoing study, the Phenomenology and Course of Pediatric Bipolar Disorders. Cases in the PEA-BP and ADHD groups were outpatients obtained by consecutive new case ascertainment, and CC subjects were from a survey conducted by the Research Triangle Institute. To fit the study phenotype, PEA-BP subjects needed to have current DSM-IV mania or hypomania with elation and/or grandiosity as one criterion. Assessments for PF were by experienced research nurses who were blind to group status. Mothers and children were separately interviewed with the Psychosocial Schedule for School Age Children-Revised. RESULTS: Compared with both ADHD and CC subjects, PEA-BP cases had significantly greater impairment on items that assessed maternal-child warmth, maternal-child and paternal-child tension, and peer relationships. CONCLUSIONS: Clinicians need to consider PF deficits when planning interventions. In the PEA-BP group, there was a 43% rate of hypersexuality with a <1% rate of sexual abuse, supporting hypersexuality as a manifestation of child mania.

Diagnostic characteristics of 93 cases of a prepubertal and early adolescent bipolar disorder phenotype by gender, puberty and comorbid attention deficit hyperactivity disorder.

OBJECTIVE: Etiopathogenetic and treatment studies require homogeneous phenotypes. Therefore, effects of gender, puberty, and comorbid attention deficit hyperactivity disorder (ADHD) on DSM-IV mania criteria and other characteristics of a prepubertal and early adolescent bipolar disorder (PEA-BP) phenotype were investigated. METHOD: Consecutively ascertained PEA-BP (with or without comorbid ADHD) outpatients (n = 93) were blindly assessed by research nurses with comprehensive instruments given to mothers and children separately, consensus conferences, and offsite blind best estimates of both diagnoses and mania items. To fit the study phenotype, subjects needed to have current DSM-IV mania or hypomania with elated mood and/or grandiosity as one criterion and to be definite cases by severity ratings. RESULTS: Subjects were aged 10.9 +/- 2.6 years, had current episode length of 3.6 +/- 2.5 years, and had early age of onset at 7.3 +/- 3.5 years. No significant differences were found by gender, puberty, or comorbid ADHD on rates of mania criteria (e.g., elation, grandiosity, racing thoughts), mixed mania, psychosis, rapid cycling, suicidality, or comorbid oppositional defiant disorder (ODD), with few exceptions. Subjects with comorbid ADHD were more likely to be younger and male. Pubertal subjects had higher rates of hypersexuality. CONCLUSIONS: These findings support that the PEA-BP phenotype is homogeneous except for differences (hyperactivity, hypersexuality) that mirror normal development.

Six-month stability and outcome of a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: Six-month follow-up data are provided on a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP). Stabilities were defined as continuous presence of PEA-BP and of individual mania criteria between baseline and 6 months. METHOD: Baseline and 6-month assessments of consecutively ascertained PEA-BP outpatients (n = 91) included comprehensive instruments given to mothers and children, separately, by research nurses; consensus conferences; and offsite blind best estimates of both diagnoses and mania items. To fit the study phenotype, subjects needed to have current DSM-IV mania or hypomania with elated mood and/or grandiosity as one mania criterion and to be definite cases by severity ratings. RESULTS: Of the 93 baseline subjects, 91 completed the 6-month assessment, for a retention rate of 97.8%. Baseline age was 10.9 +/- 2.7 years, and age of onset of current episode was 7.3 +/- 3.5 years. At 6 months, 85.7% still had full criteria and severity for mania or hypomania, and only 14.3% had recovered. Six-month stabilities of elated mood and grandiosity were high. Cox modeling and logistic regression did not show any significant effect of multiple covariates (e.g., gender, puberty, psychosis, mixed mania, rapid cycling, or naturalistic treatment). CONCLUSIONS: These longitudinal stability findings provide validation of a PEA-BP phenotype. Poor outcome was consistent with similarity of PEA-BP baseline characteristics to those of treatment-resistant adult-onset mania.